by A.A. OSUNTOKI, Ph.D
CHROMOSOME
** A nucleoprotein complex
**Carries genetic information
**Contains DNA and basic proteins
**The protein kind and types may vary in different cell types
THE GENE
The molecule of heredity
Contained on the chromosome
Every cell of an organism contains the full genetic complement (except mature rbc)
Part of the blue-print for the particular organism
Made up of DNA(deoxyribonucleic acid) in all organisms except some viruses
Sequence of DNA capable of independent expression(replicon) .
DNA
Deoxyribonucleic acid
Polymer of deoxyribonucleotides
Linked by 31-51 phosphodiester bonds
Double stranded helix
Two anti-parallel strands
Stabilized by hydrogen bonds between base pairs -AT, GC.
The bases carry genetic information
RNA
Ribonucleic acid
A close chemical relative of DNA
Present in several forms in living cells
Copied from DNA by a process called transcription
Involved in protein synthesis
THE GENETIC CODEThe information in the genome is organized into genes or cistrons
The message of genes is encoded in a triplet of nucleotides called codons
There are 64 codons
61 specify amino acids
3 specify chain termination
The genetic code is degenerate
GENE EXPRESSION
A gene is to be expressed when the gene product is being made
The gene product can be RNA or protein
Gene expression involves the central dogma
DNA RNA PROTEIN
Replication: The formation of daughter DNA strands .
Transcription: The transfer of genetic information to RNA
Translation : The conversion of the genetic information into a protein(s)
Genes act by determining protein structure.
MUTATION
Any change in the nucleotide sequence
Two broad classifications
Point mutation
Frameshift mutation
Genetic diseases result from mutations.
Saturday, April 5, 2008
MYCOPLASMA
By Dr. Oduyebo
Mycoplasma
Bacteria without cell wall (Mollicutes)
Smallest free living organisms
Some of human origin, some of animal origin
4 important species
SPECIES
M. pneumoniae
M.hominis
U.urealyticum (Ureaplasma urealyticum)
M.genitalium
Characteristics
Very small
Highly pleomorphic
Contains sterol required for growth
Resistant to penicillin
Inhibited by tetracycline or erythromycin
Can reproduce in cell free media
Use glucose as source of energy, ureaplasma requires urea
Growth requirement
Cell free media which contain lipoprotein & sterol
Heart infusion peptone broth with 2% agar, containing 30% human ascitic fluid or animal serum (horse, rabbit)
Epidemiology
Worldwide distribution
Infection rate 50-90%
Pneumonia incidence (3-30%)
Pneumonia in persons 5-20years
Pathogenesis
Transmission by means of infected respiratory secretions
Organism attaches to receptor on surface of epithelial cells
Attachment made possible by a specialised organelle at one end of the organism
Mixture of adhesins and proteins
Incubation period 1-3 weeks
Clinical findings
Asymptomatic infection
Pneumonia generally a mild disease
Atypical pneumonia (walking pneumonia)
Fever, headache, sore throat
Cough dry, blood streaked sputum,
Chest pain, striking consolidation
Illness resolves over 1-4weeks
Complications
Hemolytic anaemia, neurologic involvement, carditis, pancreatitis
LAB FINDINGS
Specimen -respiratory secretions
Culture –not routinely
Serology -complement fixation test, immunofluorescent test, haemaglutination test.
TREATMENT -tetracycline, erythromycin
PREVENTION -preventing contact with cases
Ureaplasma urealyticum
Requires 10%urea for growth
Common in the female genital tract but no disease
Urethritis in men (NGU – nongonococcal urethritis)
Mycoplasma
Bacteria without cell wall (Mollicutes)
Smallest free living organisms
Some of human origin, some of animal origin
4 important species
SPECIES
M. pneumoniae
M.hominis
U.urealyticum (Ureaplasma urealyticum)
M.genitalium
Characteristics
Very small
Highly pleomorphic
Contains sterol required for growth
Resistant to penicillin
Inhibited by tetracycline or erythromycin
Can reproduce in cell free media
Use glucose as source of energy, ureaplasma requires urea
Growth requirement
Cell free media which contain lipoprotein & sterol
Heart infusion peptone broth with 2% agar, containing 30% human ascitic fluid or animal serum (horse, rabbit)
Epidemiology
Worldwide distribution
Infection rate 50-90%
Pneumonia incidence (3-30%)
Pneumonia in persons 5-20years
Pathogenesis
Transmission by means of infected respiratory secretions
Organism attaches to receptor on surface of epithelial cells
Attachment made possible by a specialised organelle at one end of the organism
Mixture of adhesins and proteins
Incubation period 1-3 weeks
Clinical findings
Asymptomatic infection
Pneumonia generally a mild disease
Atypical pneumonia (walking pneumonia)
Fever, headache, sore throat
Cough dry, blood streaked sputum,
Chest pain, striking consolidation
Illness resolves over 1-4weeks
Complications
Hemolytic anaemia, neurologic involvement, carditis, pancreatitis
LAB FINDINGS
Specimen -respiratory secretions
Culture –not routinely
Serology -complement fixation test, immunofluorescent test, haemaglutination test.
TREATMENT -tetracycline, erythromycin
PREVENTION -preventing contact with cases
Ureaplasma urealyticum
Requires 10%urea for growth
Common in the female genital tract but no disease
Urethritis in men (NGU – nongonococcal urethritis)
RED CELL ANTIGEN
These are substances on the red cell membranes that are able to stimulate immuological response.
They are complex glycolipids or glycoproteins. There are about 300 identified red cell antigens but not all are clinically significant in blood transfusion/transplant medicine or for paternity dispute.
CHARACTERISTICS
NATURALLY OCCURING ANTIBODIES
Usually IgM
Optimun temperature of reaction below 30oC but have a wide range of tempt.
Cause red cell agglutination
Complement binding.
Does not cross the placenta.
Sensitive to 2 mercaptoethanol and dithiothreitol
Examples : ABO system, Ii system, P, MNSs and Lewis.
IMMUNE ANTIBODIES
Usually IgG
Optimum tempt. Is 37oC
Cause agglutination that is enhanced by anti IgG.
complement binding.
Crosses the placenta.
Examples; Rhesus system, Duffy system, Kell, Kidd
The following antigens are easily destroyed by enzyme treatment; MNS and Duffy.
ABO SYSTEM
STRUCTURE:
Backbone
NAcGal Gal NAcGlu Lewis a Gal L-Fucose
NAcGal or Gal
Subtypes A1, A2, A3, A4, A5,Ax, Ay.
OTHER GLYCOLIPOPROTEINS
P System P, P1, P2, Pk, p.antibody has high thermal range and may be IgG as in paroxysmal cold haemaglutinin disease.
LEWIS system:Le(a,b).Se.significant in paternity dispute.
MNS system:MN carried on glycophorin A and S on glycophorin B that are required for the invasion on plasmodium falciparum.Anti S may be immune.
Ii system: In chronic cold haemaglutinin disease, anti I in mycoplasma pneumoniae and anti-i in lymphoma
PROTEIN ANTIGEN
MNS
DUFFY:Fy(ab) a receptor for P. vivax and cytokine IL-8.
Kidd system: Jk(ab) gives transient antibodies.
Kell system: K(rare in black), k, Kp, Js, Kx on X chromosome. Lack in McLeod and CGD. K antigen is very antigenic.
Rh system.nomenclature, variants, absence-stomatocytosis, antigenicity
They are complex glycolipids or glycoproteins. There are about 300 identified red cell antigens but not all are clinically significant in blood transfusion/transplant medicine or for paternity dispute.
CHARACTERISTICS
NATURALLY OCCURING ANTIBODIES
Usually IgM
Optimun temperature of reaction below 30oC but have a wide range of tempt.
Cause red cell agglutination
Complement binding.
Does not cross the placenta.
Sensitive to 2 mercaptoethanol and dithiothreitol
Examples : ABO system, Ii system, P, MNSs and Lewis.
IMMUNE ANTIBODIES
Usually IgG
Optimum tempt. Is 37oC
Cause agglutination that is enhanced by anti IgG.
complement binding.
Crosses the placenta.
Examples; Rhesus system, Duffy system, Kell, Kidd
The following antigens are easily destroyed by enzyme treatment; MNS and Duffy.
ABO SYSTEM
STRUCTURE:
Backbone
NAcGal Gal NAcGlu Lewis a Gal L-Fucose
NAcGal or Gal
Subtypes A1, A2, A3, A4, A5,Ax, Ay.
OTHER GLYCOLIPOPROTEINS
P System P, P1, P2, Pk, p.antibody has high thermal range and may be IgG as in paroxysmal cold haemaglutinin disease.
LEWIS system:Le(a,b).Se.significant in paternity dispute.
MNS system:MN carried on glycophorin A and S on glycophorin B that are required for the invasion on plasmodium falciparum.Anti S may be immune.
Ii system: In chronic cold haemaglutinin disease, anti I in mycoplasma pneumoniae and anti-i in lymphoma
PROTEIN ANTIGEN
MNS
DUFFY:Fy(ab) a receptor for P. vivax and cytokine IL-8.
Kidd system: Jk(ab) gives transient antibodies.
Kell system: K(rare in black), k, Kp, Js, Kx on X chromosome. Lack in McLeod and CGD. K antigen is very antigenic.
Rh system.nomenclature, variants, absence-stomatocytosis, antigenicity
THE HUMAN CELL
INTRODUCTION
The cell is the fundamental unit of life
The cell elemental composition shows that the cell is 90% water. Of the remaining molecules present the dry weight is approx. 50% protein,15% CHO,15% nucleic acid,10% lipid,10% miscellaneous.
Total approx composition by element: 60%H,25%O,12%C,5%N.
BASIC STRUCTURE
The Nucleus
The nucleus is separated from the cytoplasm by an envelope consisting of two membranes with the intermembranous space between. The membranes are phospholipid bilayer structure with nuclear pore complexes. Molecules are imported and exported through the pore complexes.
The chromosomal DNA is held in nucleus in a specific fashion
The DNA is packed into chromatin fibres by it’s association with an equal mass of histone
The nucleus also contains a wide variety of other non histone proteins employed in replication and repair of DNA and it’s transcription into messenger RNA
The DNA is a double helix composed of four deoxyribonucleotides (base + sugar+phosphate) polymerised in an unbranched manner.
The nucleus is separated from the cytoplasm by an envelope consisting of two membranes with the intermembranous space between. The membranes are phospholipid bilayer structure with nuclear pore complexes. Molecules are imported and exported through the pore complexes.
The chromosomal DNA is held in nucleus in a specific fashion
The DNA is packed into chromatin fibres by it’s association with an equal mass of histone
The nucleus also contains a wide variety of other non histone proteins employed in replication and repair of DNA and it’s transcription into messenger RNA
The DNA is a double helix composed of four deoxyribonucleotides (base + sugar+phosphate) polymerised in an unbranched manner.
A gene is a sequence of deoxyribonucleotides controlling hereditary information to be transcribed into RNA and translated for the synthesis of protein.
The human genome (the totality of all genes) is commonly assumed to contain 100,000 genes.
The nuclear contents communicate with the cytosol by means of openings in the nuclear envelope called nuclear pores.
The nucleolus is a factory in nucleus where the cell’s ribosomes are assembled. When ever cells are actively producing proteins, a prominent nucleolus is apparent. In rapidly growing cancer cells, large prominent nucleoli are a discriminating feature
The CytoplasmEndoplasmic Reticulum
Diffusely distributed throughout the cytoplasm
They are flattened sheets, sacs and tubes of membrane
The ER membrane is in structural continuity with the outer membrane of the nuclear envelope.
It specialises in the synthesis and transport of lipids and membrane proteins.
The RER occurs as flattened sheets and is studded on it’s outer surface with ribosomes engaged in protein synthesis.
The SER is generally more tubular and lacks attached ribosomes. It functions in metabolisms of lipids, steroid hormones, cholesterol and other related compounds.
The ribosomes occur as free poly ribosomes or attached to RER. They bind with MRNA and translate genetic code using aa provided by TRNA to produce unique aa sequence of protein.
The Golgi Apparatus
Named after the Italian histopathologist Camilo Golgi
Usually located in the vicinity of the nucleus
A system of stacked membrane bounded sacs involved in modifying, sorting and packaging macromolecules (proteins, CHO, lipids) for secretion or for delivery to other organelles.
Numerous small vessicles around the golgi apparatus are thought to carry material between the golgi apparatus and different compartments of the cell e.g. to lysosomes, secretory vessicles, or insertion into the plasma membranes.
The Mitochondria
Mitochondria are the power plant of all eucaryotic cells.
They produce energy by burning (oxidizing or converting) CHOS and fatty acids to CO2 and water. The product is large quantity of energy rich adenosine triphosphate, (ATP). ATP is used in synthesis, chemical reactions, active transport through membranes, muscle contractions and movement of cells during division etc.
Mitochondria are rods enveloped by two unit membranes. The inner leaflet is folded to form the cristae. This is usually shelf-like, therefore increasing the inner membranes surface.
They vary in size and move freely within the cytosol aggregating in sites with high energy demand.
The Lysosomes
These are membrane bounded vessicles that contain hydrolytic enzymes involved in intracellular digestion.
The lysosomal enzymes comprise more than 40 different acid hydrolases which are optimally active at pH of about 5.0. This may be a protective mechanism for the cell, should the lysosomal enzymes escape into the cytosol with a higher pH.
There are primary and secondary lysosomes.
Secondary lysosomes are formed by fusion of primary lysosome with another type of vacoule.
Absence or deficiency of lysosomal enzymes leads to large accumulations of incompletely degraded products e.g. the storage diseases, Hunter Hurler syndrome, an x- linked recessive disorder with accumulation mucopolysaccharides
Peroxisomes
Are membrane bounded vesicles containing oxidative enzymes that generate and destroy hydrogen peroxide.
The enzymes form a detoxification system which converts toxic compounds into H2O2 and then into water.
The Cytoskeleton
These are arrays of protein filaments within the cytosol that give the cell it’s shape and provide a basis for it’s movements.
These filaments are also responsible in intracellular guidance of transport, transporting material across the cell surface, sorting and partitioning of replicated chromosomes by the mitotic spindle.
Three main kinds of cytoskeletal filaments are microtubules, actin filaments and intermediate filaments. The centriole, paired cylinders serve as templates for formation of cilia and flagella.
The Plasma Membrane
It is the outer boundary of the cell.
PM is arranged as bimolecular layer of phospholipids with hydrophilic heads oriented towards extracellular and intracellular compartments.
Hydrophobic tails are directed towards the PM center.
It is a continous sheet in which various proteins are embedded.
The Cell CycleCell Division
The time interval between mitotic divisions, the life cycle of an individual cell is called the cell cycle. Alternatively it’s a sequence of biochemical or morphological events in the life of a cell which can be mapped on a time scale.
The cells of the body are divided into three groups of cells on the basis of their proliferative capacity vis the continously dividing cells (labile cells), quiescent (stable) cells and non dividing (permanent) cells.
The phases of cell cycle include the short mitotic phase (M phase) and the non dividing phase (interphase) which usually occupies most of the life cycle of the cell.
Within the interphase are the G1phase, the S phase, and the G2 phase.
G1 phase is the interval between the M phase and the beginning of S phase.
S phase is when nuclear DNA is replicated
G2 phase is the interval between the end of S phase and the beginning of M phase
Cells progress through the cell cycle at different rates
Most of the variability is observed in G1 or to a lesser extent in G2
Other cells may leave G1 phase, cease progression and enter a quiescent phase referred to as G0.
Cell Division
The nuclei of all cells of an individual contain the same set complement of DNA, a quantity called the genome. This is present in a fixed number of chromosomes, this number being specific to each specie.
The DNA is a large molecular wt polymer consisting of deoxyribonucleotides with a double stranded structure. Each deoxyribose unit is bound to a purine or pyrimidine base which in turn is linked to a complimentary base on the other strand. Thus linking the strands together.
The bases are four with adenine only linking to thymine and cytosine only linking to guanine.
The sequence of bases in either strand of the DNA forms the genetic code for the individual .The bases are read in groups of three called codons, each coding for one aa.
In human cell there are 43 chromosomes comprising 23 homologue pairs.
Somatic cell division occurs in two phases
Firstly the chromosomes duplicate in S phase and are distributed equally between two potential daughter cells. This process is known as mitosis. The dividing cell is cleaved into genetically identical daughter cells by cytoplasmic division or cytokinesis.
Abnormalities in mitosis and cytokinesis may result in formation of two daughter cells with unequal amounts of cytoplasm and formation of binucleate and multinucleate cells respectively.
Mitosis is divided into phases: prophase, prometaphase, metaphase, anaphase and telophase.
Cell division requires the presence of the mitotic apparatus, which comprises a spindle of longitudinally arranged microtubules extending between a pair of centrioles at each pole of the dividing cell
The Prophase: the chromosomes are condensed and clearly visible in the cell nucleus. Each chromosome has duplicated during the preceding S phase and consists of two sister chromatids. The mitotic spindle begins to form outside the nucleus. This is a bipolar structure composed of microtubules and associated proteins.
Prometaphase: starts with disintegration of nuclear envelope and the mitotic spindle moves into the nuclear area . The pair of centrioles in the centrosome has duplicated and migrate towards to the opposite poles of the cell with a spindle of microtubule forming between them. Each duplicated chromosome becomes attached at the kinetochore to the microtubules
Metaphase: the chromosomes have lined up in one place half way between the spindle poles( the metaphase plate)
Anaphase: the chromosomes have separated into their two sister chromatids which are moving to opposite poles.
Telophase: the chromosomes are decondensing to regain their interphase conformation. The nuclear envelope reassembles and the nucleoli again become apparent.
Cytokinesis
The cytoplasm divides by a process known as cleavage
The plane of cytoplasmic division is defined by position of spindle equator, thus producing two cells of equal size.
RICKETTSIA
By Dr. Oduyebo
Rickettsiae
Obligate intracellular parasites
Small size
Arthropod borne
Transovarial transmission
Invade endothelial cells
Cause fever, rashes, vasculitis, eschar
Properties
Pleomorphic
Appear blue with Giemsa stain
DNA & RNA
Infect a wide range of animals
Grow in yolk sac of embryonated egg
Grow in cell culture, different parts
Cytoplasm -typhus group
Nucleus -spotted fever group
Cytoplasmic vacuole -C. burnetti
Resistant to sulphonamides
Sensitive to tetracycline, chloramphenicol
Quickly destroyed by heat
Quickly destroyed by drying except
C.burnetti, which forms spore-like structures
When in dried faeces of lice
Diagnosis
Clinical findings
fever, weakness, rashes, spleen & liver enlargement
Epidemiologic information
Serology agglutination, EIA, CFT, IF
Control
Vector control
Eliminate reservoirs
Pasteurization of milk
Protective clothing
Rickettsiae
Obligate intracellular parasites
Small size
Arthropod borne
Transovarial transmission
Invade endothelial cells
Cause fever, rashes, vasculitis, eschar
Properties
Pleomorphic
Appear blue with Giemsa stain
DNA & RNA
Infect a wide range of animals
Grow in yolk sac of embryonated egg
Grow in cell culture, different parts
Cytoplasm -typhus group
Nucleus -spotted fever group
Cytoplasmic vacuole -C. burnetti
Resistant to sulphonamides
Sensitive to tetracycline, chloramphenicol
Quickly destroyed by heat
Quickly destroyed by drying except
C.burnetti, which forms spore-like structures
When in dried faeces of lice
Diagnosis
Clinical findings
fever, weakness, rashes, spleen & liver enlargement
Epidemiologic information
Serology agglutination, EIA, CFT, IF
Control
Vector control
Eliminate reservoirs
Pasteurization of milk
Protective clothing
The Spleen and other lymphoid tissues
by
Olukemi A Esan (FMCPath)
Olukemi A Esan (FMCPath)
Types of lymphoid tissues
The primary lymphoid tissues are the Bone marrow and Thymus
Secondary lymphoid tissues include the spleen, lymph nodes and peripheral lymphoid nodules.
The Spleen
Located in the left hypochondrial region
Beneath the 9th-llth ribs.
It weighs between 150-250g in a normal adult but may enlarge in a variety of conditions.
Blood flow to the spleen
Via the splenic artery through it’s branches-trabecular arteries and central arteries which are situated in the white pulp.
These central arteries run in the central axis of the periarteriolar lymphatic sheath derived from the splenic capsule.
The central arteries give off many arterioles and capillaries some of which terminate in the white pulp while others go on to enter the red pulp.
During blood flow in the spleen, plasma skimming occurs
Most of the plasma and leucocytes go to the white pulp
Haemoconcentrated blood goes to the red pulp.
In the red pulp are 2 circulatory systems
A ‘closed’ system where the blood goes from the arteries via the sinuses back into the veins
An ‘open’system where the blood is emptied from the arterioles into the splenic bilroth cords. Here the blood cells pass through a meshwork of reticulum fibres and reticuloendothelial system cells to reach the splenic sinuses by passing through gaps in the endothelial cells lining the sinuses.
The red cells are normally flexible enough to squeeze through the endothelial slits into the sinuses.
Cells with abnormal membranes or inclusions which render them relatively inflexible remain in the cords where they either become conditioned for later transit or are destroyed.
Circulation in the spleen
Lymphatic system
The spleen has no afferent lymphatics
Efferent lymphatic vessels form around the arteries and make their exit in the hilum.
Functions of the spleen
Functions of the spleen include:
Immunologic function
Phagocytosis
Sequestration
Blood pooling
Extramedullary haemopoeisis
Blood vol regulation
Immunologic function
Largest accumilation of lymphoid cells in the body.
25% of the T lymphocytes
15% of the B lymphocytes pool are present here.
T cells are found mainly in the periarteriolar sheaths
B cells are found in the germinal centers of the white pulp.
Destruction of antibody coated rbcs
Phagocytosis & Sequestration
Phagocytosis: This is the uptake of none viable cells and foreign matter by the macrophages.
Sequestration: A reversible process whereby cells are held up temporarily before returning into circulation eg reticulocytes
Blood Pooling
The presence of an increased amount of blood in the spleen which is in continuous exchange with the circulation
eg increased platelet pool in splenomegaly.
Extramedullary Haemopoeisis
Haemopoietic stem cells and progenitor cells are present in the spleen.
They may resume their fetal role as a compensatory erythroblastic hyperplasia eg in chronic haemolytic anaemias and myelofibrosis.
Blood volume regulation
Splenomegaly is associated with an increase in plasma volume which results in a dilutional anaemia.
An increase in the red cell pool in the enlarged spleen may also cause a true anaemia in the peripheral circulation.
Causes of splenomegaly
Haematological
Leukaemias
Lymphomas
Myelofibrosis
Haemolytic anaemias
Others
Acute/chronic infections
Parasitic infections
Collagen dxs
Glycogen storage dxs/lipidosis
Sarcoidosis
Amyloidosis
Portal hypertension
Cysts
Cells with abnormal membranes or inclusions which render them relatively inflexible remain in the cords where they either become conditioned for later transit or are destroyed.
Circulation in the spleen
Lymphatic system
The spleen has no afferent lymphatics
Efferent lymphatic vessels form around the arteries and make their exit in the hilum.
Functions of the spleen
Functions of the spleen include:
Immunologic function
Phagocytosis
Sequestration
Blood pooling
Extramedullary haemopoeisis
Blood vol regulation
Immunologic function
Largest accumilation of lymphoid cells in the body.
25% of the T lymphocytes
15% of the B lymphocytes pool are present here.
T cells are found mainly in the periarteriolar sheaths
B cells are found in the germinal centers of the white pulp.
Destruction of antibody coated rbcs
Phagocytosis & Sequestration
Phagocytosis: This is the uptake of none viable cells and foreign matter by the macrophages.
Sequestration: A reversible process whereby cells are held up temporarily before returning into circulation eg reticulocytes
Blood Pooling
The presence of an increased amount of blood in the spleen which is in continuous exchange with the circulation
eg increased platelet pool in splenomegaly.
Extramedullary Haemopoeisis
Haemopoietic stem cells and progenitor cells are present in the spleen.
They may resume their fetal role as a compensatory erythroblastic hyperplasia eg in chronic haemolytic anaemias and myelofibrosis.
Blood volume regulation
Splenomegaly is associated with an increase in plasma volume which results in a dilutional anaemia.
An increase in the red cell pool in the enlarged spleen may also cause a true anaemia in the peripheral circulation.
Causes of splenomegaly
Haematological
Leukaemias
Lymphomas
Myelofibrosis
Haemolytic anaemias
Others
Acute/chronic infections
Parasitic infections
Collagen dxs
Glycogen storage dxs/lipidosis
Sarcoidosis
Amyloidosis
Portal hypertension
Cysts
Splenectomy
Indications: Rupture, removal of cysts, massive splenomegaly due to Gauchers, Congenital haemolytic states, hypersplenism.
Defer until age 5-6 years if possible
Immunisation against pneumococci, H. influenza and meningococci because of increased risk of overwhelming sepsis and meningitis.
Hypersplenism
Splenomegaly
In one or more cell lines in blood
Normal/hyperplastic BM
Reticulocytosis/large platelets
Increase splenic rbc/plat pool
Confirmed by response to splenectomy
LYMPH NODES
They are encapsulated dense collections of lymphocytes, macrophages, dendritic cells organized along the course of lymphatic vessels.
The marginal sinus is lined by phagocytes.
The cortex contains numerous follicles which are mainly aggregates of B cells.
In the paracortex are the T cells.
The medulla is the site of entry of arteries and veins and contains a mixture of B & T lymphocytes, plasma cells and macrophages.
THYMUS
It developes at about the 8th week of gestation from the 3rd and 4th brachial pouches.
It is located beneath the sternum in the superior mediastinum
Made up of an outer cortex and inner medulla.
Prothymocytes originate in the marrow and migrate to the thymus where they mature into T cells.
Maturation of T cells is accompanied by the sequential acquisition by the thymocytes of the various T cell markers.
A pre T cell is Tdt pos
Gains CD2 , CD4 & 8 in the cortex; gains CD3,rearranges the T cell receptor gene
Losses either CD4 or 8 in the medulla.
A mature T cell is CD 2,3,4/8,Tcr gene rearranged and Tdt negative
The cortex contains numerous follicles which are mainly aggregates of B cells.
In the paracortex are the T cells.
The medulla is the site of entry of arteries and veins and contains a mixture of B & T lymphocytes, plasma cells and macrophages.
THYMUS
It developes at about the 8th week of gestation from the 3rd and 4th brachial pouches.
It is located beneath the sternum in the superior mediastinum
Made up of an outer cortex and inner medulla.
Prothymocytes originate in the marrow and migrate to the thymus where they mature into T cells.
Maturation of T cells is accompanied by the sequential acquisition by the thymocytes of the various T cell markers.
A pre T cell is Tdt pos
Gains CD2 , CD4 & 8 in the cortex; gains CD3,rearranges the T cell receptor gene
Losses either CD4 or 8 in the medulla.
A mature T cell is CD 2,3,4/8,Tcr gene rearranged and Tdt negative
PERIPHERAL LYMPHOID TISSUES
Solitary lymph nodules : no capsule or afferent/efferent lymphatics
mucosa & submucosa of respiratory tract, GIT, Urinary tract and vagina.
The respiratory and GIT mucosal tissues are rich in plasma cells secreting IgA. These nodules store the precursors of the IgA producing cells.
Solitary lymph nodules : no capsule or afferent/efferent lymphatics
mucosa & submucosa of respiratory tract, GIT, Urinary tract and vagina.
The respiratory and GIT mucosal tissues are rich in plasma cells secreting IgA. These nodules store the precursors of the IgA producing cells.
Water And Electrolyte Homeostasis
written by
Dr J Onubi, MBBS , Msc , FMCPath.
Consultant chemical pathologist
Department of Pathology
Naval Hospital OJO
Lagos.
Introduction
Water and electrolyte homeostasis is one of the important components of chemical biochemistry.
Any derrangement in either of them could lead to life threatening situations that may require urgent attention .
Four major electrolyte . Na+. K+, cl- and Hco3- concentrations maintains water homoestasis.
Water Homeostasis
Homeostatic processes ensure that
Total water balance is maintained within narrow limits.
The distribution of water between the various body compartments is maintained.
Water Distribution
TBW = 42l in a 70kg man- this is about 60% total body weight < in women.
ICW = 24 L >1/2 TBW
ECW =18 L,=13L intestinal =5L intravascular
Each compartment of B W remains at constant volume .This implies that the rate of water loss must equal the rate of gains
Daily water gain = 1.5-2.5L
Daily water loss = 1.5-2.5L
The gains is through drinks and food while the loss is through ,urine , faeces, sweat and expired air.
= 200L of Water is filtered by the kidney each day.
= 10L of water enter the interstitial lumen.
In this case the whole of the ECW could be lost by passive filtration in little more than an hour, but ,under normal circumstances about 90% is reabsorbed . Consequently, the daily loss amounts to about 1.5 to 2.5 L in urine and 100ml in faeces.
=900 ml of water is loss through sweat daily . This volume is primarily controlled by skin temperature.
Respiratory water loss depends on the respiratory rate and bears no relation to the body ‘s needs for water.
Regulatory Meachanism
Normal plasma osmolality 275-295 M os/kg.
The regulatory meachanism is the osmolality of the body water which changes with either water over load or water deficit . The principal organs involved are the hypothalamus and the kidneyS.
Osmolality – Concentration of particles per Kg of water (w/w ) Mmol/ kg.
Osmolarity – Concentration of particles per volume of solution (w/V) Mmol/ L.
osmolarlity is more exact because solution concentrations expressed on a weight bases are temperature independent , where as those based on volume vary with temperature.
An increase in osmolarlity resulting from water loss, leads to:
- stimulation of thirst – increase water intake
Secretion of ADH - Increase reabsorption.
ADH – synthesized in the hypothalamus as fluids intake continues there is dilution of NA+ - decrese in ADH concentration.
If there is no counter meachanism to balance up, the cells will take the pure water leading to spatially cerebral oedema- tonsillar hermiation -
Increase in intracranial pressure ,fits and death.
However – when the osmolarlity drops the thirst center response shuts up and ADH also stops.
The kidney opens up and allows water loss.
ELECTROLYTES
They are ions capable of carrying an electric charge.
All electrolytes are dissolved in BW but distributed differently in the various compartments along concentration gradients.
Their functions include:
Volume and osmotic regulation.
Myocardial rhythm and contractility.
Cofactors in enzyme activation.
Acid – base balance.
Blood coagulation.
Four major ones, Na+, K+, Cl- and Hco-3 will be considered
Na+
Major cation of ECF.
Central role in maintaining the normal distribution of water and the osmotic pressure.
Regulation.
Amount of Na+ in the body is relatively constant.
= 3g/dly intake. Same quantity is excreted.
The kidneys have the ability to conserve or excrete large amounts of Na+, depending on the Na+ content of the ECF and the blood volume.
Approximately 80% of filtered Na+ is reabsorbed at PCT.
Small amount at Loop with water.
Remainder at the CD under influence of Aldosterone hormone secreted by adrenal cortex.
Disturbances
Lead to either Hypernatraemia or Hyponatraemia.
Hypernatraemia.
Causes - Cushing's syndrome (hyperadrenalism).
Dehydration.
Na+ intake/infusion of hypertonic Na+ solution.
DKA treated with insulin.
Hypothalamic insufficiency-loss of thirst mechanism.
Diabetes Insipidus.
Treatment
Slow infusion of hypotonic fluid.
Hyponatraemia.
Causes
GI loss – diarrhea, vomiting, fistulae.
DKA before coma stage. Large amount, of Na+ and K+ are excreted into the urine as salts of the ketoacids with replacement of water because of thirst.
Salt – losing nephritis.
Addison’s disease with depressed secretion of aldosterone and corticosteroids.
Diabetes Insipidus with compensatory intake of water.
K+
Is the major intracellular cation.
Regulation
Once tissue needs are met the remainder is excreted by the kidney.
Nearly all filtered K+ are reabsorbed at the PCT
Aldosterone aids secretion at the DT& CD in exchange for Na+.
Hyperkalaemia
Causes.
Anoxia
Metabolic acidosis
Renal tubular acidosis
Renal failure
Low urine output
Addison’s disease
artifacts
Hypokalaemia
Causes
Vomiting, diarrhea fistulae
Diuretics
Nephritis
Cushings’s syndrome
Alkalosis
Insulin overdose
Treatment
Oral or intravenous replacement of K+.
Food with high K+ content – dried fruits, bananas & orange juice.
Chloride Cl-
Major extracellular anion
Precise function in the body is not well understood; however, it is involved in maintaining osmolality, blood volume and electric neutrality.
Regulation
Filtered Cl- is reabsorbed passively with Na+ at PCT.
Excess is excreted in urine & sweat.
Na+ reabsorption is limited by the amount of Cl- available
Disorders of Cl-
Similar to Na+
Hyperchloraemia
Causes
Dehydration
ARF
Metabolic acidosis
Respiratory alkalosis
Hypochloraemia
Causes
Salt- losing nephrites
Addison’s disease
Bromide intoxication
SIADH
Renal failure
Prolonged vomiting
Bicarbonate HCO3 _
Second most abundant anion in the ECF
It is the major component of the buffering system in the blood.
It is produced following the dissociation of carbonic acid formed from CO2 and H2O
CD
CO2 + H2O H2CO3- H+ + HCO3-
CD – Carbonate dehydratase present in high concentrations in erythrocytes and renal tubular cells.
They remove H+ quickly from the plasma at the same time adding more HCO-3.
H2O is freely available
HCO3- generation is therefore accelerated if the concentration of:
CO2 raises
HCO3- falls.
H+ falls because it is either buffered by erythrocytes or excreted from the body by renal tubular cells.
An increase of intracellular PCO2, or a decrease in intracellular [ HCO3-] in the erythrocytes and renal tubular cells maintain the extracellular [HCO3-] by accelerating the production of HCO3-. thereby minimizes changes in the ratio of [HCO3-] to [CO2] = 20 : 1 and the PH. This can be calculated from Henderson- Hasselbalch equation:
PH = PK + Log [HCO3 -]
S * PCO2
S = solubility constant for CO2. If PCO2 is in mmHg , S = 0.03
PK of HCO3- system = 6.1
PH = 6.1 + Log [HCO3]
PCO2 * 0.03
Disturbances
Acidosis
Alkalosis
Acidosis occurs if there is a fall in the ratio of [HCO3-]: PCO2 in the
ECF. This is either metabolic, in which the primary abnormality in the bicarbonate buffer system is a reduction in [HCO3-]; or respiratory in which there is increase in PCO2. Compensatory change is vice versa.
Dr J Onubi, MBBS , Msc , FMCPath.
Consultant chemical pathologist
Department of Pathology
Naval Hospital OJO
Lagos.
Introduction
Water and electrolyte homeostasis is one of the important components of chemical biochemistry.
Any derrangement in either of them could lead to life threatening situations that may require urgent attention .
Four major electrolyte . Na+. K+, cl- and Hco3- concentrations maintains water homoestasis.
Water Homeostasis
Homeostatic processes ensure that
Total water balance is maintained within narrow limits.
The distribution of water between the various body compartments is maintained.
Water Distribution
TBW = 42l in a 70kg man- this is about 60% total body weight < in women.
ICW = 24 L >1/2 TBW
ECW =18 L,=13L intestinal =5L intravascular
Each compartment of B W remains at constant volume .This implies that the rate of water loss must equal the rate of gains
Daily water gain = 1.5-2.5L
Daily water loss = 1.5-2.5L
The gains is through drinks and food while the loss is through ,urine , faeces, sweat and expired air.
= 200L of Water is filtered by the kidney each day.
= 10L of water enter the interstitial lumen.
In this case the whole of the ECW could be lost by passive filtration in little more than an hour, but ,under normal circumstances about 90% is reabsorbed . Consequently, the daily loss amounts to about 1.5 to 2.5 L in urine and 100ml in faeces.
=900 ml of water is loss through sweat daily . This volume is primarily controlled by skin temperature.
Respiratory water loss depends on the respiratory rate and bears no relation to the body ‘s needs for water.
Regulatory Meachanism
Normal plasma osmolality 275-295 M os/kg.
The regulatory meachanism is the osmolality of the body water which changes with either water over load or water deficit . The principal organs involved are the hypothalamus and the kidneyS.
Osmolality – Concentration of particles per Kg of water (w/w ) Mmol/ kg.
Osmolarity – Concentration of particles per volume of solution (w/V) Mmol/ L.
osmolarlity is more exact because solution concentrations expressed on a weight bases are temperature independent , where as those based on volume vary with temperature.
An increase in osmolarlity resulting from water loss, leads to:
- stimulation of thirst – increase water intake
Secretion of ADH - Increase reabsorption.
ADH – synthesized in the hypothalamus as fluids intake continues there is dilution of NA+ - decrese in ADH concentration.
If there is no counter meachanism to balance up, the cells will take the pure water leading to spatially cerebral oedema- tonsillar hermiation -
Increase in intracranial pressure ,fits and death.
However – when the osmolarlity drops the thirst center response shuts up and ADH also stops.
The kidney opens up and allows water loss.
ELECTROLYTES
They are ions capable of carrying an electric charge.
All electrolytes are dissolved in BW but distributed differently in the various compartments along concentration gradients.
Their functions include:
Volume and osmotic regulation.
Myocardial rhythm and contractility.
Cofactors in enzyme activation.
Acid – base balance.
Blood coagulation.
Four major ones, Na+, K+, Cl- and Hco-3 will be considered
Na+
Major cation of ECF.
Central role in maintaining the normal distribution of water and the osmotic pressure.
Regulation.
Amount of Na+ in the body is relatively constant.
= 3g/dly intake. Same quantity is excreted.
The kidneys have the ability to conserve or excrete large amounts of Na+, depending on the Na+ content of the ECF and the blood volume.
Approximately 80% of filtered Na+ is reabsorbed at PCT.
Small amount at Loop with water.
Remainder at the CD under influence of Aldosterone hormone secreted by adrenal cortex.
Disturbances
Lead to either Hypernatraemia or Hyponatraemia.
Hypernatraemia.
Causes - Cushing's syndrome (hyperadrenalism).
Dehydration.
Na+ intake/infusion of hypertonic Na+ solution.
DKA treated with insulin.
Hypothalamic insufficiency-loss of thirst mechanism.
Diabetes Insipidus.
Treatment
Slow infusion of hypotonic fluid.
Hyponatraemia.
Causes
GI loss – diarrhea, vomiting, fistulae.
DKA before coma stage. Large amount, of Na+ and K+ are excreted into the urine as salts of the ketoacids with replacement of water because of thirst.
Salt – losing nephritis.
Addison’s disease with depressed secretion of aldosterone and corticosteroids.
Diabetes Insipidus with compensatory intake of water.
K+
Is the major intracellular cation.
Regulation
Once tissue needs are met the remainder is excreted by the kidney.
Nearly all filtered K+ are reabsorbed at the PCT
Aldosterone aids secretion at the DT& CD in exchange for Na+.
Hyperkalaemia
Causes.
Anoxia
Metabolic acidosis
Renal tubular acidosis
Renal failure
Low urine output
Addison’s disease
artifacts
Hypokalaemia
Causes
Vomiting, diarrhea fistulae
Diuretics
Nephritis
Cushings’s syndrome
Alkalosis
Insulin overdose
Treatment
Oral or intravenous replacement of K+.
Food with high K+ content – dried fruits, bananas & orange juice.
Chloride Cl-
Major extracellular anion
Precise function in the body is not well understood; however, it is involved in maintaining osmolality, blood volume and electric neutrality.
Regulation
Filtered Cl- is reabsorbed passively with Na+ at PCT.
Excess is excreted in urine & sweat.
Na+ reabsorption is limited by the amount of Cl- available
Disorders of Cl-
Similar to Na+
Hyperchloraemia
Causes
Dehydration
ARF
Metabolic acidosis
Respiratory alkalosis
Hypochloraemia
Causes
Salt- losing nephrites
Addison’s disease
Bromide intoxication
SIADH
Renal failure
Prolonged vomiting
Bicarbonate HCO3 _
Second most abundant anion in the ECF
It is the major component of the buffering system in the blood.
It is produced following the dissociation of carbonic acid formed from CO2 and H2O
CD
CO2 + H2O H2CO3- H+ + HCO3-
CD – Carbonate dehydratase present in high concentrations in erythrocytes and renal tubular cells.
They remove H+ quickly from the plasma at the same time adding more HCO-3.
H2O is freely available
HCO3- generation is therefore accelerated if the concentration of:
CO2 raises
HCO3- falls.
H+ falls because it is either buffered by erythrocytes or excreted from the body by renal tubular cells.
An increase of intracellular PCO2, or a decrease in intracellular [ HCO3-] in the erythrocytes and renal tubular cells maintain the extracellular [HCO3-] by accelerating the production of HCO3-. thereby minimizes changes in the ratio of [HCO3-] to [CO2] = 20 : 1 and the PH. This can be calculated from Henderson- Hasselbalch equation:
PH = PK + Log [HCO3 -]
S * PCO2
S = solubility constant for CO2. If PCO2 is in mmHg , S = 0.03
PK of HCO3- system = 6.1
PH = 6.1 + Log [HCO3]
PCO2 * 0.03
Disturbances
Acidosis
Alkalosis
Acidosis occurs if there is a fall in the ratio of [HCO3-]: PCO2 in the
ECF. This is either metabolic, in which the primary abnormality in the bicarbonate buffer system is a reduction in [HCO3-]; or respiratory in which there is increase in PCO2. Compensatory change is vice versa.
PATHOGENESIS & PHYSIOLOGY OF ACUTE INFLAMMATION
Inflammation is the reaction of the vascular and supporting elements to injury, and results in the formation of protein rich exudates, provided there has not been so severe as to destroy the area.
CARDINAL SIGNS OF INFLAMMATION:
1.Calor (heat)
2.Rubor (redness)
3.Dolor (pain)
4Tumor (swelling)
5.Functio laesa (loss of function).
CAUSES OF ACUTE INFLAMMATION INCLUDE:
1.Mechanical trauma
2.Chemical injuries
3.Radiation injuries
4. Injuries due to cold and heat
5.Injuries associated with necrosis
6.Injuries due to living organism
7Injuries due to an immunological mechanism.
DEFINITION OF TERMS:
(1) EXUDATION: The escape of fluid, proteins, and blood cells from the vascular system into the interstial tissue or body cavities.
(2) EXUDATE: An inflammatory extra vascular fluid that has a high protein concentration, much cellular debris, and a specific gravity above 1.020.
(3) TRANSUDATE: A fluid with low protein content and a specific gravity of less than 1.012. It is essentially an ultra filtrate of blood plasma resulting from hydrostatic imbalance between the arteriolar and the venular end.
(4) OEDEMA: Denotes an excess of fluid in the interstial tissue or the serous cavities. It can be an exudates or a transudate
A purulent inflammatory exudates rich in leucocytes and parenchymal cell debris
CHANGES IN ACUTE INFLAMMATION:
These changes are
1. Changes in the blood vessel walls
2. Blood flow within the vessels
3. Exudation –both fluid and cellular.
1. Changes in the blood vessel wall
The earliest response to acute injury is constriction in the small blood vessels. microvascularture Terminal-> capillaries-> post-capillary venules->venous system. It can be demonstrated in the human skin; light stroking produces a white line. This vasoconstriction is apparently due to direct mechanical stimulation of the capillaries.
Vasodilatation rapidly follows the initial constriction and persists for the duration of the inflammatory process. The first result of arteriolar dilatation is that blood flows by the most direct route to the veins through the central, or thoroughfare channels. Subsequent opening of the precapillary spincters allows blood to pass into the capillary bed, and vessels, which were temporarily shuntdown now become functional again. The inflamed part therefore appears to contain an increased number of vessels (hyperemia). In addition, their caliber is increased. The response is seen only with mild injury.
The basic mechanisms involved in vascular event are triple response and it is dependent on histamine liberated from damaged cells following injury.
The features of this triple response are (1) redline (2) flare (3) weal
1.REDLINE: After a short latent period a redline develops, at first bright red, later cyanosed. It is sharply demarcated and due capillary dilatation.
2.FLARE: After a further 15-30 seconds, a flare appears surrounding the redline. It is blotchy, has a cremated outline and it is due to arteriolar dilatation.
3.WEAL: Due to exudation of fluid through vascular wall causing increase edema and paleness of the affected part.
When the injury becomes a bit more severe, the velocity of blood flow is affected. With a moderate injury, the velocity of blood flow diminishes followed by the effect of slowing down of blood to create logging of the blood. .
This causes an increase in hydrostatic pressure. An increase hydrostatic pressure will force fluid from the intravascular to extra vascular space (leaking of fluid). This fluid contains very small protein and lacks cells hence it is called a transudate.
This makes the blood more concentrated -Haemoconcentration.
The viscosity of the blood is increased; this is very dangerous as it may cause stasis of blood. At this stage there is going to be injury to the endothelial cells. First, as a result of roughening by the blood and secondly, as a result of hypoxia. Due to this damage, a solid mass from the constituent of blood (thrombus) is formed.
The injury as can be noted is now graduating from moderate to severe. In a severe case there is stasis and thrombus formation. The thrombus can occlude the vessel, causing the necrosis of the vessel walls. A lot of erythrocytes can be found at this site of injury and the site becomes filled with blood.
Note that:
Mild injury- Hyperemia
Moderate injury - slowing down of blood flow, transudate
Severe injury - stasis followed by thrombosis; if thrombus is occlusive, there is necrosis of cells of the endothelium.
What is responsible for increase in vascular permeability?
Post-capillary venule is very important. It has the type of epithelium found in endocrine gland and glomeruli in the kidney i.e. fenestrated endothelium. This means a gap in between two adjacent endothelial cells.
This is important for the flow of fluid, it is called the inter-endothelial gap (an example of a gap junction).
It increases permeability by widening its gap. This is due to contraction of the endothelial cells. Through this gap, macromolecules move from within the gap to the perivascular spaces. The fluid now becomes an EXUDATE.
Bluing technique has really confirmed that the walls of the post-capillary venules are involved in the leakage in acute inflammation.
Inject a dye (toludene) into the vein. Cause an injury to the animal (localized injury). If truly there is increase in vascular permeability at the site of injury, the area turns blue. Toludene blue complexes with albumin. It can easily leak with albumin through the vessels when there is increased permeability. The experiment is quite subjective; it is not a quantitative method.
To quantify it, prepare and label albumin-using I125 . Add toluene blue to it to form a complex. Put a radio - counter at the site of injury.
To identify the particular vessel involved, the Albumin particle cannot be used. A heavy particle that will be trapped in the basement membrane is used. A particle of higher molecular weight- charcoal is used. It is injected as in albumin and a local injury is caused. Charcoal is trapped in the vessel wall because of the size.
A section of the vessel observed under the microscope will reveal trapped charcoal in the vessel.
This expt. shows the type of vessel involved in the leakage and that the walls of the post - capillary venules are involved.
INCREASE VASCULAR PERMEABILTY (VASCULAR LEAKING)
1.Formation of endothelial gaps in venules
2.Cytosketal reorganization (endothelial retraction)
3.Increase transcytosis across the endothelial cytoplasm.
4.Direct endothelial injury, resulting in endothelial cell necrosis and detachment
5.Delayed prolonged leakage
6.Leukocyte-mediated endothelial injury
7.Leakage from new blood vessels.
CELLULAR EVENTS (LEUCOCYTE EXTRAVASATION AND PHAGOCYTOSIS)
This is histologic hallmark of inflammation. It affords the opportunity to determine the cells involved.
Cellular components of blood are not in contact with the endothelium of the blood vessels. (Lamina flow). To get cells to leave the blood vessels, certain things must be done -the cell must be moved from the central axial flow to the periphery so that they can come in contact with the endothelium (Margination). Subsequently, individual and rows of leucocytes tumble slowly along the endothelium and adhere transiently - a process called rolling.
In time, the endothelium can be virtually lined by white cells, an appearance called pavementing. This is followed by adhesion of the polymorph to the endothelium (know as permanent attachment). Only the cells that make this permanent attachment will go through the next phase called Transmigration. In other words, cells that have attached to the endothelium will shoot out pseudopods, propel the body and squeeze through the inter - endothelial gap.
This much is known by E.M studies but the stage where it moves through the basement membrane to the perivascular space is not yet known. It is believed that the endothelium is lifted up by the polymorphs and produce holes in the membrane through which they move into the perivascular space
This is called emigration i.e. the polymorph is outside the vessel - it is in the perisvascular space.
It has always been known that there is synthesis of complementary adhesion molecules by both the polymorph and the endothelial cells.
Complementary adhesion molecules infer that the WBCs will produce a glycoprotein that is expressed on its Cell membrane. The endothelial cells produce a complementary glycoprotein. They unite in lock and key fashion. They are difficult to dislodge. These complementary adhesion molecules are important in inflammation.
Failure of their synthesis leads to blockage of the described processes, so that the infection becomes over whelming.
The emigrated cell has not reached its destination. It has to move to the site of injury.
Migration of cell is not random. It is a movement under chemical influence. The cells move against concentration gradient. It is from low to high concentration.
It is called Chemotaxis - a unidirectional movement of WBCs towards a chemical attachment.
Chemotaxis
The important thing about it is that the cells have receptors which function in the identification of chemical substance. The chemical substances form a complex with the receptors on the cell and series of reaction then take place. The synthesis of skeletal proteins is one of such reactions.
All the movements discussed previously are ligand receptor mediated.
As the pseudopod goes off, there is formation of actin filaments and contractile protein myosin, which ensure the regular directional movement (locomotion). The skeletal proteins are responsible for movement of cells and filamin; gelsolin, prolifilin and calmodulin, a calcium binding protein are involved in the assembly of myosin molecules that mediate the contraction.
The cells move towards the attractants, which are derived from injured tissue. The cells (neutrophills, macrophages) move towards the injured site. The chemical substances involved are biologically active fragment of complements. The most potent is C5a but others like C3a and C567 are also important, they are called chemotactic agents and are responsible for the movement of WBC to injured sites.
Some factors are also required to make chemo taxis effective: -These include
1. Divalent cations like mg2+ and ca2+
1. Energy (because there is locomotion). This energy is sourced from anaerobic respiration by the cells.
HOW DOES THE LEUCOCYTES SEE OR SMELL THE CHEMOTACTIC AGENTS AND HOW DO THESE SUBSTANCES INDUCE DIRECTED CELL MOVEMENT?
Not all the answers are known. Certain steps and second messengers are involved. Binding of chemotactic agents to specific receptors on the cell membranes of leucocytes results in activation of phospholipase C, leading to hydrolysis of phosphotidyl-inositol-4, 5 biphosphate (P1P2) to inositol-1, 4,5-triphosphate (IP3) and diacylglycerol (DAG) and release of calcium, first from intracellular stores and subsequent influx of extra cellular calcium.
A simple expt. is used to illustrate chemo taxis. The expt. Proves the movement is purposeful i.e. it is not random.
The Boyden chamber is divided into upper and lower chambers using a Millipore chamber. A solution is put in both chambers.
WBCs are put in the upper chamber; chemotactic agent is put in the lower chamber. A conc. Gradient is therefore created towards the lower chamber. The WBCs will wriggle through the Millipore and drop in the lower chamber. The number of cells migrating to the lower chamber will be proportional to the concentration of the chemical substances. If it is incubated, the number of cells can be counted.
This expt. has been simplified by putting a semi - preamble membrane below the Millipore so that the cells drop on this membrane. The WBCs can be easily counted under the microscope.
The next thing that the WBCs can do is to mass together - Aggregation. The cells will not attack immediately; they will only aggregate.
After aggregation comes the next crucial stage. Phagocytosis, a process by which the injurious agents are ingested by phagocytes. Phagocytosis goes along with other processes. If you are dealing with organic materials, there is phagocytosis and Degradation. If you are dealing with micro - organism, there is phagocytosis and lysis / killing.
With micro - organisms, WBCs cannot ingest them in the absence of serum. The function of serum is to supply opsonin, which enhance phagocytosis by coating the microbe. Three of them present in serum are (1) 3b and its stable form c3bi, (2) immunoglobin G, (3) collectin. C3b and Ig G coat the surface of the microbe. Once this is done the first step of phagocytosis is accomplished.
First step: Recognition - the phagocytes must recognize the microbes.
The mechanism: of recognition is that the phagocytes have receptors and C3b receptors. This forms a ligand - receptor complex. This is followed by attachment. Attachment -Once the microbe is attached to the surface of the phagocyte, the microbe is found within the indentation of the cell membrane of the WBC.
Second step: Engulfment. At the end of engulfment the microbe become internalized, i.e. it is found in the WBC cytoplasm. In the WBC, a membrane forming phagosome surrounds the microbe.
Third stage: Degradation and Killing- It is effected by lysosmes. Lysosmes fuse with the phagosome to form a complex known as phago - lysosme. Within the phagolysome, hydrolytic enzymes bath the injurious agent. If it an organic substance the enzyme will digest it. If it is a microbe it will kill it.
Mechanism of killing
This is by the production of free radicals-oxygen free. These free radicals are produced from O2 using NADPH oxides. The oxidase has 2 components - cell membrane - and cytosolic component. There is incomplete reduction of O2 to form the super - oxide (a free radical - any atom that has a free electron). The super oxide (O2) is converted to hydrogen peroxide, which is another oxygen free radical. Note that, on its own, H2O2 cannot kill all microbes hence another system present in the neutrophils (myeloperoxidase enzymes) is needed. Granules of neutrophils contain myeloperoxidase (MPO) enzyme, which in conjunction with any halide convert H2O2 to an oxy - chloride (H2O2 ® HOCL).
The combination of myeloperoxidase enzyme and a halide forms the Myeloperoxidase - halide system. It is this system that convert H2O2 to hypo - chloride which is a damaging free -radical. Most microbes are killed by HOCL.
There is a weaker system that can also be used -Ferrous pathway. It converts H2O2 to oxygen free radical.
The mechanism of killing in all these is called oxygen dependent mechanism.
Some phagocytes lack the myeloperoxidase enzyme. Therefore, they kill by O2 - independent mechanism. This mechanism will include some detergent effect on cell wall of the organism. One of the detergents is Hydrogen peroxide. The detergents are produced in large quantity and occur in the presence of bactericidal permeability protein, lysozyme, lactoferrin, major basic protein and defensins.
The final stage, extra cellular release of the products of the WBC is very important, because it modifies the inflammation response.
(1) Release of hydrolytic enzymes
(2) In macrophages, cytokines like interleukins (especially
(3) Release of free radicals interleukin1), tumor necrosis factors (TNF) a and b.
All these products will cause necrosis and cell death. Therefore when there are so many WBCs releasing these products, there will be extensive necrosis of tissues. The presence of this large collection of WBCs and their products result in abscess (collection of pus).
Any microbe that will cause large collection of WBCs, will result in release of large amount of these necrotic factors, inflammation is therefore very severe. At this stage inflammation may not be protective, it is damaging.
Q. Why is it that in acute inflammation the predominant cells are Neutrophils and in Chronic inflammation monocellular cell? .
1. - There are more neutrophils than monocytes
2. It has been established that neutrophils are faster than monocular cells.
The answer is however more complex. Even though both respond to the same chemotactic agents, they do not respond at the same degree and time.
It has been showed conclusively that in the first 6- 24hrs of an injury only polymorphs accumulate at the site. At the peak of polymorph immigration, monocytes start appearing.
Two things happen here - migration of monocytes is over much more prolonged period than neutrophils.
Monocytes have longer half life (Monocytes days to weeks, Neutrophils-6hrs) and can also replicate at the site of inflammation.
It is presently known that the most potent chemo tactic agent for monocytes is produced by decaying neutrophils and this that explains why it takes about 6- 24hrs for monocytes to appear.
Vascular and cellular changes are under the influence of chemicals - chemical mediators of acute inflammation.
There are two subgroups: -
(1) Cell and tissue – derived
(2) Plasma - derived
(1) Tissue derived mediators can be subdivided into two:
· Pre-formed: mediators present in inactive forms within cell or tissue before injury. Examples - vasoactive amines; Histamine and Serotonine as well as lysosomal enzymes of both neutrophils and macrophages.
· Newly synthesized group: they are derived from the phospholipids of the cell membrane of cells participating in inflammatory response.
Major portion of them are the metabolic products of arachidonic acid e.g. Prostaglandin especially E- series and the leucotriene especially the B4. Other example includes platelet-activating factor.
Macrophages when activated release Cytokines. Two important cytokines are Interleukine 1- and tumor necrosis factor (TNF).
1.b there is a new mediator that has been recently described. It can produce by any cell, but most commonly activated endothelial cells - Nitric oxide. It is very potent vasodilator of the endothelium and causes increase vascular permeability.
In conclusion, these substances, especially vaso-active amines take part in the early stage of acute inflammation.
However, action of these vaso-active amines is short lived and the later phase will require newly synthesized amine, especially Leucotrine B4 and prostaglandin E2.
2. Plasma derived mediator include the following:
a. Clotting factor, especially factor 12 (Hagerman factor)
b. Kinin system
c. Complement system
d. Fibrinolytic system.
a/b - between the clotting and kinin systems there is an important system i.e. the pre-Kalikreine- Kalikreine system.
Once factor 12 is activated, there is an interaction in which there is activation of the kinin and fibrolytic systems.
3. Complement System is an important mediator of all forms of reactions, especially inflammation.
It is a system of protein present in the blood. They are named using Arabic numeral with C ((‘ is complement). There are C1 to C9 complements. There are early fragments i.e. those complements activated at the early stage of classical activation.
They are C142 in that order using classical pathway,
Activation starts from C1 to C4 and to C2, after this C3 becomes activated them C5, C6, C7, C8 and C9.
3a Classical Pathway of activation: it requires an antigen- antibody complex. This pathway is very important in that complements can be divided into groups such as:
· Recognition unit (C1)
· Enzymatic activation unit (C423)
· Membrane attacking unit.(C5b6789)
The recognition unit recognizes the FC fragments of the antibody in an antigen – antibody complex. Recognition unit comprises of the first fragment (C1), which is a micro-molecule comprising of CIq, CIr and C1s fragments. The recognition molecule of Fc portion of antibody is C1q.It becomes activated and activates C1r and C1s subsequently. C1 is the active component of the recognition unit. C1s and C4 and after this it cleaves C2.
Immediately there is activated C4 and C2, a complex activated C42 is formed. This enzyme is called C3 convertase. The C3 convertase activates C3 into a large fragment (which joins C42 on the Cell- membrane and the small fragment stays dissolve in the solution). The second complex C423 also known as C5- convertase is formed.
C5- convertase activates C5. C423 are the enzymatic activation unit. The Large fragment of C5 is C5b, which remains on the surface of the cell. From this point onwards there is sequential activation of C6, C7, C8, and C9 to form C5b67, C5b678 and C5b6789 respectively. C5b6789 is the memebrane attack unit. It punches holes in the cell membrane thereby causing cell lysis.
There is a second pathway of activation known as Alternate pathway. In this way activation, starts from C3 (by passing C142). It may not involve antigen antibody. It involves properdine B and D. Many things however can activate this pathway- bacteria endotoxin, aggregated Ig especially -IgA and aggregated polysaccharide. When they get activated they start from C3.
These 2 systems will merge at C5. The only way to detect which of the pathways involved is to assay for complements.
C142 is low in classical pathway; the reverse is true for alternate pathway. C3 will be low in both cases.
Most diseases involve activation by classical pathway. But in a few kidney diseases (glomerulo nephritis) activation is by Alternative pathway.
Another important mediator of immunological response will be presence of neutrophils, platelets and monocytes.
Read about complement- how clotting factor can cause activation of Brady Kinin Via Kalikreine.
Complement fragments that play important role in inflammation.
1. Anaphylatoxins-They release Histamine from mast cells. There are two of them C3a, C5a.
2. There are chemotactic agents and the most potent is C5a. Others are C3a and C567.
3. Opsonins e.g. C3b, and? C4b, C3b, is the most potent.
These fragments have their inhibitors in precursor forms in the blood. When the pre-cursors are activated they inhibit the active fragment. This is because multisystemic inflammation has to be prevented. The active fragments are inactivated as they generated. Those without inhibitors have a very rapid decaying potential i.e. decay very fast immediately they have performed their functions.
Those that have inactivators include: -
1. C1s - esterase inactivator- a C1s inhibitor.
There is a disease of human which results as a failure to remove C1s- angioneurotic oedema.
Patient has congenital absence or deficiency of CIS esterase. There is the development of anaphylactic response. (Angioneurotic oedema- oedema of upper respiratory tract, it could cause obstruction of the pharynx and larynx resulting in sudden death).
2. C3b Inhibitor- C3b left on its own in the system will continue to cleave C3a and C3b. The danger is a situation where there will be no C3 at all - severe hypocomplementamia of C3. C3b is therefore referred to as Amplication arm. (C3b + C3 = C3a +C3b)
There are 2 ways in which C3b accumulation can occur: -
· Congenital absence of the Inhibitor.
· Diseases where inhibitor is present but C3b is stabilized.
There is a disease of man where the basic pathology is inability to metabolize / degrade C3b. It is a glomerular disease called Membrane Proliferative Glomerulonephritis (MPGN). There are two types - Types 1 and 2. Type 2 is more severe in term of the disease and in terms of depletion of C3b.
In the serum of patients, there is a factor that stabilizes C3b; therefore C3b will continue to cleave C3. The other name for the disease is Hypocomplementemic glomereulonephritis.
The factor that stabilizes C3b is called C3 nephritic factor (C3 Nef). It is thought to be an immunoglobulin.
Suppose a patient has immune complex glomerulonephritis, then the complement system already described can be applied.
Other plasma - derived products can be considered.
Factor 12 (XII) Hageman factor is very important because it is easily activated by antigen- antibody system, bacteria endotoxin, contact with collagen in the vessel wall and contact with uric acid in the joints.
It is activated to XIIa and XIIf
XII -----------------------> XIIa + XIIf
XII ----------------------->(XIIa <===รจ ( XIIf
In inflammation, the tendency is for XIIa to go to XIIF. Another name for XIIf is pre- kallikrein activator (PKA)
Pre- kallikrein_____PKA______________> Kallikrein.
A product of factor XII is therefore activator of the Kallikrein system to produce Kallikrein.
Kallikrein activates Kininogen to kinin.
Therefore Bradykininogen is converted to Bradykinin
In inflammation, we started off with vaso- active amine within the first 2-5hrs. As the cells degenerate phospolipids are formed.i.e. Prostaglandin, leuckotriene, e.t.c. These continue the process of inflammation. At the same time plasma products are activated and there is a full - blown inflammatory reaction.
Morphologic Pattern of Inflammation
The vascular, neurologic and humoral systems are important. The host reaction and injurious agents are both important. (Severity of inflammation is directly proportional to the intensity as well as the seriousness of the antigen or injurious agent.)
In acute inflammation, exudation is very important. To have exudation there must be
· vasodilation
· Increase in blood flow
· increase in vascular permeability.
The most important of the three is increased vascular permeability.
The various types of exudates are important. Exudates can be classified.
In some mild injury and inflammation, the exudates obtained can be divided into two: -
1. Serous exudates - it is just like serum. It contains little protein, scanty or no cell at all. It is seen in mild inflammation. This can be seen in viral infections or the early stage of T.B infection.
2. Fibrinous exudates - contains a lot of fibrinogen and fibrin. There is precipitation of the protein present in the fibrinous exudates on the lungs. This is called Fibrinous pleuritis. With a pair forceps, the fibrinous exudates can be lifted up from the surface of any inflammation.
Fibrinous exudates can occur as a result of immunological disease - Rheumatic carditis in which there can be fibrinous endocarditis (Bread and Butter’ pericarditidis)
Tuberculosis (at the very early stage - fibrous pleuritis is found).
Removal of exudates in some cases could return the tissue to normal. This is called Resolution in healing and repair. This can be done by fibrinolysin, which will degrade the fibrin restoring the shiny surface of the organ.
If the fibrinolysin is not enough to lyse the fibrin. Replacement takes place. This is a step from fibrinous pleuritis to fibrous pleuritis.
Fibrinous pleuritis
ORGANIZATION
fibrous pleuritis
Fibrous tissue cannot be lifted with a pair of forceps. The organ can even be attached to another structure by the fibers.
3. Serofibrinous Exudates - example is found in T.B during the stage of Ghon’s complex. There could be purulent or suppurative exudates. A purulent exudates contains a lot of neutrophils, it is yellow in colour (yellow pus). It is found in pyogenic meningitis. In pneumonia, there is purulent exudate in the alveoli. It may extend to the pleura.
A purulent exudate can also be resolved or organized.
In Pneumonia (where there is purulent exudate in the alveoli), during resolution macrophages, neutrophils release their lysosomal enzymes and digest the exudates. The macrophages will phagocytose the particulate materials. The fluid material can either be reabsorbed into circulation or the patient coughs up the fluid.
The exudate, on the other hand, may fail to resolve. In this case they become organized i.e. the lumen of the alveoli becomes obliterated by fibrous tissue i.e. it is lost or its function impaired.
Commonly in bacteria infection what is obtained is a fibrinopurulent exudate.
4. Fibrinopurulent exudate - found in most bacteria infection (meningitis, pneumonia, appendicitis (the fibrino- purulent exudate is on the serosa of the appendix). The exude is also either resolved or organized.
Type of exudate can be used to assess severity of the injury.
Site of inflammation also determines the morphology of inflammation.
Lung
Suppose there is lung infection by a pyogenic microbe and the pyogenic material is deep in the substance of the lung, a lot of suppurative exudates are formed. Because of the severity of the injury the various alveoli will give way to form a localized collection of pus forming a lung abscess.
Similar thing happens if someone is shot with Dane gun (with a lot of dirty pellets) a deep - seated abscess is formed. The complication of the abscess is that if there is infarction of tissue there wills Gangrenous necrosis.
(Abscess is a localized collection of pus in an organ or tissue of a deep - seated pyogenic infection. The pus is enclosed by fibrous tissue. When pus is release, a cavity is formed)
Site determines extent / type of inflammation.
Suppose there is an inflammation of a mucous secreting epithelium (sinusitis). The secretion is mucus and this is called a Catarrhal inflammation - This affects a mucous secreting epithelium and in this there will be proliferation of the mucous epithelium and mucuos is produced rapidly e.g. Sinusitis.
There may be an inflammation in the colon, (or a viscous) with an excavation of the mucosa.
There is a discontinuity in the surface of the organ -Ulcerative inflammation e.g. GIT as a result peptic ulceration. It used to be chemical due to acid but it is now associated with campylobacter jejuni.
Typhoid enteritis is an example; it gives rise to an ulcerative inflammation in the small intestine. Also Amoeba histolytica in the colon causing amoebic colitis as well as tuberculosis.
Also there could be ulceration in the lower limbs with impeded blood supply to the limbs e.g. children with sickle cell, elderly people with Arteriosclerosis, the patients with Diabetes.
There are situations where a micro- organism produces a very potent toxin e.g. Diphtheria.
Diphtheria affects the trachea and bronchi. The exotoxin causes necrosis of the lining of the trachea and bronchi. There is release of a lot of protein exudate within the lumen of the trachea. The protein and necrotic tissue mix together and they cover the surface of the trachea forming a layer on the rough surface. This looks like a membrane but it is not a membrane because there is no vital tissue (no cell) in the mixture. Rather it is a pseudo-membranous inflammation. In this inflammation, there is layering of denuded membrane by a pseudo-membrane. It can be found in trachea of children in Diphtheria disease, in the alveoli of children with acute respiratory distress (Hyaline membrane) syndrome.
The same lesion in an adult is adult respiratory distress syndrome (it can be due to a lot of causes burns, acid - toxicity e.t.c). There could also be a pseudo - membranous colitis (in the colon) either as a result of bacteria infection or complications from administration antibiotics especially in Gentamycin.
The individual plays an important role in the severity of inflammation. Nutrition is very important (proteins are used to form Ig). The type of disease the patient has is important. i.e a patient with chronic debilitating infection like diabetes, advanced cancer have poor inflammatory response as the immune system is overwhelmed.
Type of microbe causing inflammation is very important.
Micro-organisms And Inflammatory Response
1.staphylocoeus aureus or Streptococcus Pyogenes
2. b Hemolytic Streptococcus
(1) Could give rise to a suppurative inflammation with the possibility of abscess formation.
On the other hand, (2) may not cause undue suppuration, it may cause a lot of stroma enzymes to be produced (collagenase, Hyaluronidase streptokinase). As long as these enzymes are produced, inflammation spreads rapidly as they destroy the basement membrane, collagen e.t.c. They cause a spreading infection called cellulitis. (“phlegmon” - old term).
(2) Viral infection - what is obtained is different
(1) And (2) above give rise to classical acute inflammation with neutrophils being predominant (3) gives rise to acute inflammation with lymphocytes being predominant.
In fungal and bacteria infections such as M. Leprae and M/tuberculosis exudate is more in the intestitium. In this group the predominant cells are macrophages and modified macrophages. In addition to these are found epitheloid cells and giant cells (modified histiocytes).
This is a Granulomatous Inflammation - predominant cells are Histocytes and modified Histocytes. (Also found in syphilis). When the histocytes and modified histocytes form a mass in an organ or a tissue, the mass is called Granuloma.
The difference between Granuloma and a granulation tissue.
Granulation tissue - mass of fibroblast, proliferating immature cells with blood vessels involved in the process of repair.
Granuloma - histocytes and modified histocytes.
Immunological injury can either involve a cell - mediated or humoral response.
Immune -complex response (classical)
Both antigens - antibody complex and other complex fragments are in the exudates on the vessel wall. This will cause activation of complements. This will attract polymorphs to the region.
This cause vasculitis. There is a fibrinoid change of vessel wall i.e. it is granular and pinkish. It is a definite morphologic pattern of immune complex injury. The adjective "fibrinoid" does not particularly mean it contains fibrin. The content includes complements, neutrophils, hemorrhage and oedema.
Local and systemic effects of Acute Inflammation
Local Effects –
These are known as cardinal signs of acute inflammation.
1.Redness (Rubor).
Flare – is as a result of opening up of the capillaries. This causes dilation and increased blood flow. Temperature of the area arises by about 10 C.
2.Heat (calor)
3.Swelling (oedema) as a result of leakage of fluid due to increased vascular permeability.
4.Direct irritation as well as compression of the nerve twitch or fiber gives pain.
5. Pain (Dolor)
6. The fifth sign is LOSS OF FUNCTION. (Functio laesa).
These are local signs of acute inflammation.
Systemic Effect
Depends on the type of inflammation - organism or agent responsible. What is common to all of them is fever (rise in body temperature). This is due to the release of chemical factors especially interleukines and prostaglandin; they cause a change in the thermostat of the hypothalamus.
Also because of the increase in metabolic rate, the patient develops an increase in heart rate - Tachycardia.
Some of the infections (bacterial) result in outpouring of neutrophils into the blood (Neutrophilia). Also some proteins appear in the blood during this period. They are called C - reactive proteins. This causes an elevation in ESR. These effects are found in classical cases. In some disorders there are variations:
Viral infection - no neutrophilia, leucocytosis with a rise in lymphocytes.
Typhoid enteritis - high fever with brady- cardia (contrary) to Tachycardia xteristic of other bacteria infection).
Salmonella - a decrease in WBC count (leucopoenia) contrary to increase in WBC count in other bacterial infections.
CARDINAL SIGNS OF INFLAMMATION:
1.Calor (heat)
2.Rubor (redness)
3.Dolor (pain)
4Tumor (swelling)
5.Functio laesa (loss of function).
CAUSES OF ACUTE INFLAMMATION INCLUDE:
1.Mechanical trauma
2.Chemical injuries
3.Radiation injuries
4. Injuries due to cold and heat
5.Injuries associated with necrosis
6.Injuries due to living organism
7Injuries due to an immunological mechanism.
DEFINITION OF TERMS:
(1) EXUDATION: The escape of fluid, proteins, and blood cells from the vascular system into the interstial tissue or body cavities.
(2) EXUDATE: An inflammatory extra vascular fluid that has a high protein concentration, much cellular debris, and a specific gravity above 1.020.
(3) TRANSUDATE: A fluid with low protein content and a specific gravity of less than 1.012. It is essentially an ultra filtrate of blood plasma resulting from hydrostatic imbalance between the arteriolar and the venular end.
(4) OEDEMA: Denotes an excess of fluid in the interstial tissue or the serous cavities. It can be an exudates or a transudate
A purulent inflammatory exudates rich in leucocytes and parenchymal cell debris
CHANGES IN ACUTE INFLAMMATION:
These changes are
1. Changes in the blood vessel walls
2. Blood flow within the vessels
3. Exudation –both fluid and cellular.
1. Changes in the blood vessel wall
The earliest response to acute injury is constriction in the small blood vessels. microvascularture Terminal-> capillaries-> post-capillary venules->venous system. It can be demonstrated in the human skin; light stroking produces a white line. This vasoconstriction is apparently due to direct mechanical stimulation of the capillaries.
Vasodilatation rapidly follows the initial constriction and persists for the duration of the inflammatory process. The first result of arteriolar dilatation is that blood flows by the most direct route to the veins through the central, or thoroughfare channels. Subsequent opening of the precapillary spincters allows blood to pass into the capillary bed, and vessels, which were temporarily shuntdown now become functional again. The inflamed part therefore appears to contain an increased number of vessels (hyperemia). In addition, their caliber is increased. The response is seen only with mild injury.
The basic mechanisms involved in vascular event are triple response and it is dependent on histamine liberated from damaged cells following injury.
The features of this triple response are (1) redline (2) flare (3) weal
1.REDLINE: After a short latent period a redline develops, at first bright red, later cyanosed. It is sharply demarcated and due capillary dilatation.
2.FLARE: After a further 15-30 seconds, a flare appears surrounding the redline. It is blotchy, has a cremated outline and it is due to arteriolar dilatation.
3.WEAL: Due to exudation of fluid through vascular wall causing increase edema and paleness of the affected part.
When the injury becomes a bit more severe, the velocity of blood flow is affected. With a moderate injury, the velocity of blood flow diminishes followed by the effect of slowing down of blood to create logging of the blood. .
This causes an increase in hydrostatic pressure. An increase hydrostatic pressure will force fluid from the intravascular to extra vascular space (leaking of fluid). This fluid contains very small protein and lacks cells hence it is called a transudate.
This makes the blood more concentrated -Haemoconcentration.
The viscosity of the blood is increased; this is very dangerous as it may cause stasis of blood. At this stage there is going to be injury to the endothelial cells. First, as a result of roughening by the blood and secondly, as a result of hypoxia. Due to this damage, a solid mass from the constituent of blood (thrombus) is formed.
The injury as can be noted is now graduating from moderate to severe. In a severe case there is stasis and thrombus formation. The thrombus can occlude the vessel, causing the necrosis of the vessel walls. A lot of erythrocytes can be found at this site of injury and the site becomes filled with blood.
Note that:
Mild injury- Hyperemia
Moderate injury - slowing down of blood flow, transudate
Severe injury - stasis followed by thrombosis; if thrombus is occlusive, there is necrosis of cells of the endothelium.
What is responsible for increase in vascular permeability?
Post-capillary venule is very important. It has the type of epithelium found in endocrine gland and glomeruli in the kidney i.e. fenestrated endothelium. This means a gap in between two adjacent endothelial cells.
This is important for the flow of fluid, it is called the inter-endothelial gap (an example of a gap junction).
It increases permeability by widening its gap. This is due to contraction of the endothelial cells. Through this gap, macromolecules move from within the gap to the perivascular spaces. The fluid now becomes an EXUDATE.
Bluing technique has really confirmed that the walls of the post-capillary venules are involved in the leakage in acute inflammation.
Inject a dye (toludene) into the vein. Cause an injury to the animal (localized injury). If truly there is increase in vascular permeability at the site of injury, the area turns blue. Toludene blue complexes with albumin. It can easily leak with albumin through the vessels when there is increased permeability. The experiment is quite subjective; it is not a quantitative method.
To quantify it, prepare and label albumin-using I125 . Add toluene blue to it to form a complex. Put a radio - counter at the site of injury.
To identify the particular vessel involved, the Albumin particle cannot be used. A heavy particle that will be trapped in the basement membrane is used. A particle of higher molecular weight- charcoal is used. It is injected as in albumin and a local injury is caused. Charcoal is trapped in the vessel wall because of the size.
A section of the vessel observed under the microscope will reveal trapped charcoal in the vessel.
This expt. shows the type of vessel involved in the leakage and that the walls of the post - capillary venules are involved.
INCREASE VASCULAR PERMEABILTY (VASCULAR LEAKING)
1.Formation of endothelial gaps in venules
2.Cytosketal reorganization (endothelial retraction)
3.Increase transcytosis across the endothelial cytoplasm.
4.Direct endothelial injury, resulting in endothelial cell necrosis and detachment
5.Delayed prolonged leakage
6.Leukocyte-mediated endothelial injury
7.Leakage from new blood vessels.
CELLULAR EVENTS (LEUCOCYTE EXTRAVASATION AND PHAGOCYTOSIS)
This is histologic hallmark of inflammation. It affords the opportunity to determine the cells involved.
Cellular components of blood are not in contact with the endothelium of the blood vessels. (Lamina flow). To get cells to leave the blood vessels, certain things must be done -the cell must be moved from the central axial flow to the periphery so that they can come in contact with the endothelium (Margination). Subsequently, individual and rows of leucocytes tumble slowly along the endothelium and adhere transiently - a process called rolling.
In time, the endothelium can be virtually lined by white cells, an appearance called pavementing. This is followed by adhesion of the polymorph to the endothelium (know as permanent attachment). Only the cells that make this permanent attachment will go through the next phase called Transmigration. In other words, cells that have attached to the endothelium will shoot out pseudopods, propel the body and squeeze through the inter - endothelial gap.
This much is known by E.M studies but the stage where it moves through the basement membrane to the perivascular space is not yet known. It is believed that the endothelium is lifted up by the polymorphs and produce holes in the membrane through which they move into the perivascular space
This is called emigration i.e. the polymorph is outside the vessel - it is in the perisvascular space.
It has always been known that there is synthesis of complementary adhesion molecules by both the polymorph and the endothelial cells.
Complementary adhesion molecules infer that the WBCs will produce a glycoprotein that is expressed on its Cell membrane. The endothelial cells produce a complementary glycoprotein. They unite in lock and key fashion. They are difficult to dislodge. These complementary adhesion molecules are important in inflammation.
Failure of their synthesis leads to blockage of the described processes, so that the infection becomes over whelming.
The emigrated cell has not reached its destination. It has to move to the site of injury.
Migration of cell is not random. It is a movement under chemical influence. The cells move against concentration gradient. It is from low to high concentration.
It is called Chemotaxis - a unidirectional movement of WBCs towards a chemical attachment.
Chemotaxis
The important thing about it is that the cells have receptors which function in the identification of chemical substance. The chemical substances form a complex with the receptors on the cell and series of reaction then take place. The synthesis of skeletal proteins is one of such reactions.
All the movements discussed previously are ligand receptor mediated.
As the pseudopod goes off, there is formation of actin filaments and contractile protein myosin, which ensure the regular directional movement (locomotion). The skeletal proteins are responsible for movement of cells and filamin; gelsolin, prolifilin and calmodulin, a calcium binding protein are involved in the assembly of myosin molecules that mediate the contraction.
The cells move towards the attractants, which are derived from injured tissue. The cells (neutrophills, macrophages) move towards the injured site. The chemical substances involved are biologically active fragment of complements. The most potent is C5a but others like C3a and C567 are also important, they are called chemotactic agents and are responsible for the movement of WBC to injured sites.
Some factors are also required to make chemo taxis effective: -These include
1. Divalent cations like mg2+ and ca2+
1. Energy (because there is locomotion). This energy is sourced from anaerobic respiration by the cells.
HOW DOES THE LEUCOCYTES SEE OR SMELL THE CHEMOTACTIC AGENTS AND HOW DO THESE SUBSTANCES INDUCE DIRECTED CELL MOVEMENT?
Not all the answers are known. Certain steps and second messengers are involved. Binding of chemotactic agents to specific receptors on the cell membranes of leucocytes results in activation of phospholipase C, leading to hydrolysis of phosphotidyl-inositol-4, 5 biphosphate (P1P2) to inositol-1, 4,5-triphosphate (IP3) and diacylglycerol (DAG) and release of calcium, first from intracellular stores and subsequent influx of extra cellular calcium.
A simple expt. is used to illustrate chemo taxis. The expt. Proves the movement is purposeful i.e. it is not random.
The Boyden chamber is divided into upper and lower chambers using a Millipore chamber. A solution is put in both chambers.
WBCs are put in the upper chamber; chemotactic agent is put in the lower chamber. A conc. Gradient is therefore created towards the lower chamber. The WBCs will wriggle through the Millipore and drop in the lower chamber. The number of cells migrating to the lower chamber will be proportional to the concentration of the chemical substances. If it is incubated, the number of cells can be counted.
This expt. has been simplified by putting a semi - preamble membrane below the Millipore so that the cells drop on this membrane. The WBCs can be easily counted under the microscope.
The next thing that the WBCs can do is to mass together - Aggregation. The cells will not attack immediately; they will only aggregate.
After aggregation comes the next crucial stage. Phagocytosis, a process by which the injurious agents are ingested by phagocytes. Phagocytosis goes along with other processes. If you are dealing with organic materials, there is phagocytosis and Degradation. If you are dealing with micro - organism, there is phagocytosis and lysis / killing.
With micro - organisms, WBCs cannot ingest them in the absence of serum. The function of serum is to supply opsonin, which enhance phagocytosis by coating the microbe. Three of them present in serum are (1) 3b and its stable form c3bi, (2) immunoglobin G, (3) collectin. C3b and Ig G coat the surface of the microbe. Once this is done the first step of phagocytosis is accomplished.
First step: Recognition - the phagocytes must recognize the microbes.
The mechanism: of recognition is that the phagocytes have receptors and C3b receptors. This forms a ligand - receptor complex. This is followed by attachment. Attachment -Once the microbe is attached to the surface of the phagocyte, the microbe is found within the indentation of the cell membrane of the WBC.
Second step: Engulfment. At the end of engulfment the microbe become internalized, i.e. it is found in the WBC cytoplasm. In the WBC, a membrane forming phagosome surrounds the microbe.
Third stage: Degradation and Killing- It is effected by lysosmes. Lysosmes fuse with the phagosome to form a complex known as phago - lysosme. Within the phagolysome, hydrolytic enzymes bath the injurious agent. If it an organic substance the enzyme will digest it. If it is a microbe it will kill it.
Mechanism of killing
This is by the production of free radicals-oxygen free. These free radicals are produced from O2 using NADPH oxides. The oxidase has 2 components - cell membrane - and cytosolic component. There is incomplete reduction of O2 to form the super - oxide (a free radical - any atom that has a free electron). The super oxide (O2) is converted to hydrogen peroxide, which is another oxygen free radical. Note that, on its own, H2O2 cannot kill all microbes hence another system present in the neutrophils (myeloperoxidase enzymes) is needed. Granules of neutrophils contain myeloperoxidase (MPO) enzyme, which in conjunction with any halide convert H2O2 to an oxy - chloride (H2O2 ® HOCL).
The combination of myeloperoxidase enzyme and a halide forms the Myeloperoxidase - halide system. It is this system that convert H2O2 to hypo - chloride which is a damaging free -radical. Most microbes are killed by HOCL.
There is a weaker system that can also be used -Ferrous pathway. It converts H2O2 to oxygen free radical.
The mechanism of killing in all these is called oxygen dependent mechanism.
Some phagocytes lack the myeloperoxidase enzyme. Therefore, they kill by O2 - independent mechanism. This mechanism will include some detergent effect on cell wall of the organism. One of the detergents is Hydrogen peroxide. The detergents are produced in large quantity and occur in the presence of bactericidal permeability protein, lysozyme, lactoferrin, major basic protein and defensins.
The final stage, extra cellular release of the products of the WBC is very important, because it modifies the inflammation response.
(1) Release of hydrolytic enzymes
(2) In macrophages, cytokines like interleukins (especially
(3) Release of free radicals interleukin1), tumor necrosis factors (TNF) a and b.
All these products will cause necrosis and cell death. Therefore when there are so many WBCs releasing these products, there will be extensive necrosis of tissues. The presence of this large collection of WBCs and their products result in abscess (collection of pus).
Any microbe that will cause large collection of WBCs, will result in release of large amount of these necrotic factors, inflammation is therefore very severe. At this stage inflammation may not be protective, it is damaging.
Q. Why is it that in acute inflammation the predominant cells are Neutrophils and in Chronic inflammation monocellular cell? .
1. - There are more neutrophils than monocytes
2. It has been established that neutrophils are faster than monocular cells.
The answer is however more complex. Even though both respond to the same chemotactic agents, they do not respond at the same degree and time.
It has been showed conclusively that in the first 6- 24hrs of an injury only polymorphs accumulate at the site. At the peak of polymorph immigration, monocytes start appearing.
Two things happen here - migration of monocytes is over much more prolonged period than neutrophils.
Monocytes have longer half life (Monocytes days to weeks, Neutrophils-6hrs) and can also replicate at the site of inflammation.
It is presently known that the most potent chemo tactic agent for monocytes is produced by decaying neutrophils and this that explains why it takes about 6- 24hrs for monocytes to appear.
Vascular and cellular changes are under the influence of chemicals - chemical mediators of acute inflammation.
There are two subgroups: -
(1) Cell and tissue – derived
(2) Plasma - derived
(1) Tissue derived mediators can be subdivided into two:
· Pre-formed: mediators present in inactive forms within cell or tissue before injury. Examples - vasoactive amines; Histamine and Serotonine as well as lysosomal enzymes of both neutrophils and macrophages.
· Newly synthesized group: they are derived from the phospholipids of the cell membrane of cells participating in inflammatory response.
Major portion of them are the metabolic products of arachidonic acid e.g. Prostaglandin especially E- series and the leucotriene especially the B4. Other example includes platelet-activating factor.
Macrophages when activated release Cytokines. Two important cytokines are Interleukine 1- and tumor necrosis factor (TNF).
1.b there is a new mediator that has been recently described. It can produce by any cell, but most commonly activated endothelial cells - Nitric oxide. It is very potent vasodilator of the endothelium and causes increase vascular permeability.
In conclusion, these substances, especially vaso-active amines take part in the early stage of acute inflammation.
However, action of these vaso-active amines is short lived and the later phase will require newly synthesized amine, especially Leucotrine B4 and prostaglandin E2.
2. Plasma derived mediator include the following:
a. Clotting factor, especially factor 12 (Hagerman factor)
b. Kinin system
c. Complement system
d. Fibrinolytic system.
a/b - between the clotting and kinin systems there is an important system i.e. the pre-Kalikreine- Kalikreine system.
Once factor 12 is activated, there is an interaction in which there is activation of the kinin and fibrolytic systems.
3. Complement System is an important mediator of all forms of reactions, especially inflammation.
It is a system of protein present in the blood. They are named using Arabic numeral with C ((‘ is complement). There are C1 to C9 complements. There are early fragments i.e. those complements activated at the early stage of classical activation.
They are C142 in that order using classical pathway,
Activation starts from C1 to C4 and to C2, after this C3 becomes activated them C5, C6, C7, C8 and C9.
3a Classical Pathway of activation: it requires an antigen- antibody complex. This pathway is very important in that complements can be divided into groups such as:
· Recognition unit (C1)
· Enzymatic activation unit (C423)
· Membrane attacking unit.(C5b6789)
The recognition unit recognizes the FC fragments of the antibody in an antigen – antibody complex. Recognition unit comprises of the first fragment (C1), which is a micro-molecule comprising of CIq, CIr and C1s fragments. The recognition molecule of Fc portion of antibody is C1q.It becomes activated and activates C1r and C1s subsequently. C1 is the active component of the recognition unit. C1s and C4 and after this it cleaves C2.
Immediately there is activated C4 and C2, a complex activated C42 is formed. This enzyme is called C3 convertase. The C3 convertase activates C3 into a large fragment (which joins C42 on the Cell- membrane and the small fragment stays dissolve in the solution). The second complex C423 also known as C5- convertase is formed.
C5- convertase activates C5. C423 are the enzymatic activation unit. The Large fragment of C5 is C5b, which remains on the surface of the cell. From this point onwards there is sequential activation of C6, C7, C8, and C9 to form C5b67, C5b678 and C5b6789 respectively. C5b6789 is the memebrane attack unit. It punches holes in the cell membrane thereby causing cell lysis.
There is a second pathway of activation known as Alternate pathway. In this way activation, starts from C3 (by passing C142). It may not involve antigen antibody. It involves properdine B and D. Many things however can activate this pathway- bacteria endotoxin, aggregated Ig especially -IgA and aggregated polysaccharide. When they get activated they start from C3.
These 2 systems will merge at C5. The only way to detect which of the pathways involved is to assay for complements.
C142 is low in classical pathway; the reverse is true for alternate pathway. C3 will be low in both cases.
Most diseases involve activation by classical pathway. But in a few kidney diseases (glomerulo nephritis) activation is by Alternative pathway.
Another important mediator of immunological response will be presence of neutrophils, platelets and monocytes.
Read about complement- how clotting factor can cause activation of Brady Kinin Via Kalikreine.
Complement fragments that play important role in inflammation.
1. Anaphylatoxins-They release Histamine from mast cells. There are two of them C3a, C5a.
2. There are chemotactic agents and the most potent is C5a. Others are C3a and C567.
3. Opsonins e.g. C3b, and? C4b, C3b, is the most potent.
These fragments have their inhibitors in precursor forms in the blood. When the pre-cursors are activated they inhibit the active fragment. This is because multisystemic inflammation has to be prevented. The active fragments are inactivated as they generated. Those without inhibitors have a very rapid decaying potential i.e. decay very fast immediately they have performed their functions.
Those that have inactivators include: -
1. C1s - esterase inactivator- a C1s inhibitor.
There is a disease of human which results as a failure to remove C1s- angioneurotic oedema.
Patient has congenital absence or deficiency of CIS esterase. There is the development of anaphylactic response. (Angioneurotic oedema- oedema of upper respiratory tract, it could cause obstruction of the pharynx and larynx resulting in sudden death).
2. C3b Inhibitor- C3b left on its own in the system will continue to cleave C3a and C3b. The danger is a situation where there will be no C3 at all - severe hypocomplementamia of C3. C3b is therefore referred to as Amplication arm. (C3b + C3 = C3a +C3b)
There are 2 ways in which C3b accumulation can occur: -
· Congenital absence of the Inhibitor.
· Diseases where inhibitor is present but C3b is stabilized.
There is a disease of man where the basic pathology is inability to metabolize / degrade C3b. It is a glomerular disease called Membrane Proliferative Glomerulonephritis (MPGN). There are two types - Types 1 and 2. Type 2 is more severe in term of the disease and in terms of depletion of C3b.
In the serum of patients, there is a factor that stabilizes C3b; therefore C3b will continue to cleave C3. The other name for the disease is Hypocomplementemic glomereulonephritis.
The factor that stabilizes C3b is called C3 nephritic factor (C3 Nef). It is thought to be an immunoglobulin.
Suppose a patient has immune complex glomerulonephritis, then the complement system already described can be applied.
Other plasma - derived products can be considered.
Factor 12 (XII) Hageman factor is very important because it is easily activated by antigen- antibody system, bacteria endotoxin, contact with collagen in the vessel wall and contact with uric acid in the joints.
It is activated to XIIa and XIIf
XII -----------------------> XIIa + XIIf
XII ----------------------->(XIIa <===รจ ( XIIf
In inflammation, the tendency is for XIIa to go to XIIF. Another name for XIIf is pre- kallikrein activator (PKA)
Pre- kallikrein_____PKA______________> Kallikrein.
A product of factor XII is therefore activator of the Kallikrein system to produce Kallikrein.
Kallikrein activates Kininogen to kinin.
Therefore Bradykininogen is converted to Bradykinin
In inflammation, we started off with vaso- active amine within the first 2-5hrs. As the cells degenerate phospolipids are formed.i.e. Prostaglandin, leuckotriene, e.t.c. These continue the process of inflammation. At the same time plasma products are activated and there is a full - blown inflammatory reaction.
Morphologic Pattern of Inflammation
The vascular, neurologic and humoral systems are important. The host reaction and injurious agents are both important. (Severity of inflammation is directly proportional to the intensity as well as the seriousness of the antigen or injurious agent.)
In acute inflammation, exudation is very important. To have exudation there must be
· vasodilation
· Increase in blood flow
· increase in vascular permeability.
The most important of the three is increased vascular permeability.
The various types of exudates are important. Exudates can be classified.
In some mild injury and inflammation, the exudates obtained can be divided into two: -
1. Serous exudates - it is just like serum. It contains little protein, scanty or no cell at all. It is seen in mild inflammation. This can be seen in viral infections or the early stage of T.B infection.
2. Fibrinous exudates - contains a lot of fibrinogen and fibrin. There is precipitation of the protein present in the fibrinous exudates on the lungs. This is called Fibrinous pleuritis. With a pair forceps, the fibrinous exudates can be lifted up from the surface of any inflammation.
Fibrinous exudates can occur as a result of immunological disease - Rheumatic carditis in which there can be fibrinous endocarditis (Bread and Butter’ pericarditidis)
Tuberculosis (at the very early stage - fibrous pleuritis is found).
Removal of exudates in some cases could return the tissue to normal. This is called Resolution in healing and repair. This can be done by fibrinolysin, which will degrade the fibrin restoring the shiny surface of the organ.
If the fibrinolysin is not enough to lyse the fibrin. Replacement takes place. This is a step from fibrinous pleuritis to fibrous pleuritis.
Fibrinous pleuritis
ORGANIZATION
fibrous pleuritis
Fibrous tissue cannot be lifted with a pair of forceps. The organ can even be attached to another structure by the fibers.
3. Serofibrinous Exudates - example is found in T.B during the stage of Ghon’s complex. There could be purulent or suppurative exudates. A purulent exudates contains a lot of neutrophils, it is yellow in colour (yellow pus). It is found in pyogenic meningitis. In pneumonia, there is purulent exudate in the alveoli. It may extend to the pleura.
A purulent exudate can also be resolved or organized.
In Pneumonia (where there is purulent exudate in the alveoli), during resolution macrophages, neutrophils release their lysosomal enzymes and digest the exudates. The macrophages will phagocytose the particulate materials. The fluid material can either be reabsorbed into circulation or the patient coughs up the fluid.
The exudate, on the other hand, may fail to resolve. In this case they become organized i.e. the lumen of the alveoli becomes obliterated by fibrous tissue i.e. it is lost or its function impaired.
Commonly in bacteria infection what is obtained is a fibrinopurulent exudate.
4. Fibrinopurulent exudate - found in most bacteria infection (meningitis, pneumonia, appendicitis (the fibrino- purulent exudate is on the serosa of the appendix). The exude is also either resolved or organized.
Type of exudate can be used to assess severity of the injury.
Site of inflammation also determines the morphology of inflammation.
Lung
Suppose there is lung infection by a pyogenic microbe and the pyogenic material is deep in the substance of the lung, a lot of suppurative exudates are formed. Because of the severity of the injury the various alveoli will give way to form a localized collection of pus forming a lung abscess.
Similar thing happens if someone is shot with Dane gun (with a lot of dirty pellets) a deep - seated abscess is formed. The complication of the abscess is that if there is infarction of tissue there wills Gangrenous necrosis.
(Abscess is a localized collection of pus in an organ or tissue of a deep - seated pyogenic infection. The pus is enclosed by fibrous tissue. When pus is release, a cavity is formed)
Site determines extent / type of inflammation.
Suppose there is an inflammation of a mucous secreting epithelium (sinusitis). The secretion is mucus and this is called a Catarrhal inflammation - This affects a mucous secreting epithelium and in this there will be proliferation of the mucous epithelium and mucuos is produced rapidly e.g. Sinusitis.
There may be an inflammation in the colon, (or a viscous) with an excavation of the mucosa.
There is a discontinuity in the surface of the organ -Ulcerative inflammation e.g. GIT as a result peptic ulceration. It used to be chemical due to acid but it is now associated with campylobacter jejuni.
Typhoid enteritis is an example; it gives rise to an ulcerative inflammation in the small intestine. Also Amoeba histolytica in the colon causing amoebic colitis as well as tuberculosis.
Also there could be ulceration in the lower limbs with impeded blood supply to the limbs e.g. children with sickle cell, elderly people with Arteriosclerosis, the patients with Diabetes.
There are situations where a micro- organism produces a very potent toxin e.g. Diphtheria.
Diphtheria affects the trachea and bronchi. The exotoxin causes necrosis of the lining of the trachea and bronchi. There is release of a lot of protein exudate within the lumen of the trachea. The protein and necrotic tissue mix together and they cover the surface of the trachea forming a layer on the rough surface. This looks like a membrane but it is not a membrane because there is no vital tissue (no cell) in the mixture. Rather it is a pseudo-membranous inflammation. In this inflammation, there is layering of denuded membrane by a pseudo-membrane. It can be found in trachea of children in Diphtheria disease, in the alveoli of children with acute respiratory distress (Hyaline membrane) syndrome.
The same lesion in an adult is adult respiratory distress syndrome (it can be due to a lot of causes burns, acid - toxicity e.t.c). There could also be a pseudo - membranous colitis (in the colon) either as a result of bacteria infection or complications from administration antibiotics especially in Gentamycin.
The individual plays an important role in the severity of inflammation. Nutrition is very important (proteins are used to form Ig). The type of disease the patient has is important. i.e a patient with chronic debilitating infection like diabetes, advanced cancer have poor inflammatory response as the immune system is overwhelmed.
Type of microbe causing inflammation is very important.
Micro-organisms And Inflammatory Response
1.staphylocoeus aureus or Streptococcus Pyogenes
2. b Hemolytic Streptococcus
(1) Could give rise to a suppurative inflammation with the possibility of abscess formation.
On the other hand, (2) may not cause undue suppuration, it may cause a lot of stroma enzymes to be produced (collagenase, Hyaluronidase streptokinase). As long as these enzymes are produced, inflammation spreads rapidly as they destroy the basement membrane, collagen e.t.c. They cause a spreading infection called cellulitis. (“phlegmon” - old term).
(2) Viral infection - what is obtained is different
(1) And (2) above give rise to classical acute inflammation with neutrophils being predominant (3) gives rise to acute inflammation with lymphocytes being predominant.
In fungal and bacteria infections such as M. Leprae and M/tuberculosis exudate is more in the intestitium. In this group the predominant cells are macrophages and modified macrophages. In addition to these are found epitheloid cells and giant cells (modified histiocytes).
This is a Granulomatous Inflammation - predominant cells are Histocytes and modified Histocytes. (Also found in syphilis). When the histocytes and modified histocytes form a mass in an organ or a tissue, the mass is called Granuloma.
The difference between Granuloma and a granulation tissue.
Granulation tissue - mass of fibroblast, proliferating immature cells with blood vessels involved in the process of repair.
Granuloma - histocytes and modified histocytes.
Immunological injury can either involve a cell - mediated or humoral response.
Immune -complex response (classical)
Both antigens - antibody complex and other complex fragments are in the exudates on the vessel wall. This will cause activation of complements. This will attract polymorphs to the region.
This cause vasculitis. There is a fibrinoid change of vessel wall i.e. it is granular and pinkish. It is a definite morphologic pattern of immune complex injury. The adjective "fibrinoid" does not particularly mean it contains fibrin. The content includes complements, neutrophils, hemorrhage and oedema.
Local and systemic effects of Acute Inflammation
Local Effects –
These are known as cardinal signs of acute inflammation.
1.Redness (Rubor).
Flare – is as a result of opening up of the capillaries. This causes dilation and increased blood flow. Temperature of the area arises by about 10 C.
2.Heat (calor)
3.Swelling (oedema) as a result of leakage of fluid due to increased vascular permeability.
4.Direct irritation as well as compression of the nerve twitch or fiber gives pain.
5. Pain (Dolor)
6. The fifth sign is LOSS OF FUNCTION. (Functio laesa).
These are local signs of acute inflammation.
Systemic Effect
Depends on the type of inflammation - organism or agent responsible. What is common to all of them is fever (rise in body temperature). This is due to the release of chemical factors especially interleukines and prostaglandin; they cause a change in the thermostat of the hypothalamus.
Also because of the increase in metabolic rate, the patient develops an increase in heart rate - Tachycardia.
Some of the infections (bacterial) result in outpouring of neutrophils into the blood (Neutrophilia). Also some proteins appear in the blood during this period. They are called C - reactive proteins. This causes an elevation in ESR. These effects are found in classical cases. In some disorders there are variations:
Viral infection - no neutrophilia, leucocytosis with a rise in lymphocytes.
Typhoid enteritis - high fever with brady- cardia (contrary) to Tachycardia xteristic of other bacteria infection).
Salmonella - a decrease in WBC count (leucopoenia) contrary to increase in WBC count in other bacterial infections.
Oedema
DEFINITION: The accumulation of abnormal amounts of fluid in the interstitium or body cavities.
CAUSES:
Increased hydrostatic pressure
A. Impaired venous return
B. Arteriolar dilatation
Reduced oncotic pressure of plasma
A. Reduced intake
B. Increased loss
C. Decreased production
Sodium retention
A. Excessive salt intake with reduced renal function
B. Increased tubular reabsorption of sodium
Lymphatic obstruction
A. Inflammatory
B. Neoplastic
C. Post surgical
D. Post irradiation
PATHOGENESIS
Arterial end oncotic pressure venous end
35mmHg 25mmHg 15mmHg
MORPHOLOGY
Subcutaneous tissue- localised or generalised (anasarca)
Body cavities- hydrothorax or pleural effusion; hydropericardium or pericardial effusion; hydroperitoneum or ascites
Organs- pulmonary oedema, cerebral oedema; Both can be fatal.
CAUSES:
Increased hydrostatic pressure
A. Impaired venous return
B. Arteriolar dilatation
Reduced oncotic pressure of plasma
A. Reduced intake
B. Increased loss
C. Decreased production
Sodium retention
A. Excessive salt intake with reduced renal function
B. Increased tubular reabsorption of sodium
Lymphatic obstruction
A. Inflammatory
B. Neoplastic
C. Post surgical
D. Post irradiation
PATHOGENESIS
Arterial end oncotic pressure venous end
35mmHg 25mmHg 15mmHg
MORPHOLOGY
Subcutaneous tissue- localised or generalised (anasarca)
Body cavities- hydrothorax or pleural effusion; hydropericardium or pericardial effusion; hydroperitoneum or ascites
Organs- pulmonary oedema, cerebral oedema; Both can be fatal.
COR PULMONALE
Cor Pulmonale
1. Is pulmonary (left sided) HHD secondary to pulmonary hypertension induced by intrinsic disease of the lungs or pulmonary vasculature.
2. It is characterized by Left Ventricular Hypertrophy
3. Massive pulmonary embolism usually results in Chronic Cor Pulmonale
4. Acute Cor Pulmonale is a cause of sudden death
5. Systemic Hypertension can cause Cor Pulmonale
The following lung diseases can result in Cor Pulmonale
1. Chronic Obstructive Pulmonary Disease
2. Diffuse Pulmonary Interstitial Fibrosis
3. Pneumoconiosis
4. Cystic Fibrosis
5. Bronchiectasis
The following statements are true of Cor pulmonale
1. Primary Pulmonary Hypertension is a known cause
2. Kyphoscoliosis and marked obesity predispose to it
3. A nutmeg appearance of the liver is classical in acute cases
4. Haemosiderosis may be seen in the spleen
5. Severe pulmonary oedema is always present
In Chronic Cor Pulmonale these features may be present
1. Right ventricular wall thickening of >0.5cm.
2. Hypertrophied trabeculae
3. Thickened outflow tract
4. Ventricular septum bulges to the left compressing LV
5. Tricuspid regugitation
1. Is pulmonary (left sided) HHD secondary to pulmonary hypertension induced by intrinsic disease of the lungs or pulmonary vasculature.
2. It is characterized by Left Ventricular Hypertrophy
3. Massive pulmonary embolism usually results in Chronic Cor Pulmonale
4. Acute Cor Pulmonale is a cause of sudden death
5. Systemic Hypertension can cause Cor Pulmonale
The following lung diseases can result in Cor Pulmonale
1. Chronic Obstructive Pulmonary Disease
2. Diffuse Pulmonary Interstitial Fibrosis
3. Pneumoconiosis
4. Cystic Fibrosis
5. Bronchiectasis
The following statements are true of Cor pulmonale
1. Primary Pulmonary Hypertension is a known cause
2. Kyphoscoliosis and marked obesity predispose to it
3. A nutmeg appearance of the liver is classical in acute cases
4. Haemosiderosis may be seen in the spleen
5. Severe pulmonary oedema is always present
In Chronic Cor Pulmonale these features may be present
1. Right ventricular wall thickening of >0.5cm.
2. Hypertrophied trabeculae
3. Thickened outflow tract
4. Ventricular septum bulges to the left compressing LV
5. Tricuspid regugitation
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