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 <===è ( 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.