Inflammation
Inflammation is the body's reaction or response to invasion by an infectious agent, antigen challenge or even just physical or traumatic damage to cells, tissues. A body's response to tissue damage depends on:
1) What has caused the damage?
2) Its location
3) Its severity
The word inflammation is derived from the latin word ' inflamatio' which means " to set on fire". It is a protective attempt by the body of an organism to remove the injurious stimuli as well as initiate the healing process for the tissue. In many cases, the damage caused by physical means does not involve infection. Many times inflammation is related to infection, but there lies difference between the two. Infection is caused by an exogenous organism while inflammation is the response of the organism to the pathogen. Healing of wounds is not possible in absence of inflammation.
If an infection occurs, then the body's innate system works in concert with the adaptive immune responses for limitating damage and repairing tissues. The cells of the immune system are widely distributed throughout the body, but if an infection occurs, it is necessary to concentrate them and their products at the site of infection. When pathogens breach the outer barriers of the innate immunity i.e. skin and mucous membrane, the infection and tissue injury can induce cascade of inflammatory events.
Inflammation has five main symptoms. They were described by Celsus. These symptoms are:
a) Redness (rubor): Redness at the site of the infection is caused due to increase in blood flow.
b) Swelling (tumor): Swelling is caused by accumulation of fluids at the site of infection.
c) Heat (calor): Heat is due to increase in temperature at the infected site.
d) Pain (dolors): Pain is the result of chemical release stimulating nerve endings.
The main purpose of inflammation is to bring fluid, proteins and cells from the blood into the damaged tissues. Mechanism of inflammation is necessary if damage and infection has occured because the tissues are normally bathed in extracellular lymph that lacks most of the proteins and cells that are present in the blood. Since the majority of proteins are too large to cross the blood vessels endothelium, there has to be a mechanism that allows cells and proteins to gain access to extravascular sites where and when they are needed if damage occurs.
Inflammation is classified in two groups:
1) Acute inflammation
2) Chronic inflammation
Acute inflammation:
This type of inflammation is the initial response of the body to harmful stimuli and is achieved by the increase movement of plasma and leukocytes from blood to the injured site. Acute inflammation leads to the complete elimination of pathogen followed by resolution of damage, disappearance of leukocytes from the tissue and full regeneration of tissue function.
Main features of acute inflammation:
a) Vasodilation: This occurs within minutes after tissue injury. The blood volume heats the tissue and causes it to redden.
b) Increased permeability: the vascular permeability increases which results in the leakage of fluid from blood vessels and diffusible components enters the site. this accumulates the fluid and causes swelling to tissue i.e. edema. This allows larger molecules than usual to escape from capillaries and thus allow soluble mediators of immunity to reach the site of inflammation.
c) Extravasation: If there has been a sufficient damage to the tissue or an infection occurs, the acute cellular response follows over the next few hours. Within this phase, leukocytes attach to the endothelial cells within the blood vessels in the inflammated region and pass through the walls of capillaries and into the tissue spaces and reach the infected area. These leukocytes phagocytose invading pathogen and release molecular mediators that tribute to the inflammatory response.
d) Sensitivity to pain: Some of the released mediators such as bradykinin increase the sensitivity to pain.
e) If vessel is damage, fibrinogen and fibronectin are deposited at the site of injury, platelets aggregate and becomes activated and the red cells stack together to help stop bleeding and aid clot formation. The dead and dying cells contribute pus formation.
f) The mononuclear cell infiltrate composed of macrophages and lymphocytes appear. The macrophages are involved in microbial killing, clearing up cellular and tissue debris and remodelling of tissue.
g) Over the next few weeks, resolution may occur i.e. the normal tissue architecture is restored. blood clot are removed by fibrinolysis.
Systems involved in inflammation:
During acute inflammation, when the fluid exudes from the blood stream, three systems get activated:-
1) kinin system:
The kinin system is an enzymatic cascade. They are liberated from precursor molecule kininogens by action of various protease. The system is activated when the plasma clotting factor, called Haegman factor is activate following tissue injury. Haegman factor together with kallikrein is bound to the high molecular weight kininogen and negatively charged surface before exposure to tissue damage. these factors then activates prekallikrein to form kallikrein, which are generated by enzymes released from damaged tissue. Kallikrein cleaves high molecular weight kininogens to produce bradykinin and lysyl bradykinin is released by cleavage of low molecular weight kininogens. In lysyl bradykinin formation, various tissue and enzyme activates prekallikrein to kallikrein. This kallikrein increases vascular permeability, causes vasodilation, induces pain and triggers contraction of smooth muscles.
2) Clotting system:
The clotting system is triggered very rapidly after the tissue injury to prevent bleeding and limit the spread of invading pathogen in the bloodstream. This system triggered by the interaction of P-selectin, a cell adhesion molecule and P selectin glycoprotein ligand -1(PSGL-1), a glycoprotein which binds to P-selectin, accompanied by the release of tissue factor from the activated monocytes. Thrombin acts as a soluble fibrinogen in tissue fluid or plasma to produce insoluble strands of fibrin and fibrinopeptide. Fibrin is a monomer which polymerize spontaneously to form insoluble gel.The insoluble fibrin stands then crisscross each other i.e. they aggregates together with aggregated platelets to block the damaged blood vessel and prevent further bleeding.
Fibrinopeptides acts as inflammatory mediators, inducing increased vascular permeability. Activated platelets release CD40L, a protein, which leads to increased production of proinflammatory cytokines IL6, IL8, and increased expression of cell adhesion molecules.
3) Fibrinolytic system:
Removal of fibrin clot from the injured tissue is achieved by fibrinolytic system. removal of clot is called as fibrinolysis.
Fibrinolytic system yields plasmin generated mediators of inflammation. Plasmin is a proteolytic enzyme which is formed by the activation of plasminogen by plasma or tissue activators, mainly urokinase. Triggering of fibrinolysis occurs when plasminogen, its activators and fibrin are in close proximity. Both plasminogen and plasminogen activators are bind avidly to fibrin as the clot forms. This close association prevents the inhibition of plasmin activity by the inhibitors. The plasmin breaks down the fibrin clot into degradation products which are chemotactic for neutrophils. Many of the vascular changes are induced by this system. Some changes are due to to mediators like histamine, serotonin. histamine is a mediator and causes vasodilation. It is stored in basophils and mast cells and they are chemotactic for eosinophils. Serotonin is stored in platelets.
Various cells involved in Inflammation:
Within a few hours of onset of these vascular changes, neutrophils adhere to the endothelial cells and migrate out of the blood in the tissue spaces. They are generally the first cell type to bind to the inflammed endothelium and extravasate into the tissue. When endothelial becomes becomes inflammed, P selectin is released and becomes available at the cell surface for binding to neutrophils. neutrophils express L selectin and PSGL-1, both cell adhesion molecules to mediate the rolling on the inflammed endothelium. E and P selectin binds to PSGL-1 present on neutrophils. This interaction teethers the neutrophils briefly to the endothelial cell, but the shearing force of the blood flow soon detaches the cell. Selectin molecules on endothelial cells again teether the leukocyte. this process is repeated so that the cell tumbles end over end along the endothelium. this type of binding is called as rolling.
As the neutrophils rolls, it is activated by various chemoattractants. These are either permanent features of endotheliul cells or secreated locally by cells involbed in the inflammatory response. The most common chemoattractant for neutrophils are chemokines. They represent a superfamily of 30 chemotactic cytokines acting as vital initiators of inflammatory reactions. The process of rolling down slows the cell long enough to allow interactions between chemokines presented on the surface of the endothelium and receptors on the leukocytes.
Interleukin8 (IL8) and monocyte chemotactic protein (MCP1) are more widely produced and they represent the first line of defence. IL-8 are produced in glomeruli. They have two binding sites, one for their specific receptors expressed on the surface of leukocytes and a second for the carbohydrate groups, which allows them to attach to surface of endothelium. Binding of these chemoattractants triggers an activating signal mediated by G proteins. This signal induces a confirmation change in the integrin molecules in the neutrophils membrane increasing their affinity for immunoglobulin super family adhesion molecules (ICAM's) on endothelium. integrins clustering on the leukocytes allows the cell to bind more tightly to the endothelium.
The neutrophils then squezzes between two neighbouring endothelial cells without disrupting the integrity of endothelial barrier.
Chronic Inflammation:
This type of inflammation has a slow onset and persists for weeks. In this case infection is not cleared completely. Most pathogenic organism have developed system to detect the immune response that would eliminate them. In that case body often tries to contain the persistent infection or minimize damage it causes.
The main cells involved in chronic inflammation are macrophages and lymphocytes. The activation of B-lymphocytes produces plasma cells, which manufacture and secreate antibodies to fight specific type of antigens. Eosinophils are also involved in chronic inflammation. They contain a substance called as major basic protein whic destroys certain antigens. A key feature of chronic inflammation is collagen formation. Connective tissues enter the area of tissue injury and produce collagen which is necesary to replace the tissue lost during long term inflammation.
Termination of inflammation:
The inflammation is terminated when it is no longer needed. The short half life of the inflammatory terminators helps in intrinsic termination of inflammation. After the entering tissues, granulocytes switch of prostaglandins and leukotrines to lipoxins, which initiate termination sequence. This ceases neutrophil recruitment and apoptosis is engagged. Consequently apoptopic neutrophils undergo phagocytosis leading to neutrophil clearance. This releases anti inflamatory cytokines resulting in the departure of macrophages through the lymphatics.
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