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Inflammation: Vascular events and leukocyte migration

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INFLAMMATION: INTRODUCTION, VASCULAR EVENTS & LEUKOCYTE MIGRATION

Author: Sanketh DS, MDS

INTRODUCTION

Inflammation is fundamentally, a protective response of the body against any offending agent or tissue damage. It involves responses of the vascular tissues and leukocytes which help in getting rid of the primary cause of insult and necrotic cells or tissues resulting as a consequence of the insult.

Inflammation could be acute or chronic depending on the duration of the response. Acute inflammation is a rapid response, developing within minutes and could last up to a few hours to days. If the insult or damage is not repaired by the acute response, the inflammatory response could become prolonged thus becoming chronic. Chronic inflammation could go on for few weeks to many months.

CAUSE

Inflammation could be caused by multiple factors ranging from external agents like microbes, drugs and allergens, physical agents like temperature, any form of mechanical injury and other factors like genetic and immunologic disorders. Tissue necrosis due to ischemia, mechanical or chemical injury could also induce inflammation.

CARDINAL SIGNS OF INFLAMMATION

There are 5 cardinal signs of inflammation, which actually are a macro-level or an external manifestation of the microscopic events happening during inflammation. Inflammation kick starts with vasodilation of arterioles and capillaries near the site of tissue insult and this leads to “RUBOR” or redness. Vasodilation results in increased blood flow causing “CALOR” or heat. Leakage of plasma fluids from the vessels and accumulation in the extra-vascular space causes “TUMOR” or swelling. Chemical mediators of inflammation like histamine and prostaglandins released by mast cells and leukocytes may cause “DOLOR” or pain. Swelling and pain may cause loss of function, of the tissue involved and is called “FUNCTIO LAESA” or loss of function.

VASCULAR EVENTS

An inflammatory response begins with an insult which could be exogenous or endogenous. Any form of insult causes cell damage and damaged cells release certain molecules are called “Damage Associated Molecular Patterns (DAMPs)”. These molecules are recognized by receptors on leukocytes like macrophages or dendritic cells. On recognition leukocytes release pro-inflammatory cytokines.

Similarly microbes have specific molecules called “Pathogen Associated Molecular Patterns (PAMPs)” which could be recognized by receptors on leukocytes. On recognition leukocytes release pro-inflammatory cytokines and also other cytokines that help lymphocyte activation. Now, pro-inflammatory cytokines could cause de-granulation of nearby mast cells. De-granulation results in release of inflammatory mediators like histamine, prostaglandins, leukotrienes and more pro-inflammatory cytokines. This cascade of events kick starts an acute inflammatory process.

1) Acute inflammation begins with vasodilation of arterioles and capillaries. Vasodilation could be caused by histamine, leukotrienes and prostaglandins.
2) This is followed by an increased vascular permeability. Histamine and leukotrienes can cause retraction of the endothelial cells in the vessels creating small gaps. Plasma proteins leak out of the blood vessel through these gaps and accumulate in the extra-vascular space causing oedema. This plasma rich fluid leaking out of the vessel is called an exudate.
3) Leakage of plasma proteins disturbs the axial flow of blood.  It increases blood viscosity thereby slowing down or causing stasis of blood flow. This results in red blood cells getting concentrated at the centre with leukocytes being pushed to the periphery near the vessel wall.

LEUKOCYTE RECRUITMENT

Acute inflammation serves to recruit leukocytes to the site of infection or injury in order to eliminate the offending agents and damaged tissue. Neutrophils and monocytes are key leukocytes that are recruited and are capable of phagocytosis. However in acute inflammation, neutrophils are the first batch of leukocytes to be recruited to the site of infection. Migration of monocytes follows many hours later. Leukocyte recruitment to the site of infection involves a series of steps.

1) Once the blood flow slows down, leukocytes are pushed to the periphery and move along in close association to the endothelium. This is called margination.
2) Pro-inflammatory cytokines like IL-1 and TNF-α released by macrophages and mast cells cause endothelial cells and leukocytes to express what are called adhesion molecules. Adhesion molecules on the endothelium are called selectins and those on leukocytes are called sialyl Lewis X proteins. Sialyl Lewis X proteins bind with selectins causing leukocytes to slow down and tumble along the endothelium. This is called “Rolling”.
3) Rolling and slowing down, helps leukocytes firmly adhere to the endothelium. This is accomplished by binding of surface proteins on leukocytes called integrins to adhesion molecules on the endothelium called, VCAM – vascular cell adhesion molecule. Again, expression of VCAMs on the endothelium are induced by pro-inflammatory cytokines IL-1 and TNF-α.
4) The next step involves the transmigration of adherent leukocytes through the endothelial gaps. This process called diapedesis is induced by chemokines.
5) Once in the extravascular space, leukocytes migrate towards the site of infection along a concentration gradient, a process called chemotaxis. Chemotaxis is induced by a variety of chemokines produced by mast cells, complement proteins and the microbes themselves. Examples of chemokines are IL-8, LTB4 and complement proteins like C5a.

Neutrophils predominate in the site of infection for the first 6-24 hours followed by monocytes getting into action post 24-48 hours. After recruitment to the site of infection leukocytes recognize microbes or dead cells and kill them by a process called phagocytosis

REFERENCES

Robbins and Cotran, Pathologic Basis of Disease. Kumar, Abbas, Fausto, Aster. 8th Edition.

Kumar, Abbas, Fausto, Aster JC. Robbins Basic Pathology. 10th ed.Elsevier; 2018.

Abbas AK, Litchman AH, Pillai S. Cellular and Molecular Immunology. Abbas, Litchman, Pillai. 8th Edition.Saunders;2015.

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