INFLAMMATION AND REPAIR

InflammationOverview of Inflammation Inflammation is a protective response, designed to rid

the organism of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues)

it can sometimes be inappropriately triggered or poorly controlled, and is thus the cause of tissue injury in many disorders.

Inflammation is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes

may be acute or chronic is terminated when the offending agent is eliminated

Acute InflammationAcute inflammation is a rapid host

response that serves to deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or

tissue injury

Figure: major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth); (2) extravasation and extravascular deposition of plasma fluid and proteins (edema); (3) leukocyte emigration and accumulation in the site of injury.

Local manifestations of acute inflammation:

1. Vascular dilation and increased blood flow (causing erythema and

warmth);2. Extravasation and extravascular

deposition of plasma fluid and proteins (edema);

3. Leukocyte emigration and accumulation in the site of injury

STIMULI FOR ACUTE INFLAMMATION

Infections (bacterial, viral, fungal, parasitic) and microbial toxins

Tissue necrosis from any cause, including ischemia

Foreign bodies (splinters, dirt, sutures) Immune reactions (also called

hypersensitivity reactions)

REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION

Changes in Vascular Flow and CaliberVasodilation &

increased blood flow

increased permeability of

the microvasculatur

e

outpouring of protein-rich fluid into the extravascular

tissues

stasis: vascular congestion (producing localized redness)

Increased Vascular Permeability (Vascular Leakage)

REACTIONS OF LEUKOCYTES IN INFLAMMATION

A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents

Most important leukocytes in inflammation are the ones capable of phagocytosis, namely neutrophils and macrophages

These leukocytes ingest and kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances.

Leukocytes also produce growth factors that aid in repair.

Downside: may also injure normal host tissues

Processes involving leukocytes in inflammation

Processes involving leukocytes1. Recruitment of Leukocytes from the blood into

extravascular tissues (Sites of Infection and Injury)

2. Recognition of microbes and necrotic tissues3. Removal of the offending agent

Processes involving leukocytes in inflammation

Recruitment of Leukocytes

Leukocyte activation (Recognition of Microbes and Dead Tissues)

Removal of the Offending Agents

Vascular endothelium is

activated and can bind leukocytes

Migration of leukocytes across the

endothelium and vessel wall

Migration of leukocytes in the tissues toward a

chemotactic stimulus

Recognition of the offending agents,

which deliver signals

Activate the leukocytes to ingest

and destroy the offending agents and

amplify the inflammatory

reaction

Phagocytosis and intracellular killing

The journey of leukocytes from the vessel lumen to the interstitial tissue is called extravasation. Extravasation can be divided into the following steps:

i. In the lumen: In normally flowing blood in venules, red cells are confined to a central axial column, displacing the leukocytes toward the wall of the vessel. Because blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called margination. Subsequently, individual and then rows of leukocytes adhere transiently to the endothelium, detach and bind again, thus rolling on the vessel wall. The cells finally come to rest at some point where they adhere firmly.

Extravasation

ii. Migration across the endothelium and vessel wall (transmigration or diapedesis): Chemokines act on the adherent leukocytes and stimulate the cells to migrate through inter endothelial spaces toward the chemical concentration gradient, that is, toward the site of injury or infection where the chemokines are being produced.

iii. Migration in the tissues toward a chemotactic stimulus: After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by a process called chemotaxis. Both exogenous and endogenous substances can act as chemoattractants. The most common exogenous agents are bacterial products. Endogenous chemoattractants include several chemical mediators such as cytokines.

Extravasation (contd.)

Fig: The multistep process of leukocyte migration through blood vessels

Phagocytosis

Engulfment of microorganisms or other cells and foreign particles by phagocytes is called phagocytosis. Phagocytosis involves three sequential steps:

1. Recognition and attachment: Phargocytosis of microbes and dead cells is initiated by recognition of the particles by receptors expressed on the leukocyte surface. Mannose receptors and scavenger receptors are two important macrophage receptors that recognize, bind and ingest microbes.

2. Engulfment: During engulfment, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosome.

3. Killing and Degradation: Microbial killing is accomplished largely by oxygen dependent mechanism. Microbial killing can also occur through the action of other substances in leukocyte granules.

Phagocytosis (contd.)

Figure: process of phagocytosis

Chronic InflammationChronic inflammation is inflammation of

prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations.

Causes: Persistent infections (certain viruses,

fungi, and parasites) Immune-mediated inflammatory

diseases Prolonged exposure to potentially toxic

agents