Chemical Mediators of Inflammation

Chemical Mediators of Inflammation

Dr. Raid Jastania

Chemical Mediators of Inflammation

• Mediators can be plasma proteins, typically synthesized in the liver and released to the circulation in an inactive form. complement system, Kinins, and coagulation factors.

• Mediators can be produced by cells (WBC, endothelial cells, fibroblast). This include arachidonic acid metabolites, cytokines and vasoactive amines.

Chemical Mediators of Inflammation

• List of chemical mediators:– Vasoactive amines (eg. histamine)– Plasma proteases (Kinins, Clotting factors,

Complement system)– Arachidonic Acid metabolites (PG,

Leukotrienes)– Cytokines (Interleukins, chemokines)

Chemical Mediators of Inflammation

• act on specific receptor on cell surface. • may induce the production other mediators. • may act by autocrine, paracrine, or

endocrine fashion. • may act on one cell type or many cell types.• tightly regulated by their short half-life and

by inhibitors.• Mediators may have harmful effect

Chemical Mediators of Inflammation

• Histamine:– Source: mast cells– Action: vasodilation and increase

vascular permeability by endothelial contraction.

– Stimuli: trauma, heat, IgE reaction, C3a, C5a (anaphylatoxins), IL-1, IL-8

Chemical Mediators of Inflammation

• Arachidonic Acid metabolites:– Source: phospholipid of cells by the

action of Phospholipase A2.– Stimuli: physical, chemical injury, C5a– 2 pathways: • 1.      Cyclooxygenase: produce

prostaglandins PG, action: vascular changes, pain, platelet function

• 2.      Lipoxygenase: produce Leukotrienes, eg. LTB4 act as chemotactic agent

Chemical Mediators of Inflammation

• Arachidonic Acid metabolites:– Aspirin and NSAID’s inhibit

cyclooxygenase activity and result in decrease in PG production and control of pain and fever.

– Steroids inhibit Phospholipase A2, and hence all arachidonic acid metabolites.

Chemical Mediators of Inflammation

• Cytokines: IL-1, and TNF:– Source: macrophages– Stimuli: injury, immune complex, other

mediators– Action: activation of endothelial cells,

neutrophils and fibroblasts, They have systemic effect as well.

Chemical Mediators of Inflammation

• Cytokines: IL-1, and TNF:– IL-1 and TNF act on the thermoregulatory center

in the hypothalamus and induce the production of PGE and result in Fever.

– They also enhance the release of WBC’s from the bone marrow and result in Leukocytosis (15,000-20,000 per microliter).

– They also induce the bone marrow to produce WBC’s.

– IL-6 acts on the liver to increase the production of complement components and coagulation factors.

Morphologic Patterns of Inflammation

• Serous Inflammation• Fibrinous Inflammation• Suppurative Inflammation• Ulceration

Morphologic Patterns of Inflammation

• Serous Inflammation:• abundant watery effusion fluid

(exude/transudate). • Serous inflammation commonly occurs in

the serosal surfaces (peritoneum, pericardium, pleura).

• Examples: peritonitis, pericarditis, pleuritis, skin burn, viral infections.

Morphologic Patterns of Inflammation

• Fibrinous Inflammation:• severe injury to the vessels. • Example: trauma, bacterial infections. • excessive blood clotting and fibrin• organization, • may lead to fibrous adhesions. Example:

restrictive pericarditis, fibrous adhesion in the peritoneum.

Morphologic Patterns of Inflammation

• Suppurative Inflammation:• pus accumulation (neutrophils,

exudate fluid and cellular debris) • typical in bacterial infections eg.

staph infection of skin• may lead to abscess formation.

Morphologic Patterns of Inflammation

• Ulceration:• Ulcer can be acute or chronic. • Ulceration is necrosis of the epithelial

surface (of skin, GIT, respiratory, urogenital tract) with underlying inflammation (acute or chronic).

• Peptic ulcer is a typical example. • Ulcer may result from physical or

chemical injury, or ischemic necrosis.

Defect in Leukocyte Function

1. Defect in adhesion: – Leukocyte adhesion deficiency-1 (LAD-1) is a defect in

the integrin LFA-1– Leukocyte adhesion deficiency-2 (LAD-2) is due to

absence of sialyl-Lewis X.2. Defect in microbial killing:

– Chronic granulomatous disease results from defect in oxidative burst function.

3. Defect in phagolysosome formation– Chediak-Higashi syndrome result from impaired

lysosomal degranulation.

Home work

• Exercise• Case discussion