Describe the degeneration of arachidonic acid metabolites and their role in inflammation.

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid present in membrane phospholipids and stimulate vascular and cellular reactions in acute inflammation.

Arachidonic acid is a 20 carbon polyunsaturated fatty acid that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid.

Arachidonic acid derived mediators are synthesized by two major classes of enzymes

1. Cyclooxygenases
2. Lipooxygenases

Cyclooxygenase pathway:

Arachidonic acid - Prostaglandin G2 - Prostaglandin H2 - Prostacyclin PGI2, Thrombaxane A2 - PGD2 - PGE2.

Lipooxygenase pathway:

5HPETE - Leukotriene A4 -  Leukotriene C4 - Leukotriene D4, Leukotriene E4 and Lipoxin A4 and Lipoxin B4

Principal actions of arachidonic acid metabolites in inflammation:

1. Vasodilation - PGI2, PGE1, PGE2, PGD2
2. Vasoconstriction - Thromboxane A2, Leukotrienes C4, D4, E4
3. Increased vascular permeability - Leukotrienes C4, D4, E4
4. Chemotaxis, leukocyte adhesion - Leukotrienes B4

Short note on Chemokines.

Chemokines are a family of small proteins that act primarily as chemoattractants for specific types of leukocytes.
They are classified into four major groups according to the arrangement of cysteine (C) residues in the proteins.

1. C-X-C Chemokines - have one amino acid residue separating the first two of the four conserved cysteine residues.
2. C-C Chemokines - has first two conserved cysteine residues adjacent.
3. C Chemokines - lack the first and third of the four conserved cysteines.
4. CX3C Chemokines - Contain three amino acids between the two cysteines.

Chemokines have two main functions:

1. In acute inflammation - Chemokines stimulate leukocyte attachment to endothelium and they stimulate migration of leukocytes in tissues to the site of infection or tissue damage.
2. Maintanance of tissue architecture - Some chemokines are produced constitutively in tissues and are sometimes called homeostatic chemokines.

State the consequences of complement activation.

The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions.
The critical step in complement activation is the proteolysis of the third complement, C3. Cleavage of C3 can occur by one of three pathways.

1. The classical pathway - Triggered by fixation of C1 to antibody antigen complex.
2. The alternative pathway - Triggered by microbial surface molecules.
3. The lectin pathway - In which plasma mannose binding lectin binds to carbohydrates on microbes and directly activates C1.

The complement system has three main functions:

1. Inflammation - C3a, C5a and to a lesser extent C4a.
2. Opsonization and phagocytosis - C3b and iC3b acts as opsonins.
3. Cell lysis - The deposition of the MAC on cells makes these cells permeable to water and ions and results in death of the cells.