Platelet Activating Factor (PAF)

PLATELET ACTIVATING FACTOR (PAF)

Like eicosanoids, platelet activating factor (PAF) is a cell membrane derived polar lipid with intense biological activity; discovered in 1970s and now recognized to be an important signal molecule. PAF is acetyl glyceryl etherphosphoryl choline.

Synthesis And Degradation

PAF is synthesized from precursor phospholipids present in cell membrane by the following reactions:

The second step is rate limiting. Antigen-antibody reaction and a variety of mediators stimulate PAF synthesis in a Ca2+ dependent manner on demand: there are no preformed stores of PAF. In contrast to eicosanoids, the types of cells which synthesize PAF is quite limited—mainly WBC, platelets, vascular endothelium and kidney cells.

PAF is degraded in the following manner:

Actions     

PAF has potent actions on many tissues/organs.

Platelets Aggregation and release reaction; also releases TXA₂; i.v. injection results in intravascular thrombosis.

WBC PAF is chemotactic to neutrophils, eosinophils and monocytes. It stimulates neutrophils to aggregate, to stick to vascular endothelium and migrate across it to the site of infection. It also prompts release of lysosomal enzymes and LTs and generation of superoxide radical by the polymorphs. The chemotactic action may be mediated through release of LTB₄. It induces degranulation of eosinophils.

Blood Vessels Vasodilatation mediated by release of EDRF occurs → fall in BP on i.v. injection. Decreased coronary blood flow has been observed on intracoronary injection, probably due to formation of platelet aggregates and release of TXA₂.

PAF is the most potent agent known to increase vascular permeability. Wheal and flare occur at the site of intradermal injection.

Injected into the renal artery PAF reduces renal blood flow and Na+ excretion by direct vasoconstrictor action, but this is partly counteracted by local PG release.

Visceral Smooth Muscle Contraction occurs by direct action as well as through release of LTC₄, TXA₂ and PGs. Aerosolized PAF is a potent bronchoconstrictor. In addition, it produces mucosal edema, secretion and a delayed and longlasting bronchial hyperresponsiveness. It also stimulates intestinal and uterine smooth muscle.

Stomach PAF is ulcerogenic: erosions and mucosal bleeding occur shortly after i.v. injection of PAF. The gastric smooth muscle contracts.

Mechanism Of Action

Membrane bound specific PAF receptors have been identified. The PAF receptor is a Gprotein coupled receptor which exerts most of the actions through intracellular messengers IP₃/DAG → Ca2+ release.

As mentioned above, many actions of PAF are mediated/augmented by PGs, TXA₂ and LTs which may be considered its extracellular messengers. PAF also acts intracellularly, especially in the endothelial cells; rise in PAF concentration within the endothelial cells is associated with exposure of neutrophil binding sites on their surface. Similarly, its pro-aggregatory action involves unmasking of fibrinogen binding sites on the surface of platelets.

PAF Antagonists

A number of natural and synthetic PAF receptor antagonists have been investigated. Important among these are ginkgolide B (from a Chinese plant), and some structural analogues of PAF. The PAF antagonists have many fold therapeutic potentials like treatment of stroke, intermittent claudication, sepsis, myocardial infarction, shock, g.i. ulceration, asthma and as contraceptive. Some of them have been tried clinically but none has been found worth marketing. Alprazolam and triazolam antagonize some actions of PAF.

Pathophysiological Roles

PAF has been implicated in many physiological processes and pathological states, especially those involving cell to cell interaction. These are:

1. Inflammation: Generated by leukocytes at the site of inflammation PAF appears to participate in the causation of vasodilatation, exudation, cellular infiltration and hyperalgesia.

2. Bronchial asthma: Along with LTC₄ and LTD₄, PAF appears to play a major role by causing bronchoconstriction, mucosal edema and secretions. It is unique in producing prolonged airway hyperreactivity, so typical of bronchial asthma patient.

3. Anaphylactic (and other) shock conditions: are associated with high circulating PAF levels.

4. Haemostasis and thrombosis: PAF may participate by promoting platelet aggregation.

5. Rupture of mature graafian follicle and implantation: Early embryos which produce PAF have greater chance of implanting. However, PAF is not essential for reproduction.

6. Ischaemic states of brain, heart and g.i.t., including g.i. ulceration.