FACTOR

In 1971, HENSON demonstrated that a soluble factor released from leukocytes

caused platelets to aggregate.

BENVENISTE and his coworkers characterized the factor as a polar lipid and

named it platelet-activating factor.

During this period, MUIRHEAD described an antihypertensive polar renal lipid

(APRL) produced by interstitial cells of the renal medulla that proved to be

identical to PAF.

HANAHAN & COWORKERS then synthesized acetyl-glyceryl-ether-

phosphoryl-choline. (AGEPC) and determined that this phospholipid had

chemical and biological properties identical with those of PAF.

Independent determination of the structures of PAF and APRL showed them

to be structurally identical to AGEPC.

The commonly accepted name for this substance is platelet-activating factor

(PAF); however, its actions extend far beyond platelets.

PAF is 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine.

PAF contains a long-chain alkyl group joined to the glycerol backbone in an ether

linkage at position 1 and an acetyl group at position 2.

PAF actually represents a family of phospholipids because the alkyl group at

position 1 can vary in length from 12 to 18 carbon atoms.

In human neutrophils, PAF consists predominantly of a mixture of the 16- and 18-

carbon ethers, but its composition may change when cells are stimulated.

PAF is synthesized by platelets, neutrophils, monocytes, mast cells, eosinophils, renal

mesangial cells, renal medullary cells, and vascular endothelial cells.

The major pathway by which PAF is generated involves the precursor 1-O-alkyl-2-

acyl-glycerophosphocholine.

PAF is synthesized from this substrate in two steps .

1) Involves the action of phospholipase A2, with the formation of 1-O-alkyl-2-

lyso-glycerophosphocholine (lyso-PAF) and a free fatty acid (usually AA) .

Eicosanoid and PAF biosynthesis thus is closely coupled, and deletion of cPLA2

in mice leads to an almost complete loss of both prostanoid and PAF generation.

2) The second, rate-limiting step is performed by the acetyl coenzyme-A-lyso-PAF

acetyltransferase.

PAF synthesis also can occur de novo;

a phosphocholine substituent is transferred to alkyl acetyl glycerol by a distinct

lysoglycerophosphate acetylcoenzyme-A transferase.

This pathway may contribute to physiological levels of PAF for normal cellular

functions.

The synthesis of PAF may be stimulated during antigen–antibody reactions or by

a variety of agents, including chemotactic peptides, thrombin, collagen, and other

autacoids.

PAF also can stimulate its own formation. Both the phospholipase and

acetyltransferase are Ca2+-dependent enzymes; thus, PAF synthesis is regulated

by the availability of Ca2+.

The inactivation of PAF also occurs in two steps .

1) Initially, the acetyl group of PAF is removed by PAF acetyl hydrolase to form

lyso-PAF

2) Lyso-PAF is then converted to a 1-O-alkyl-2-acyl-glycerophosphocholine by an

acyltransferase.

In addition to these enzymatic routes. Paf-like molecules can be formed from the oxidative

fragmentation of membrane phospholipids (oxpls) .

These compounds are increased in settings of oxidant stress such as cigarette smoking.

They differ structurally from PAF in that they contain a fatty acid at the sn-1 position of

glycerol joined through an ester bond and various short-chain acyl groups at the sn-2

position.

Oxpls mimic the structure of paf closely enough to bind to its receptor and elicit the same

responses.

Unlike the synthesis of paf, which is highly controlled, oxpl production is unregulated;

degradation by paf acetyl hydrolase, therefore, is necessary to suppress the toxicity of

oxpls.

Levels of paf acetyl hydrolase (also known as lipoprotein-associated phospholipase a2)

are increased in colon cancer, cardiovascular disease & stroke.

Polymorphisms have been associated with altered risk of cardiovascular events.

Extracellular PAF exerts its actions by stimulating a specific GPCR that is expressed in

numerous cell types.

The PAF receptor's strict recognition requirements, including a specific head group and

specific atypical sn-2 residue, also are met by oxPLs.

The PAF receptor couples with Gq to activate the PLC–IP3–Ca2+ pathway and

phospholipases A2 and D such that AA is mobilized from diacylglycerol, resulting in the

synthesis of PGs, TxA2, or LTs, which may function as extracellular mediators of the

effects of PAF.

PAF also may exert actions without leaving its cell of origin.

For example, PAF is synthesized in a regulated fashion by endothelial cells stimulated by

inflammatory mediators.

This PAF is presented on the surface of the endothelium, where it activates the

PAF receptor on juxtaposed cells, including platelets, polymorphonuclear

leukocytes, and monocytes, and acts co-operatively with P-selectin to promote

adhesion.

Endothelial cells under oxidant stress release oxPLs, which activate leukocytes

and platelets and can spread tissue damage.

CVS

PAF is a potent dilator in most vascular beds; when administered intravenously,

it causes hypotension in all species studied.

PAF-induced vasodilation is independent of effects on sympathetic innervation,

the renin–angiotensin system, or arachidonate metabolism and likely results

from a combination of direct and indirect actions.

PAF induces vasoconstriction or vasodilation depending on the concentration,

vascular bed, and involvement of platelets or leukocytes.

For example, the intracoronary administration of very low concentrations of

PAF increases coronary blood flow by a mechanism that involves the release of

a platelet-derived vasodilator.

Coronary blood flow is decreased at higher doses by the formation of

intravascular aggregates of platelets and/or the formation of TXA2.

The pulmonary vasculature is also constricted by PAF and a similar mechanism is

thought to be involved.

Intradermal injection of PAF causes an initial vasoconstriction followed by a

typical wheal and flare.

PAF increases vascular permeability and edema in the same manner as histamine

and bradykinin. but PAF is more potent than histamine or bradykinin by three

orders of magnitude.

Platelets

PAF potently stimulates platelet aggregation in vitro.

While this is accompanied by the release of TxA2 and the granular contents of the

platelet, PAF does not require the presence of TxA2 or other aggregating agents

to produce this effect.

The intravenous injection of PAF causes formation of intravascular platelet

aggregates and thrombocytopenia.

Leukocytes PAF stimulates polymorphonuclear leukocytes to aggregate, to release LTs and

lysosomal enzymes and to generate superoxide.

Since LTB4 is more potent in inducing leukocyte aggregation, it may mediate the

aggregatory effects of PAF.

PAF also promotes aggregation of monocytes and degranulation of eosinophils. It

is chemotactic for eosinophils, neutrophils, and monocytes and promotes

endothelial adherence and diapedesis of neutrophils.

When given systemically,PAF causes leukocytopenia, with neutrophils showing

the greatest decline.

Intradermal injection causes the accumulation of neutrophils and mononuclear

cells at the site of injection.

Inhaled PAF increases the infiltration of eosinophils into the airways.

Smooth Muscle PAF generally contracts gastrointestinal, uterine, and pulmonary smooth muscle.

PAF enhances the amplitude of spontaneous uterine contractions; quiescent

muscle contracts rapidly in a phasic fashion.

These contractions are inhibited by inhibitors of PG synthesis.

PAF does not affect tracheal smooth muscle but contracts airway smooth

muscle. Most evidence suggests that another autacoid (e.g., LTC4 or TxA2)

mediates this effect of PAF.

When given by aerosol, PAF increases airway resistance as well as the

responsiveness to other bronchoconstrictors.

PAF also increases mucus secretion and the permeability of pulmonary

microvessels; this results in fluid accumulation in the mucosal and submucosal

regions of the bronchi and trachea.

Kidney

When infused intrarenally in animals, PAF decreases renal blood flow, glomerular

filtration rate, urine volume, and excretion of Na+ without changes in systemic

hemodynamics

These effects are the result of a direct action on the renal circulation.

PAF exerts a receptor-mediated biphasic effect on afferent arterioles, dilating

them at low concentrations and constricting them at higher concentrations.

The vasoconstrictor effect appears to be mediated, at least in part, by COX

products, whereas vasodilation is a consequence of the stimulation of NO

production by endothelium.

Stomach

In addition to contracting the fundus of the stomach, PAF is the most potent

known ulcerogen.

When given intravenously, it causes hemorrhagic erosions of the gastric mucosa

that extend into the submucosa.

PAF generally is viewed as a mediator of pathological events.

Dysregulation of PAF signaling or degradation has been associated with somehuman diseases, aided by data from genetically modified animals.

Platelets

Since PAF is synthesized by platelets and promotes aggregation, it was proposedas the mediator of cyclooxygenase inhibitor–resistant, thrombin-inducedaggregation.

However, PAF antagonists fail to block thrombin-induced aggregation, eventhough they prolong bleeding time and prevent thrombus formation in someexperimental models.

Thus, PAF does not function as an independent mediator of platelet aggregationbut contributes to thrombus formation in a manner analogous to TxA2 and ADP.

INFLAMMATORY AND ALLERGIC RESPONSES

The proinflammatory actions of PAF and its elaboration by endothelial cells,leukocytes, and mast cells under inflammatory conditions are well characterized.

PAF and PAF-like molecules are thought to contribute to the pathophysiology ofinflammatory disorders, including anaphylaxis, bronchial asthma, endotoxic shock,and skin diseases.

The plasma concentration of PAF is increased in experimental anaphylactic shock,and the administration of PAF reproduces many of its signs and symptoms,suggesting a role for the autacoid in anaphylactic shock.

In addition, mice overexpressing the PAF receptor exhibit bronchial hyperreactivityand increased lethality when treated with endotoxin.

PAF receptor knockout mice display milder anaphylactic responses to exogenousantigen challenge, including less cardiac instability, airway constriction, andalveolar edema; they are, however, still susceptible to endotoxic shock.

Despite the broad implications of these observations, the effects of PAF

antagonists in the treatment of inflammatory and allergic disorders have been

disappointing.

Although PAF antagonists reverse the bronchoconstriction of anaphylactic

shock and improve survival in animal models, the impact of these agents on

animal models of asthma and inflammation is marginal.

Similarly, in patients with asthma, PAF antagonists partially inhibit the

bronchoconstriction induced by antigen challenge but not by challenges by

methacholine, exercise, or inhalation of cold air.

These results may reflect the complexity of these pathological conditions and the

likelihood that other mediators contribute to the inflammation associated with

these disorders.