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paf

Platelet activating factor

Introduction:

  • A soluble substance demonstrated to be released from leukocytes which caused platelet aggreg. (1971), which was confirmed & named PAF;
  • Also at this time an antiHT polar renal lipid (APRL) produced by interstitial cells of renal medulla was described, & this was concluded to be identical to PAF in 1979 & was then also synthesised & shown to be AGEPC - a phospholipid.
  • PAF actually represents a family of phospholipids & like the eicosanoids including prostaglandins are not stored in cells but synthesised in response to stimulation.

Biosynthesis:

  • Precursor is 1-O-alkyl-2-acyl-glycerophosphocholine - a lipid found in high [] in membranes of many cells;
  • 1st step: Plipase A2 converts it to lyso-PAF & a FFA (usually arachid.acid)
  • 2nd rate-limiting step:
    • lyso-PAF converted to PAF:
      • by acetyl-coA, catalysed by lyso-PAF acetyltransferase;
  • Both steps are regulated by Ca availability and stimulated by:
    • Ag-Ab reactions, chemotactic peptides, thrombin, collagen;
    • other autacoids & PAF itself;
  • Occurs mainly in platelets, neutrophils, eosinophils, mast cells, monocytes, renal medullary cells, vascular endothelial cells;
  • Usually synthesis → release from cell & act on G-protein-coupled receptors but in endothelial cells, it acts i/cellularly;

Inactivation of PAF:

  • Plasma & cytosolic PAF acetylhydrolase forms lyso-PAF which is then converted back to the PAF precursor by an acyltransferase which is inhibited by Ca;

Pharmacology of PAF:

CVS:

  • A potent vasodil. but high [] may → decr. flow due to plat.effect;
  • incr. vasc. permeability (1000 hist.) & promotes oedema formation;

Platelets:

  • potent plat. aggreg. & release of TXA2;

Leukocytes:

  • PMNL aggregation & release of LT's, lysosomals & superoxide chemotactic for eosinophils, neutrophils, & monocytes;
  • incr. neutrophil adherence & diapedesis;

Sm.muscle:

  • contracts GIT, uterine, pulm. sm.muscle;
  • → delayed (~3D) & prolonged (1-4wks) bronchial hyperreact.
  • → incr. mucus prod. & incr. perm. pulm.microvessels;
  • → most potent known ulcerogen;

Kidney:

  • decr. RBF, decr.GFR, decr. urine volume, decr. Na excretion; incr. vasodil.PG's;

Reproduction:

  • role in ovulation, implantation & parturition;

PAF Receptor Antagonists:

  • development still in infancy (disc. 1987);
  • Triazolobenzodiazepines (eg. alprazolam, triazolam)
  • Ginkgolide B (from Ginkgo biloba) - a terpene;
  • ? Role in: asthma Rx; anaphylactic shock Rx; contraceptives;
paf.txt · Last modified: 2008/09/23 00:18 (external edit)