Effect of cyclosporin A and inhibitors of arachidonic acid metabolism on blood flow and cyclo-oxygenase products in rat skin allografts.
Using skin blood flow as a measurement of skin graft rejection in rats, it has been shown that in both isografts and allografts the blood flow at first increases above the normal, after which the flow in isografts returns to normal while that in allografts ceases at the onset of rejection. Cyclosporin A (CSA) 5-40 mg kg-1 intramuscularly produced a dose-related inhibition of graft rejection and the pattern of blood flow in the treated allografts became similar to that in isografts in that it remained about 20% above normal throughout the period of treatment. Indomethacin (Indo), inhibitor of cyclo-oxygenase and benoxaprofen (Ben), inhibitor of cyclo-oxygenase and lipoxygenase, caused an enhancement of the onset of rejection and an early cessation of blood flow in allografts. The total content of 4 cyclo-oxygenase products (COP), (prostaglandin E2 (PGE2), PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane B2 (TxB2] increased both in isografts and allografts, but when individual COP were expressed as a percentage of the total, only 6-oxo-PGF1 alpha (the stable metabolite of prostacyclin) increased in allografts. This increased proportion was reduced to normal by a dose of CSA which prolonged graft survival. Indo and Ben partially inhibited COP formation and in particular that of 6-oxo-PGF1 alpha. In addition, CSA caused a dose-related inhibition of the prostacyclin produced by zymosan-activated macrophages. These findings in the rat suggest that prostacyclin is partly responsible for the increase in blood flow in allografts prior to rejection; that CSA inhibits both the recruitment of prostacyclin-producing macrophages and prostacyclin formation directly; and that inhibitors of cyclo-oxygenase enhance skin graft rejection by abrogating the immunoregulatory activity of prostacyclin.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D011422:Propionates / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D016038:Skin Transplantation; D014181:Transplantation Immunology
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D003524:Cyclosporins; D011422:Propionates; C011677:benoxaprofen; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin