THE ROLE OF PLATELET-ACTIVATING-FACTOR AND OTHER LIPID MEDIATORS IN INFLAMMATORY ANGIOGENESIS

Chronic inflammatory diseases are often accompanied by intense angioge nesis. A model of inflammatory angiogenesis is the murine air pouch gr anuloma which has a hyperangiogenic component. Proinflammatory lipid m ediator generation is also a hallmark of chronic inflammation and the role of endogenous production of these mediators in angiogenesis is no t known. The 14 kDa phospholipase A(2) (PLA(2)) deacylates phospholipi d, liberating arachidonic acid, which is used for leukotriene producti on, and lysophospholipid, which can drive the production of platelet-a ctivating factor (PAF). Therefore, SE 203347, an inhibitor of the 14 k Da PLA(2), zileuton, an inhibitor of 5-lipoxygenase, and Ro 24-4736 a PAF receptor antagonist were evaluated for their effects in the murine air pouch granuloma. SE 203347 reduced both LTB4 and PAF, but not PGD (2) levels measured in the day 6 granuloma. This correlated with a sig nificant reduction in angiogenesis. Zileuton reduced LTB4 levels as ex pected, but did not significantly inhibit angiogenesis, whereas Ro 24- 4736 potently reduced angiogenesis. These data support the hypothesis that PAF, and to a lesser extent leukotrienes contribute to the angiog enic phenotype in chronic inflammation. (C) 1998 Elsevier Science B.V.