The role of platelet activating factor and other lipid mediators in inflammatory angiogenesis

Jeffrey R Jackson , Brian Bolognese , Clare A Mangar , Walter C Hubbard , Lisa A Marshall , James D Winkler
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引用次数: 37

Abstract

Chronic inflammatory diseases are often accompanied by intense angiogenesis. A model of inflammatory angiogenesis is the murine air pouch granuloma which has a hyperangiogenic component. Proinflammatory lipid mediator generation is also a hallmark of chronic inflammation and the role of endogenous production of these mediators in angiogenesis is not known. The 14 kDa phospholipase A2 (PLA2) deacylates phospholipid, liberating arachidonic acid, which is used for leukotriene production, and lysophospholipid, which can drive the production of platelet-activating factor (PAF). Therefore, SB 203347, an inhibitor of the 14 kDa PLA2, 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. SB 203347 reduced both LTB4 and PAF, but not PGD2 levels measured in the day 6 granuloma. This correlated with a significant reduction in angiogenesis. Zileuton reduced LTB4 levels as expected, 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 angiogenic phenotype in chronic inflammation.

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血小板活化因子及其他脂质介质在炎性血管生成中的作用
慢性炎症性疾病常伴有强烈的血管生成。炎性血管生成的一个模型是小鼠气袋肉芽肿,它具有高血管生成成分。促炎脂质介质的产生也是慢性炎症的一个标志,这些介质的内源性生产在血管生成中的作用尚不清楚。14 kDa的磷脂酶A2 (PLA2)使磷脂去酰化,释放花生四烯酸,用于白三烯的生产,和溶血磷脂,可以驱动血小板活化因子(PAF)的生产。因此,我们评价了14kda PLA2抑制剂SB 203347、5-脂氧合酶抑制剂zileuton和PAF受体拮抗剂Ro 24-4736在小鼠气袋肉芽肿中的作用。SB 203347降低了第6天肉芽肿的LTB4和PAF水平,但没有降低PGD2水平。这与血管生成的显著减少相关。Zileuton如预期的那样降低了LTB4水平,但没有显著抑制血管生成,而Ro 24-4736则有效地降低了血管生成。这些数据支持了PAF和白三烯在较小程度上促进慢性炎症血管生成表型的假设。
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