Recombinant human lipocortin 1 inhibits thromboxane release from guinea-pig isolated perfused lung

Abstract

The guinea-pig perfused isolated lung, used in conjunction with the cascade superfusion system to measure the release of thromboxane A₂(TXA₂), is a simple and convenient model for assessing the inhibition by glucocorticoids of eicosanoid formation^1–8. Dexamethasone inhibits the release of TXA₂ from the lung when it is stimulated by agents such as RCS-RF² of leukotrienes,^4,8 but not when bradykinin or arachidonic acid are used^1–7. Using this model we have shown that the glucocorticoids suppress eicosanoid generation by cells through the induction of a family of phospho-lipase A₂-inhibitory proteins^5,6 now termed the 'lipocortins'⁹. Recently the primary structure of one form of lipocortin has been elucidated and the human gene cloned¹⁰. Lipocortin 1 is a polar monomeric protein with anti-phospholipase properties in vitro^10,11 and we now report that when infused into guinea-pig lung preparations this protein has the same inhibitory profile as the glucocorticoids but with a more rapid onset of action. This is the first demonstration that eicosanoid formation can be inhibited by a recombinant phospholipase inhibitory protein applied extracellularly.