Synthesis of arachidonic acid-derived lipoxygenase end cytochrome P450 products in the intact human lung vasculature

Lipoxygenase (LO) and cytochrome P450 monooxygenase products of arachidonic acid (AA) have been implicated in a large number of vasoregulatory process es. In intact, blood-free, perfused and ventilated human lungs (n = 8), iso lated during surgery for bronchial carcinoma, we analyzed leukotrienes (LTs ), hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EE Ts) by sequential sampling of the recirculating buffer fluid. For the analy sis we used multistep, solid-phase extraction, isocratic reversed-phase hig h-performance liquid chromatography, with elution of all metabolites within one run and photodiode array detection to obtain full UV spectra of elutin g compounds. We detected no LT release in a 15-min baseline period, but the admixture of the calcium ionophore A23187 with the buffer fluid provoked t he rapid appearance of all LTs. Some baseline release of 15-HETE was observ ed, and in response to A23187, maximum buffer concentrations were noted for 5-HETE, with 8-HETE, 9-HETE, 11-HETE, and 12-HETE being detected at lower levels. Marked baseline liberation of 11,12-EET and 8,9-EET was observed. I n response to A23187, high oxirane buffer concentrations were registered, w hich far surpassed those of LTs and HETEs. The eicosanoid release was paral leled by a limited pulmonary artery presser response and progressive vascul ar leakage. We conclude that ex-vivo-perfused human lungs release EETs > LT s > HETEs into the vascular compartment in response to inflammatory challen ge. The marked oxirane synthesis in the lung vasculature may have major imp act on lung vasoregulation when considering the possible function of these AA epoxides as endothelium-derived hyperpolarizing factors.