MODULATION OF PULMONARY LEUKOTRIENE FORMATION AND PERFUSION-PRESSURE BY BESTATIN, AN INHIBITOR OF LEUKOTRIENE A(4) HYDROLASE

We investigated the effects of bestatin, a prototype leukotriene A(4) (LTA(4)) hydrolase inhibitor, on leukotriene (LT) formation and pulmon ary artery perfusion pressure (P-pa) in isolated, perfused rat lungs. In lung parenchymal strips stimulated with a 10 mu M concentration of the Ca2+ ionophore A23187, bestatin inhibited LTB(4) formation with an IC50 = 10.4 +/- 3.0 mu M (mean +/- SD, N = 4). It did not alter cyste inyl LT formation, confirming that it inhibited LTA(4) hydrolase selec tively, without inhibiting phospholipase, 5-lipoxygenase, or LTC(4) sy nthase. In isolated, perfused lungs stimulated with 10 mu M A23187, 30 0 mu M bestatin inhibited LTB(4) release by 72.2 +/- 10.6% (mean +/- S EM, N = 6, P < 0.01) but had no significant effect on LTE(4) formation (P > 0.5). In these perfused lungs, bestatin did not alter the change in P-pa following stimulation with A23187. This effect is consistent with the insubstantial re-direction of LTA(4) toward formation of vaso spactic cysteinyl LTs. Separate experiments used lungs from rats treat ed with lipopolysaccharide endotoxin in vivo, prior to isolation, perf usion, and stimulation with 5 mu M formyl-methionyl-leucyl-phenylalani ne, in vitro. In these inflamed lungs, 750 mu M bestatin inhibited LTB (4) formation (P < 0.05) and increased LTE(4) formation (P < 0.05), co mpatible with selective inhibition of LTA(4) hydrolase. The re-directi on of LTA(4) metabolism toward formation of cysteinyl LTs by inflamed, perfused lungs did not cause an increase in P-pa.