MODULATING PHOSPHATIDIC-ACID METABOLISM DECREASES OXIDATIVE INJURY INRAT LUNGS

We determined that lisofylline, a potent inhibitor of oleate-and linol eate-containing phosphatidic acid formation (half-maximal inhibitory c oncentration = 40 nM), prevented oxidant-mediated capillary leak in is olated rat lungs given interleukin-8 (IL-8) intratracheally and perfus ed with human neutrophils. Lung leak was prevented by lung, but not ne utrophil, lisofylline pretreatment. Furthermore, although lisofylline inhibited IL-8-stimulated neutrophil production of phosphatidic acid i n vitro, it did not prevent IL-8-stimulated neutrophil adherence, chem otaxis, or intracellular calcium mobilization or N-formyl-Met-Leu-Phe (fMLP)-stimulated oxidant production in vitro. Lisofylline also preven ted acute capillary leak in isolated rat lungs perfused only with the oxidant generator purine-xanthine oxidase but did not scavenge O-2(-). or H2O2 in vitro. Finally, lisofylline-mediated protection against lu ng leak in both models was associated with alterations in lung membran e free fatty acid acyl composition (as reflected by the decreased rati o [linoleate + oleate]/[palmitate]). We conclude that lisofylline prev ented both neutrophil-dependent and neutrophil-independent oxidant-ind uced capillary leak in isolated rat lungs and that protection appears to be mediated by blocking intrinsic lung linoleoyl phosphatidic acid metabolism. We speculate that lisofylline, in addition to our previous ly reported effects on cytokine signaling by intrapulmonary mononuclea r cells, alters intrinsic pulmonary capillary membrane composition and renders this barrier less vulnerable to oxidative damage.