Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs.
Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)
Littner
M R
MR
Department of Medicine, Sepulveda Veterans Affairs Medical Center, CA 91343.
Lott
F D
FD
D000704:Analysis of Variance; D000818:Animals; D034341:Aristolochic Acids; D002374:Catalase / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008555:Melitten / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010477:Perfusion / Q000379:methods / Q000706:statistics & numerical data; D010616:Phenanthrenes / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011652:Pulmonary Circulation / Q000187:drug effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000009:adverse effects; D012128:Respiratory Distress Syndrome / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology
D034341:Aristolochic Acids; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; D008555:Melitten; C000228:aristolochic acid I; D002374:Catalase; D010741:Phospholipases A; D054467:Phospholipases A2