PROTECTIVE EFFECT OF MEPACRINE ON HYPOXIA-REOXYGENATION-INDUCED ACUTE LUNG INJURY IN RATS

Mepacrine, a cell membrane stabilizer and inhibitor of phospholipase Az (PLA(2)), exerts a protective effect on ischemia-reperfusion injury in heart; however, its effect in lungs has not been examined. This study aimed to determine whether mepacrine pretreatment attenuates ischemia-reperfusion lung injury simulated by hypoxia reoxygenation and to identify possible mechanisms for such protection. Acute lung injury was induced in Sprague-Dawley rats by ventilation with 5% CO2-95% N-2 and 5% CO2-95% air. Pretreatment with 0.06 mM mepacrine significantly attenuated the acute lung injury. Capillary filtration coefficient, lung weight gain, and protein concentration of lung lavage fluid were significantly lower in mepacrine-treated rats than in rats exposed to hypoxia reoxygenation alone. Steroid dexamethasone, another potential PLA(2) inhibitor, had almost no protective effect. Mepacrine but not dexamethasone caused dose-dependent attenuation of the increase in leukocyte chemiluminescence produced by exposure to phorbol myristate acetate. Mepacrine also dose-dependently inhibited production of tumor necrosis factor-alpha (TNF-alpha) by human monocytes; dexamethasone was much less effective in decreasing TNF-alpha production. We conclude that mepacrine but not dexamethasone can significantly attenuate a hypoxia-reoxygenation-induced injury of the lung. This protective effect of mepacrine may not be the result of its inhibition of PLA(2) but rather of its downregulation of oxygen radical production by circulating or resident leukocytes or its attenuation of TNF-alpha production by macrophages.