Phospholipase A2 mediates nitric oxide production by alveolar macrophages and acute lung injury in pancreatitis.

Objective Reportedly, nitric oxide (NO) derived from alveolar macrophages (AMs) and increased serum phospholipase A 2 (PLA 2 ) activity are associated with the pathogenesis of lung injury in acute pancreatitis. The authors examined the possibility that PLA 2 causes, in part, the induction of NO production by AMs in pancreatitis. Methods Pancreatitis was induced in rats by selective pancreatic duct ligation (SPL). AMs were stimulated with PLA 2 or SPL rat serum, with or without administration of the PLA 2 inhibitor quinacrine. Then NO production from the AMs was measured by the Griess method, inducible NO synthase mRNA expression of AMs was analyzed by the reverse transcription-polymerase chain reaction, and cytotoxic effects of AMs on human umbilical vein endothelial cells was examined by a 51 Cr release assay. In vivo, the effect of quinacrine on lung injury was determined by measuring the arterial blood oxygen pressure (Pao 2 ), lung weight, and lung permeability using Evans blue dye concentration of SPL rat. Results In vitro, the serum with high PLA 2 activity induced NO production by rat AMs. PLA 2 (50 ng/ml) induced significant amounts of NO production, inducible NO synthase mRNA expression, and cytotoxicity toward the human umbilical vein endothelial cells in normal rat AMs, and these activities were significantly inhibited by quinacrine. In vivo, rats with pancreatitis that were given quinacrine showed decreased concentrations of NO 2 - and NO 3 in the bronchoalveolar lavage fluid, and the Pao 2 , lung edema, and lung permeability were improved significantly. Conclusion PLA 2 induces AMs to release NO, which contributes to lung injury in acute pancreatitis. This lung injury was prevented by the administration of the PLA 2 inhibitor quinacrine.