Speyer Cecilia L, Neff Thomas A, Warner Roscoe L, Guo Ren-Feng, Sarma J Vidya, Riedemann Niels C, Murphy Megan E, Murphy Hedwig S, Ward Peter A
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Am J Pathol. 2003 Dec;163(6):2319-28. doi: 10.1016/S0002-9440(10)63588-2.
The role of endogenous NO in the regulation of acute lung injury is not well defined. We investigated the effects of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the acute inflammatory response in mouse lungs. Acute lung injury was induced by intratracheal instillation of bacterial lipopolysaccharide (LPS) into wild-type (WT) mice and mice deficient in iNOS (iNOS(-/-)) or eNOS (eNOS(-/-)). Endpoints of inflammatory injury were myeloperoxidase (MPO) content and leak of albumin into lung. Inflammatory injury was similar in WT and eNOS(-/-) mice but was substantially increased in iNOS(-/-) mice. Bronchoalveolar lavage (BAL) fluids of iNOS(-/-) and WT mice showed similar levels of CXC chemokines (MIP-2, KC) but enhanced levels of CC chemokines (MCP-1, MCP-3). Increased lung content of MPO in iNOS(-/-) mice was reduced by anti-MCP-1 to values found in WT mice. In vitro stimulation of microvascular endothelial cells with LPS and IFN gamma revealed elevated production of CXC and CC chemokines in cells from iNOS(-/-) mice when compared to endothelial cells from iNOS(+/+) mice. Peritoneal macrophages from iNOS(-/-) donors also revealed increased production of CC chemokines after stimulation with LPS and interferon (IFN gamma). These data indicate that absence of iNOS causes enhanced lung inflammatory responses in mice which may be related to enhanced production of MCP-1 by endothelial cells and macrophages. It appears that iNOS affects the lung inflammatory response by regulating chemokine production.
内源性一氧化氮(NO)在急性肺损伤调节中的作用尚未明确界定。我们研究了诱导型一氧化氮合酶(iNOS)和内皮型一氧化氮合酶(eNOS)对小鼠肺部急性炎症反应的影响。通过向野生型(WT)小鼠以及iNOS基因缺陷(iNOS(-/-))或eNOS基因缺陷(eNOS(-/-))的小鼠气管内滴注细菌脂多糖(LPS)来诱导急性肺损伤。炎症损伤的终点指标为髓过氧化物酶(MPO)含量以及白蛋白向肺内的渗漏。WT小鼠和eNOS(-/-)小鼠的炎症损伤相似,但iNOS(-/-)小鼠的炎症损伤显著增加。iNOS(-/-)小鼠和WT小鼠的支气管肺泡灌洗(BAL)液中CXC趋化因子(MIP-2、KC)水平相似,但CC趋化因子(MCP-1、MCP-3)水平升高。抗MCP-1可使iNOS(-/-)小鼠肺内升高的MPO含量降低至WT小鼠的水平。与iNOS(+/+)小鼠的内皮细胞相比,用LPS和干扰素γ(IFNγ)体外刺激微血管内皮细胞时,iNOS(-/-)小鼠的细胞中CXC和CC趋化因子的产生增加。来自iNOS(-/-)供体的腹腔巨噬细胞在用LPS和干扰素(IFNγ)刺激后也显示CC趋化因子的产生增加。这些数据表明,iNOS缺失会导致小鼠肺部炎症反应增强,这可能与内皮细胞和巨噬细胞中MCP-1产生增加有关。看来iNOS通过调节趋化因子的产生来影响肺部炎症反应。