Regulatory effects of NOS on acute lung inflammatory responses in mice
Regulatory effects of NOS on acute lung inflammatory responses in mice
复制标题
DOI：
10.1016/s0002-9440(10)63588-2
复制
发表时间：
2003-12-01
影响因子：
6
通讯作者：
Ward, PA
中科院分区：
文献类型：
--
作者：
Speyer, CL;Neff, TA;Ward, PA
内源性NO在急性肺损伤中的作用尚不明确。本实验观察了诱导型一氧化氮合酶（inducible nitric oxide synthase，iNOS）和内皮型一氧化氮合酶（endothelial NOS，eNOS）在小鼠肺急性炎症反应中的作用。通过向野生型（WT）小鼠和iNOS（-/-）或eNOS（-/-）缺陷型小鼠气管内滴注细菌脂多糖（LPS）诱导急性肺损伤。以髓过氧化物酶（MPO）含量和白蛋白漏出为炎性损伤的终点。WT和eNOS（-/-）小鼠的炎症损伤相似，但在iNOS（-/-）小鼠中显著增加。iNOS-/-和WT小鼠的支气管肺泡灌洗液（BAL）显示出相似的CXC趋化因子（MIP-2、KC）水平，但CC趋化因子（MCP-1、MCP-3）水平增加。iNOS（-/-）小鼠肺组织MPO含量增加，但抗MCP-1抗体可降低至WT小鼠的水平。用LPS和IFN γ体外刺激微血管内皮细胞显示，与来自iNOS（+/+）小鼠的内皮细胞相比，来自iNOS（-/-）小鼠的细胞中CXC和CC趋化因子的产生增加。来自iNOS（-/-）供体的腹膜巨噬细胞在用LPS和干扰素（IFN γ）刺激后也显示CC趋化因子的产生增加。这些数据表明，iNOS的缺乏导致小鼠中增强的肺部炎症反应，这可能与内皮细胞和巨噬细胞产生MCP-1的增强有关。看来iNOS通过调节趋化因子的产生来影响肺部炎症反应。
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 IFNgamma 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 (IFNgamma). 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.