Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9063, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Inflammation. 2019 Feb;42(1):185-198. doi: 10.1007/s10753-018-0883-7.
Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen species (ROS), produced in part by the neutrophil NADPH oxidase 2 (Nox2), have been implicated in the pathogenesis of ALI. Previous studies in our laboratory demonstrated the development of pulmonary inflammation in Nox2-deficient (gp91) mice that was absent in WT mice in a murine model of SIRS. Given this finding, we hypothesized that Nox2 in a resident cell in the lung, specifically the alveolar macrophage, has an essential anti-inflammatory role. Using a murine model of SIRS, we examined whole-lung digests and bronchoalveolar lavage fluid (BALf) from WT and gp91 mice. Both genotypes demonstrated neutrophil sequestration in the lung during SIRS, but neutrophil migration into the alveolar space was only present in the gp91 mice. Macrophage inflammatory protein (MIP)-1α gene expression and protein secretion were higher in whole-lung digest from uninjected gp91 mice compared to the WT mice. Gene expression of MIP-1α, MCP-1, and MIP-2 was upregulated in alveolar macrophages obtained from gp91 mice at baseline compared with WT mice. Further, ex vivo analysis of alveolar macrophages, but not bone marrow-derived macrophages or peritoneal macrophages, demonstrated higher gene expression of MIP-1α and MIP-2. Moreover, isolated lung polymorphonuclear neutrophils migrate to BALf obtained from gp91 mice, further providing evidence of a cell-specific anti-inflammatory role for Nox2 in alveolar macrophages. We speculate that Nox2 represses the development of inflammatory lung injury by modulating chemokine expression by the alveolar macrophage.
急性肺损伤 (ALI) 作为全身炎症反应综合征 (SIRS) 的组成部分发展，导致发病率和死亡率显著增加。活性氧 (ROS) 部分由中性粒细胞 NADPH 氧化酶 2 (Nox2) 产生，已被牵连到 ALI 的发病机制中。我们实验室的先前研究表明，在 SIRS 的小鼠模型中，Nox2 缺陷 (gp91) 小鼠肺部炎症的发展在 WT 小鼠中不存在。鉴于这一发现，我们假设 Nox2 在肺的常驻细胞中，特别是肺泡巨噬细胞中，具有重要的抗炎作用。我们使用 SIRS 的小鼠模型，检查了 WT 和 gp91 小鼠的全肺消化物和支气管肺泡灌洗液 (BALf)。两种基因型在 SIRS 期间均显示出肺中性粒细胞的隔离，但只有 gp91 小鼠中存在中性粒细胞迁移到肺泡空间。未注射 gp91 小鼠的全肺消化物中巨噬细胞炎症蛋白 (MIP)-1α 基因表达和蛋白分泌均高于 WT 小鼠。与 WT 小鼠相比，gp91 小鼠的肺泡巨噬细胞中 MIP-1α、MCP-1 和 MIP-2 的基因表达上调。此外，gp91 小鼠肺泡巨噬细胞而非骨髓来源的巨噬细胞或腹腔巨噬细胞的体外分析显示 MIP-1α 和 MIP-2 的基因表达更高。此外，分离的肺多形核白细胞向 gp91 小鼠的 BALf 迁移，进一步证明了 Nox2 在肺泡巨噬细胞中具有特定的抗炎作用。我们推测 Nox2 通过调节肺泡巨噬细胞趋化因子的表达来抑制炎症性肺损伤的发展。
