CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury
CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury
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DOI：
10.1165/rcmb.2003-0197oc
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发表时间：
2004-06-01
影响因子：
6.4
通讯作者：
Hasegawa, Y
中科院分区：
文献类型：
--
作者：
Hashimoto, N;Kawabe, T;Hasegawa, Y
已知活化的肺泡巨噬细胞（AMphi）通过产生各种介质而构成肺部炎症反应的关键调节剂。然而，激活的AMphi在急性肺损伤（ALI）和急性呼吸窘迫综合征中的作用还不太清楚。为了解决这个问题，我们研究了脂多糖（LPS）诱导的肺损伤模型中激活AMphi在体内的作用，重点是通过CD 40的激活，这是抗原呈递细胞激活的最重要的途径之一。在没有CD 40的情况下，LPS诱导的ALI在其组织学损伤程度和中性粒细胞向肺中的募集方面显著降低。此外，在CD 40缺陷（CD 40 KO）小鼠中，肺中炎症介质（如肿瘤坏死因子-α、白细胞介素-1 β、巨噬细胞炎症蛋白2或基质金属蛋白酶）的释放显著减少。为了阐明CD 40基因敲除小鼠减轻ALI的机制，我们研究了AMphi的体外功能。从CD 40 KO小鼠纯化的AMphi不能诱导诱导型一氧化氮合酶（NOS）的表达由LPS，虽然诱导型一氧化氮合酶在野生型AMphi的LIPS独立的CD 40-CD 154相互作用。CD 40表面表达的丧失足以干扰LPS诱导的AMphi中NOS的表达。同样基于组织硝基酪氨酸染色，CD 40 KO小鼠组织中的活性氧和氮中间体似乎减少。这些结果表明，AMphi通过CD 40的活化不仅参与了与CD 154相互作用的扩增，而且还参与了CD 40自身介导的ALI的发生发展过程，阻断CD 40可能成为治疗LPS诱导的ALI和急性呼吸窘迫综合征的靶点之一。
Activated alveolar macrophages (AMphi) are known to constitute a critical modulator of the lung inflammatory response through the production of various mediators. However, the role of activated AMphi in acute lung injury (ALI) and acute respiratory, distress syndrome is less well known. To address this issue, we examined a lipopolysaccharide (LPS)-induced lung injury model for the role of activated AMphi in vivo, focusing on activation through CD40, which is one of the most important pathways for the activation of antigen-presenting cells. Without CD40, LPS-induced ALI was significantly reduced in its histological degree of injury and recruitment of neutrophils into the lung. In addition, the release in the lung of inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1beta, macrophage inflammatory protein 2, or matrix metalloproteinase was significantly reduced in mice deficient in CD40 (CD40KO). To elucidate the mechanism of this attenuation of ALI in CD40KO mice, we studied the function of AMphi ex vivo. AMphi purified from CD40KO mice could not induce expression of inducible nitric oxide synthase (NOS) by LPS, although iNOS in wild-type AMphi was induced by LIPS independently of CD40-CD154 interaction. The loss of surface expression of CD40 was enough to interrupt the expression of NOS in AMphi in response to LPS. Also based on the tissue nitrotyrosine staining, the reactive oxygen and nitrogen intermediates seemed to be reduced in tissue in CD40KO mice. These results indicated that activation of AMphi through CD40 might be involved not only in amplification by the interaction with CD154 but also in the development of ALI by CD40 itself, and that the functional blockade of CD40 would yield one of the targets for the treatment of LPS-induced ALI and acute respiratory distress syndrome.