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CD40 Plays a Crucial Role in Lipopolysaccharide-Induced Acute Lung Injury

Department of Medicine, Division of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

Address correspondence to: Tsutomu Kawabe, M.D., Ph.D., Department of Medicine, Division of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466–8550, Japan. E-mail: kawabet{at}med.nagoya-u.ac.jp

Activated alveolar macrophages (AM) are known to constitute a critical modulator of the lung inflammatory response through the production of various mediators. However, the role of activated AM 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 AM 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-, interleukin-1ß, 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 AM ex vivo. AM purified from CD40KO mice could not induce expression of inducible nitric oxide synthase (iNOS) by LPS, although iNOS in wild-type AM was induced by LPS independently of CD40–CD154 interaction. The loss of surface expression of CD40 was enough to interrupt the expression of iNOS in AM 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 AM 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.

Abbreviations: 3-amino-9-ethylcarbazole, AEC • acute lung injury, ALI • alveolar macrophages, AM • antigen-presenting cells, APC • acute respiratory distress syndrome, ARDS • bronchoalveolar lavage, BAL • deficient in CD40, CD40KO • enzyme-linked immunosorbent assay, ELISA • interferon, IFN • interleukin, IL • lipopolysaccharide, LPS • macrophage inflammatory protein 2, MIP-2 • matrix metalloproteinase, MMP • nitric oxide, NO • inducible NO synthase, iNOS • phosphate-buffered saline, PBS • polyvinylidene difluoride, PVDF • scavenger receptor A, SRA • TNF receptor-associated factor, TRAF • toll-like receptor, TLR • tumor necrosis factor-, TNF- • tyramide signal amplification, TSA • wild-type, WT

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