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Published ahead of print on December 23, 2003, doi:10.1165/rcmb.2003-0197OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 808-815

A more recent version of this article appeared on June 1, 2004
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Submitted on May 23, 2003
Revised on December 23, 2003

CD40 Plays a Crucial Role in LPS-induced Acute Lung Injury

Naozumi Hashimoto1, Tsutomu Kawabe1*, Kazuyoshi Imaizumi1, Toru Hara1, Masakazu Okamoto1, Katsuyuki Kojima1, Kaoru Shimokata1, and Yoshinori Hasegawa1

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

* To whom correspondence should be addressed. E-mail: kawabet{at}med.nagoya-u.ac.jp.

Activated alveolar macrophages (AM{phi}) are known to constitute a critical modulator of the lung inflammatory response through the production of various mediators. However, the role of activated AM{phi} in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is less well known. To address this issue, we examined an LPS-induced lung injury model for the role of activated AM{phi} in vivo, focusing on activation through CD40, which is one of the most important pathways for the activation of antigen-presenting cells (APC). 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} (TNF-{alpha}), interleukin (IL)-1{beta}, macrophage inflammatory protein 2 (MIP-2), or matrix metalloproteinase (MMP)-9 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{phi} ex vivo. AM{phi} purified from CD40KO mice could not induce expression of inducible NO synthase (iNOS) by LPS, although iNOS in wild-type AM{phi} 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{phi} 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{phi} 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 ARDS.




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