CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury

Naozumi Hashimoto, Tsutomu Kawabe, Kazuyoshi Imaizumi, Toru Hara, Masakazu Okamoto, Katsuyuki Kojima, Kaoru Shimokata, Yoshinori Hasegawa

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Activated alveolar macrophages (AMφ) are known to constitute a critical modulator of the lung inflammatory response through the production of various mediators. However, the role of activated AMφ 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 AMφ 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-α, 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 AMφ ex vivo. AMφ purified from CD40KO mice could not induce expression of inducible nitric oxide synthase (iNOS) by LPS, although iNOS in wild-type AMφ 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 AMφ 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 AMφ 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.

Original languageEnglish
Pages (from-to)808-815
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume30
Issue number6
DOIs
Publication statusPublished - 01-06-2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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