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論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema.
掲載誌名	正式名：American journal of physiology. Lung cellular and molecular physiology 略　 称：Am J Physiol Lung Cell Mol Physiol ISSNコード：1522-1504(Electronic)1040-0605(Linking)
巻・号・頁	303(2),pp.L141-51
著者・共著者	Shigeta Ayako†, Tada Yuji, Wang Ji-Yang, Ishizaki Shunsuke, Tsuyusaki Junichi, Yamauchi Keita, Kasahara Yasunori, Iesato Ken, Tanabe Nobuhiro, Takiguchi Yuichi, Sakamoto Akemi, Tokuhisa Takeshi, Shibuya Kazutoshi, Hiroshima Kenzo, West James, Tatsumi Koichiro
発行年月	2012/07
概要	Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.
DOI	10.1152/ajplung.00337.2011
文献番号	22610351