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(American Journal of Pathology. 2006;169:740-749.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060086

E- and P-Selectins Synergistically Inhibit Bleomycin-Induced Pulmonary Fibrosis

Mayuka Horikawa*, Manabu Fujimoto*, Minoru Hasegawa*, Takashi Matsushita*, Yasuhito Hamaguchi*, Ayako Kawasuji*, Yukiyo Matsushita*, Tomoyuki Fujita*, Fumihide Ogawa{dagger}, Kazuhiko Takehara*, Douglas A. Steeber{ddagger} and Shinichi Sato*{dagger}

From the Department of Dermatology,* Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; the Department of Dermatology,{dagger} Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; and the Department of Biological Sciences,{ddagger} University of Wisconsin–Milwaukee, Milwaukee, Wisconsin

The development of bleomycin-induced lung injury, which is a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. Therefore, bleomycin-induced lung fibrosis was examined in E-selectin–/– mice, P-selectin–/– mice, and E-selectin–/– mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice. E-selectin–/– mice treated with anti-P-selectin mAb exhibited augmented lung fibrosis histologically, increased lung collagen deposition, and increased mortality compared to wild-type mice. Furthermore, lung interferon-{gamma} mRNA expression decreased in E-selectin–/– mice treated with anti-P-selectin mAb relative to wild-type mice, while tumor necrosis factor-{alpha} and interleukin-6 mRNA expression increased in these mice. Similar changes were observed in E-selectin–/– mice, albeit to a lesser extent than those treated with anti-P-selectin mAb. Remarkably, flow cytometric analysis revealed that the frequency of interferon-{gamma}-producing natural killer T (NKT) cells in the bronchoalveolar lavage was decreased in E-selectin–/– mice and E-selectin–/– mice treated with anti-P-selectin mAb compared with wild-type mice. Moreover, the majority of NKT cells expressed high levels of CXCR3, suggesting that NKT cell infiltration is also dependent on CXCR3 expression. These results suggest that E- and P-selectins synergistically inhibit lung fibrosis by promoting the recruitment of NKT cells.




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