Inhibition of Cell Apoptosis and Amelioration of Pulmonary Fibrosis by Thrombomodulin

• Published in: The American journal of pathology Vol. 187; no. 10; pp. 2312 - 2322
• Main Authors: Fujiwara, Kentaro, Kobayashi, Tetsu, Fujimoto, Hajime, Nakahara, Hiroki, D'Alessandro-Gabazza, Corina N., Hinneh, Josephine A., Takahashi, Yoshinori, Yasuma, Taro, Nishihama, Kota, Toda, Masaaki, Kajiki, Masahiro, Takei, Yoshiyuki, Taguchi, Osamu, Gabazza, Esteban C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2017
• Subjects: A549 Cells; Administration, Intranasal; Administration, Intravenous; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - pathology; Animals; Apoptosis - drug effects; Disease Progression; Female; Humans; Injections, Intraperitoneal; Lung - metabolism; Mice, Inbred C57BL; Mice, Transgenic; Pneumonia - complications; Pneumonia - drug therapy; Pneumonia - pathology; Pulmonary Fibrosis - complications; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - pathology; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Thrombomodulin - administration & dosage; Thrombomodulin - blood; Thrombomodulin - therapeutic use; Transforming Growth Factor beta1 - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2017.06.013

Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin (rhTM) improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of rhTM in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor-β1 that develop spontaneously pulmonary fibrosis, and wild-type mice treated with bleomycin were used as models of lung fibrosis. rhTM was administered to mice by i.p. injection or by the intranasal route. Therapy with rhTM significantly decreased the concentration of high mobility group box1, interferon-γ, and fibrinolytic markers, the expression of growth factors including transforming growth factor-β1, and the degree of lung fibrosis. rhTM significantly suppressed apoptosis of lung epithelial cells in in vivo and in vitro experiments. The results of the present study demonstrated that rhTM can inhibit bleomycin-induced pulmonary fibrosis and transforming growth factor-β1–driven exacerbation and progression of pulmonary fibrosis, and that apart from its well-recognized anticoagulant and anti-inflammatory properties, rhTM can also suppress apoptosis of lung epithelial cells.