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Danyang Li,1 Tong Wang,2 Qianli Ma,3 Lu Zhou,1 Yanqing Le,1 Yafei Rao,1 Liang Jin,1 Yuqiang Pei,1 Yaning Cheng,4 Chen Huang,5 Xiaoyan Gai,1 Yongchang Sun1 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Thoracic Surgery, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 4School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People’s Republic of China; 5Center of Basic Medical Research, Peking University Third Hospital, Beijing, 100191, People’s Republic of ChinaCorrespondence: Xiaoyan Gai; Yongchang Sun, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Email gxy81wfl79@163.com; suny@bjmu.edu.cnBackground: It has been reported that a disintegrin and metalloproteinase 9 (ADAM9) is involved in the pathogenesis of cigarette smoke (CS)-associated chronic obstructive pulmonary disease (COPD). But how CS exposure leads to upregulation of ADAM9 remains unknown.Methods: Patients who underwent lobectomy for a solitary pulmonary nodule were enrolled and divided into three groups: non-smokers with normal lung function, smokers without COPD and smoker patients with COPD. Immunoreactivity of interleukin (IL)-17A and ADAM9 in small airways and alveolar walls was measured by immunohistochemistry. Wild-type and Il17a−/− C57BL/6 mice were exposed to CS for six months, and ADAM9 expression in the airway epithelia was measured by immunoreactivity. In addition, the protein and mRNA expression levels of IL-17A and ADAM9 were assessed in CS extract (CSE) and/or IL-17A-treated human bronchial epithelial (HBE) cells.Results: The immunoreactivity of ADAM9 was increased in the

Jing Xiong,1 Jieyu Tian,2 Lu Zhou,1 Yanqing Le,1 Yongchang Sun1 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, Beijing 100045, People’s Republic of ChinaCorrespondence: Yongchang SunDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86 156 1196 3697Email suny@bjmu.edu.cnBackground and Purpose: Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease, which is associated with various comorbidities including osteoporosis. Interleukin(IL)-17 has been reported to play important roles in the pathogenesis of COPD and also associated with bone destruction in inflammatory diseases. However, the role of IL-17A in COPD-related osteoporosis is yet unknown. The purpose of our study was to investigate the potential contribution of IL-17A in COPD-related bone loss.Materials and Methods: We examined the bone mass and bone microarchitecture in wild-type and IL-17A-/- mice exposed to long-term cigarette smoke (CS). Osteoclast activities and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in bone tissues were assessed, and the blood levels of inflammatory cytokines were measured.Results: Less bone loss as well as attenuated emphysema were shown in IL-17A-/- mice compared with wild-type mice. CS-exposed IL-17A-/- mice had decreased TRAP+ osteoclast numbers and lower RANKL expression compared with CS-exposed wild-type mice. Inflammatory cytokines including IL-6 and IL-1β in circulation were decreased in IL-17A-/- mice exposed to CS compared with wild-type mice.Conclusion: This study indicates that IL-17A is involved in CS-induced bone loss and may be a common link between COPD and os

Lu Zhou,1 Yanqing Le,1 Jieyu Tian,2 Xia Yang,2 Rong Jin,3 Xiaoyan Gai,1 Yongchang Sun1 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China; 2Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China; 3Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China Background and purpose: Cigarette smoke (CS) induces alveolar destruction through overproduction of proteinases including matrix metalloproteinase (MMP)-9 by alveolar macrophages (AMs). Receptor activator of nuclear factor-κB ligand (RANKL) functions in immune regulation and cytokine secretion; whether it is involved in CS-induced MMP-9 expression is unknown. The purpose of our study was to investigate the expression and functional role of RANKL pathway in MMP-9 production pertaining to the pathogenesis of COPD. Materials and methods: We first localized RANKL and its receptor RANK in the lungs of mice exposed to long-term CS exposure. Next, we studied RANKL and RANK expression under CS extract (CSE) stimulation in vitro. Lastly, we studied the in vitro biological function of RANKL in CS-induced production of MMP-9. Results: Both RANKL and RANK were highly expressed in AMs in CS-exposed mice, but not in the control mice. In vitro, CSE increased the expressions of RANKL and RANK in macrophages. AMs responded to CSE and RANKL stimulation by overexpressing MMP-9, and CSE-induced MMP-9 expression was partly blocked by using monoclonal anti-RANKL antibody. Conclusion: RANKL/RANK pathway mediates CS-induced MMP-9 expression in AMs, suggesting a novel mechanism for CS-associated emphysema. Keywords: COPD, receptor activator of nuclear factor-κB ligand, RANK, alveolar macrophages, MMP-9