title: Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis.
abstract: Intestinal ischemia has a high mortality and often causes acute lung injury (ALI), which is a serious complication, and is accompanied by high mortality up to 40%. An intense local and systemic inflammation occurs during intestinal ischemia/reperfusion (IR)-induced lung injury resulting from activation of immune responses. It has been reported that one component of complement, C5a, is indispensable for the full development of IR-induced lung injury, whereas the detailed molecular mechanism remains to be elucidated. In this study, we found that intestinal IR induced ALI-like symptoms, and C5a receptor (C5aR) expression was upregulated in alveolar macrophages, which are resident macrophages in lung tissue and are important in pulmonary homeostasis. C5a produced during lung injury binds to C5aR in alveolar macrophages, initiates downstream signaling that promotes autophagy, leading to apoptosis of alveolar macrophages. Using Mφ-ATG5(-/-) mice, in which the atg5 is deficient specifically in macrophages and autophagy is inhibited, we confirmed that in vivo C5a interacting with C5aR induced autophagy in alveolar macrophages, which promoted alveolar macrophage apoptosis. Further study indicated that autophagy was induced through C5aR-mediated degradation of bcl-2. Taken together, our results demonstrated that C5aR-mediated autophagy induced apoptosis in alveolar macrophages, disrupting pulmonary homeostasis and contributing to the development of ALI. This novel mechanism suggests new therapeutic potential of autophagy regulation in ALI.
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: Q-F
authors.initials: QF
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: 1] Institute of Medical Intervention Engineering, Tongji University, No.727 North Zhongshan Road, Shanghai, China [2] Department of Interventional Radiology, Shanghai Tenth People's Hospital, Tongji University, No. 301, Yanchang Road, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a