title: mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis.
abstract: The mammalian target of rapamycin (mTOR) signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs) was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1(fx/+) (STT). Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yao-Song
authors.initials: YS
authors.lastname: Gui
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Lianmei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xinlun
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Weixun
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Zeng
authors.affiliation: Department of Thoracic Surgery, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Baiqiang
authors.initials: B
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001761:Bleomycin; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001761:Bleomycin; D058570:TOR Serine-Threonine Kinases