title: Calpain-activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma.
abstract: BACKGROUND
  Allergic asthma is characterized by inflammation and airway remodelling. Airway remodelling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodelling. However, the role of calpain in airway smooth muscle remodelling remains unknown.
  
  
  OBJECTIVE
  To investigate the role of calpain in asthmatic airway remodelling as well as the underlying mechanism.
  
  
  METHODS
  The mouse asthma model was made by ovalbumin sensitization and challenge. Calpain conditional knockout mice were studied in the model. Airway smooth muscle cells (ASMCs) were isolated from smooth muscle bundles in airway of rats. Cytokines IL-4, IL-5, TNF-α, and TGF-β1, and serum from patients with asthma were selected to treated ASMCs. Collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs were analysed.
  
  
  RESULTS
  Inhibition of calpain using calpain knockout mice attenuated airway smooth muscle remodelling in mouse asthma models. Cytokines IL-4, IL-5, TNF-α, and TGF-β1, and serum from patients with asthma increased collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs, which were blocked by the calpain inhibitor MDL28170. Moreover, MDL28170 reduced cytokine-induced increases in Rictor protein, which is the most important component of mammalian target of rapamycin complex 2 (mTORC2). Blockage of the mTORC2 signal pathway prevented cytokine-induced phosphorylation of Akt, collagen-I synthesis, and cell proliferation of ASMCs and attenuated airway smooth muscle remodelling in mouse asthma models.
  
  
  CONCLUSIONS
  Our results indicate that calpain mediates cytokine-induced collagen-I synthesis and proliferation of ASMCs via the mTORC2/Akt signalling pathway, thereby regulating airway smooth muscle remodelling in asthma.
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: S-S
authors.initials: SS
authors.lastname: Rao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Mu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: P-C
authors.initials: PC
authors.lastname: Cai
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Song
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: F-Z
authors.initials: FZ
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Lin
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.affiliation: Queen's University Cancer Research Institute, Kingston, ON, Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: H-Z
authors.initials: HZ
authors.lastname: Shi
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei, China.
authors.forename: W-L
authors.initials: WL
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei, China.
authors.forename: H
authors.initials: H
authors.lastname: Ye
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D024042:Collagen Type I / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D024042:Collagen Type I; D016207:Cytokines; D004151:Dipeptides; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C071482:calpeptin; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D002154:Calpain
keywords: PI3K/Akt pathway; airway smooth muscle cells; asthma; calpain; remodelling