Calpain-activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma.
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 AND CLINICAL RELEVANCE
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.
['Rao|S-S|SS|', 'Mu|Q|Q|', 'Zeng|Y|Y|', 'Cai|P-C|PC|', 'Liu|F|F|', 'Yang|J|J|', 'Xia|Y|Y|', 'Zhang|Q|Q|', 'Song|L-J|LJ|', 'Zhou|L-L|LL|', 'Li|F-Z|FZ|', 'Lin|Y-X|YX|', 'Fang|J|J|', 'Greer|P A|PA|', 'Shi|H-Z|HZ|', 'Ma|W-L|WL|', 'Su|Y|Y|', 'Ye|H|H|']
D056151:Airway Remodeling D000818:Animals D001249:Asthma D002154:Calpain D049109:Cell Proliferation D024042:Collagen Type I D016207:Cytokines D004151:Dipeptides D004195:Disease Models, Animal D000076225:Mechanistic Target of Rapamycin Complex 2 D051379:Mice D018345:Mice, Knockout D009130:Muscle, Smooth D032389:Myocytes, Smooth Muscle D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D000076226:Rapamycin-Insensitive Companion of mTOR Protein D015398:Signal Transduction
remodelling asthma calpain airway smooth muscle cells PI3K/Akt pathway