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Published on: January 16, 2015
MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive
Yong Wang1, Juan Liu1, Jie-Sen Zhou1
1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; and.
Abstract:
Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD.
Insights
Mechanistic target of rapamycin (MTOR) suppresses inflammation and emphysema in chronic obstructive pulmonary disease (COPD). MTOR activation may offer a new therapeutic strategy for COPD patients.
Area of Science:
- Pulmonary Medicine
- Cellular Biology
- Molecular Pathology
Background:
- Airway epithelial cell death and inflammation are key features of chronic obstructive pulmonary disease (COPD).
- The role of mechanistic target of rapamycin (MTOR) in COPD pathogenesis, particularly its regulation of cellular processes like autophagy and apoptosis, remains largely unknown.
- Cigarette smoke (CS) is a primary etiological factor in COPD, inducing significant cellular stress and inflammation in the airways.
Purpose of the Study:
- To investigate the role of MTOR in regulating CS-induced cell death, airway inflammation, and emphysema.
- To elucidate the molecular mechanisms by which MTOR influences CS-induced pathological changes in the airways.
- To explore the potential of MTOR as a therapeutic target for COPD.
Main Methods:
- Analysis of MTOR and TSC2 expression in human COPD airways and CS-exposed mouse lungs.
- In vitro studies using human bronchial epithelial cells treated with CS extract (CSE) to assess MTOR activity, autophagy, apoptosis, and necroptosis.
- Investigation of the NF-κB pathway's role in CSE-induced cytokine release.
- In vivo studies using mice with targeted knockdown of MTOR in airway epithelial cells exposed to CS.
Main Results:
- MTOR expression was decreased, while TSC2 expression was increased in COPD airways and CS-exposed lungs.
- CSE activated TSC2, inhibited MTOR, and induced autophagy, apoptosis, and necroptosis via the TSC2-MTOR axis, regulating IL-6 and IL-8 production through NF-κB.
- Mice with reduced MTOR in airway epithelial cells showed exacerbated CS-induced airway inflammation and emphysema, with heightened cell death pathways.
Conclusions:
- MTOR plays a crucial role in suppressing CS-induced airway inflammation and emphysema.
- The TSC2-MTOR pathway modulates CS-induced autophagy, apoptosis, and necroptosis, impacting COPD pathogenesis.
- MTOR activation presents a potential novel therapeutic strategy for managing COPD.
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