Mechanisms coupling the mTOR pathway to chronic obstructive pulmonary disease (COPD) pathogenesis

Chronic Obstructive Pulmonary Disease (COPD) is a poorly reversible respiratory disorder distinguished by dyspnea, cough, expectoration and exacerbations due to abnormality of airways or emphysema. In this review, we consider the therapeutic potential of targeting Mammalian target of Rapamycin (mTOR) for treating COPD. The mTOR is a highly conserved serine-threonine protein kinase that integrates signals from growth factors and nutrients to control protein synthesis, lipid biogenesis and metabolism. Dysregulated mTOR pathway signaling due to genetic factors or cigarette smoking impairs autophagy, driving the buildup of abnormal cells and damaged proteins, resulting in inflammation and oxidative stress. Persistent mTOR activation also contributes to pulmonary vascular cell proliferation, facilitating the development of pulmonary resistance in COPD. Rapamycin, an inhibitor of mTOR, prevents the buildup of senescent cells in the lungs of COPD patients and inhibits the release of lung tissue-damaging proteases. mTOR also impacts the corticosteroid sensitivity in COPD patients by regulating the levels of histone deacetylases. The emerging role of gut-lung axis dysbiosis in the progression of COPD and its influence on mTOR further highlights the relevance of the mTOR pathway in COPD pathophysiology.