Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Cigarette smoking is a major risk factor and several predisposing genetic factors have been implicated in COPD pathogenesis. Although a variety of drugs are available for symptomatic relief, the complicated biology of COPD has so far eluded researchers’ hopes of finding a cure. This work describes a mouse model of COPD in which the antioxidant protein sestrin 2 is identified as a possible drug target for the treatment of COPD. The inactivation of sestrin 2 in this COPD mouse model significantly improves both pulmonary morphology and function. This implies that patients with COPD might benefit from treatment with sestrin antagonists.
Mice lacking the short splice variant of the latent transforming growth factor beta (TGF-β) binding protein 4 (Ltbp4S) develop pulmonary emphysema reminiscent of COPD. Here, mutational inactivation of the antioxidant protein sestrin 2 (sesn2) in Ltbp4S knockout mice partially rescues the emphysema phenotype. This phenotypic rescue is associated with an improvement of pulmonary elastic fiber structure and the activation of the TGF-β and mammalian target of rapamycin (mTOR) signal transduction pathways. The rescue could be blocked by the TGF-β type I receptor (TβR1) inhibitor SB431542, but was not blocked by antioxidants, indicating that the effect of the sesn2 mutation on mTOR is TGF-β dependent. The induction of the TGF-β pathway in the lungs of Ltbp4S−/−sesn2−/− double mutant mice induced the expression of several TGF-β target genes, including that encoding tropoelastin. Lack of elastin, or accelerated degradation of elastin, contributes to emphysema and the authors suggest that the induction of tropoelastin by the sesn2 mutation is a crucial factor in the functional recovery of the Ltbp4S mutant lung. Mutants also maintain normal levels of profibrotic gene expression despite increased TGF-β signaling, which should help reduce pathology.
Implications and future directions
The results imply that sesn2 plays an important role in the pathogenesis of COPD by affecting several signal transduction pathways that are involved in tissue repair and regeneration. Future studies will determine whether the sesn2 mutation can protect mice from developing pulmonary emphysema after chronic exposure to tobacco smoke – an animal model that closely mimics human COPD. Additionally, sesn2 expression may be altered in the lungs of patients with COPD and could thus serve as a diagnostic marker.