AbstractsBiology & Animal Science

Chronic obstructive pulmonary disease (COPD) is the fourth ranking cause of death worldwide. Despite the extensive efforts that have been made so far, the disease remains still incurable due to a lack of therapeutic targets that can prevent from the development or even reverse already established disease. Only symptoms can be alleviated to some degree, by the current treatments available. Thus, it still causes high morbidity, mortality, disability, health resources depletion and socioeconomic burden. One of the major components of COPD is pulmonary emphysema caused by the destruction and of alveoli after exposure to noxious particles and gases, with cigarette smoke and smoke from heating and cooking being the most prominent. The disruption of signaling pathways responsible for lung integrity maintenance is thought to be a key point in the development of emphysema. Reactive oxygen species generated after the exposure to smoke could disrupt these alveolar maintenance programs. It has already been reported that the inactivation of the sestrin 2 gene, encoding the member of a family of highly conserved antioxidant proteins, can partially rescue the disease phenotype in a genetic mouse model of emphysema. This primarily contradictory finding that deletion of an antioxidant protein can protect from a genetically induced emphysema was attributed to the restoration of impaired TGF-beta signaling. Sestrin 2 has also been shown to inhibit mTOR. This led to the hypothesis that sestrin 2 might play a role in emphysema development in a chronic model of tobacco smoke exposure. To this end, wild type and knockout mice were exposed to smoke of a 140mg/m3 total particulate matter (TPM) concentration, for 6 hours/day, 5 days/week for a period of 8 months. The wild type mice developed pulmonary emphysema as indicated functionally by a significant increase in pulmonary compliance and pulmonary hypertension indicated by a significant increase in right ventricular systolic pressure. Morphometric evaluation also revealed significant structural changes: increase in airspace% and mean linear intercept, and decrease in alveolar septal wall thickness. In contrast the loss of function of sestrin 2 resulted in the prevention of emphysema development in the knockout mice which demonstrated no significant changes in these parameters when compared to respective controls. Sestrin 2 and PDGFRbeta mRNA were up- and down- regulated respectively in the lungs of wild type mice after smoke exposure. Furthermore, sestrin 2 knockout mice exhibited increased numbers of alveolar epithelial type II cells and decreased numbers of apoptotic cells after smoke exposure when compared to wild type mice. This study demonstrated that the mutational inactivation of sestrin 2 induces PDGFRbeta signaling which preserves lung integrity by initiating a cascade of events also involving KGF and mTOR signaling that results in increased ATII cell proliferation and elastin production. If these data are transferrable to the human situation, a sestrin 2 antagonist could be…