A major component of COPD is pulmonary emphysema caused by a progressive destruction of alveolar walls with consequent loss

1378 INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a global epidemic of major proportions that is predicted to become the third most common cause of death and fifth most frequent cause of chronic disability by 2030 (http://www.who.int/respiratory/copd/ burden/en/). Cigarette smoking is a major risk factor, but several predisposing genetic factors have also been implicated in the pathogenesis of COPD (Hersh et al., 2006; Repapi et al., 2010). A major component of COPD is pulmonary emphysema caused by a progressive destruction of alveolar walls with consequent loss of respiratory function. Although the mechanisms causing the emphysema are largely unknown, reactive oxygen species (ROS) induced by cigarette smoke and/or other environmental pollutants are thought to gradually disrupt signalling pathways responsible for maintaining lung integrity (Tuder and Petrache, 2012). SESN2 belongs to a family of highly conserved antioxidant proteins with poorly understood functions. In mammalian cells, SESN2 is believed to reduce oxidative stress by rescuing the peroxidase activity of overoxidised peroxiredoxins (Budanov et al., 2004) and by activating the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) (Bae et al., 2013), which is a potent antioxidant gene inducer. However, independently of its antioxidant function, SESN2 inhibits mammalian target of rapamycin (mTOR) (Budanov and Karin, 2008), a prometabolic serine/threonine kinase that controls protein synthesis, cell growth, autophagy and cell death. The activation of the rapamycin-sensitive component of mTOR (mTORC1) has been associated with reduced pathology in experimental and human emphysemas (Weichhart et al., 2008; Wempe et al., 2010; Yoshida et al., 2010). Thus, SESN2 seems to simultaneously block ROS accumulation and mTOR signalling, which are believed to have opposite effects in the pathogenesis of COPD. We and others have previously reported that mice with an inactivating mutation of the small splice variant of the latent transforming growth factor beta 4 gene (Ltbp4S KO) are born with alveolar septation defects that worsen with age (Dabovic et al., 2009; Sterner-Kock et al., 2002). By the age of 4-5 months, Ltbp4S KO lungs develop symptoms reminiscent of the centrilobular emphysema that is associated with late-stage COPD (Sterner-Kock et al., 2002). This phenotype is partially rescued by the inactivation of SESN2 in Ltbp4S/Sesn2 double-knockout mice (Wempe et al., 2010). Based on this observation, we hypothesised that the Sesn2 mutation would protect mice from developing emphysema after chronic exposure to cigarette smoke (an animal model that more closely mimics human COPD than does the Ltbp4S KO mouse), and that Sesn2 expression might be altered in the lungs of individuals with COPD. Here we show that the mutational inactivation of Sesn2 protects mice against developing cigarette smoke-induced pulmonary emphysema. Moreover, we identify SESN2 as a repressor of PDGFRβ signalling, and PDGFRβ signalling as an upstream regulator of alveolar maintenance programmes. We further show that SESN2 is Disease Models & Mechanisms 6, 1378-1387 (2013) doi:10.1242/dmm.013482