Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Abstract

Rationale: The discovery that retinoic acid-related orphan receptor (Rora)-a is highly expressed in lungs of patients with COPD led us to hypothesize that Rora may contribute to the pathogenesis of emphysema. Objectives: To determine the role of Rora in smoke-induced emphysema. Methods: Cigarette smoke extract in vitro and elastase or cigarette smoke exposure in vivo were used to model smoke-related cell stress and airspace enlargement. Lung tissue from patients undergoing lung transplantation was examined for markers of DNA damage and Rora expression. Measurements and Main Results: Rora expression was induced by cigarette smoke in mice and in cell culture. Gene expression profiling of Rora-null mice exposed to cigarette smoke demonstrated enrichment for genes involved in DNA repair. Rora expression increased and Rora translocated to the nucleus after DNA damage. Inhibition of ataxia telangiectasia mutated decreased the induction of Rora. Gene silencing of Rora attenuated apoptotic cell death in response to cigarette smoke extract, whereas overexpression of Rora enhanced apoptosis. Rora-deficient mice were protected from elastase and cigarette smoke induced airspace enlargement. Finally, lungs of patients with COPD showed evidence of increased DNA damage even in the absence of active smoking. Conclusions: Taken together, these findings suggest that DNA damage may contribute to the pathogenesis of emphysema, and that Rora has a previously unrecognized role in cellular responses to genotoxicity. These findings provide a potential link between emphysema and features of premature ageing, including enhanced susceptibility to lung cancer.Keywords: chronic obstructive pulmonary disease; p53; retinoic acidrelated orphan receptor-a; senescence; apoptosis Retinoic acid-related orphan receptor-a (Rora) is a nuclear hormone receptor named for its sequence homology with the retinoic acid receptor; its designation as "orphan" indicates that its natural ligand is unknown. We discovered that Rora expression is robustly increased in lungs of patients with chronic obstructive pulmonary disease (COPD), and this led us to examine whether Rora contributes to the pathogenesis of this disease. Little is known about the role of Rora in the lung, although its absence had been reported to lead paradoxically to increased LPS-induced lung inflammation (1) and decreased allergic inflammation (2). Outside the lung, Rora has been implicated in processes as diverse as osteogenic differentiation (3), circadian rhythm (4), apolipoprotein transcription (5), and Purkinje cell development (6). Gene expression profiling in Rora-null mice led us to the hypothesis that this nuclear receptor is involved in responses to DNA damage.Although the contribution of DNA damage to COPD has not been examined in detail, there are theoretical reasons to believe that genotoxicity could be involved in the pathogenesis of emphysema. Compromised DNA damage repair is known to result in accelerated ageing, as occurs in progeroid syndromes (7). Individuals with these syn...

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