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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)-α 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.

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

Shi Y,Cao J,Gao J,Zheng L,Goodwin A,An CH,Patel A,Lee JS,Duncan SR,Kaminski N,Pandit KV,Rosas IO,Choi AM,Morse D

doi

10.1164/rccm.201111-2023OC

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

412-9

issue

eissn

1073-449X

issn

1535-4970

pii

rccm.201111-2023OC

journal_volume

186

pub_type

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Retinoic acid-related orphan receptor-α is induced in the setting of DNA damage and promotes pulmonary emphysema.