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.

• Authors: Ying Shi, Jiaofei Cao, Jane Gao, Liang Zheng, Andrew Goodwin, Chang Hyoek An, Avignat Patel, Janet S Lee, Steven R Duncan, Naftali Kaminski, Kusum V Pandit, Ivan O Rosas, Augustine M K Choi, Danielle Morse
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 186 Issue 5 Pg. 412-9 (Sep 01 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 22744720 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Nuclear Receptor Subfamily 1, Group F, Member 1
• RORA protein, human
• Rora protein, mouse
• Tobacco Smoke Pollution

Topics

• Animals
• Biomarkers (metabolism)
• Cells, Cultured
• DNA Damage (physiology)
• DNA Repair
• Disease Models, Animal
• Gene Expression Profiling
• Humans
• Lung (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Neurologic Mutants
• Nuclear Receptor Subfamily 1, Group F, Member 1 (metabolism)
• Oligonucleotide Array Sequence Analysis
• Pulmonary Disease, Chronic Obstructive (genetics, metabolism)
• Pulmonary Emphysema (etiology, genetics, metabolism)
• Tobacco Smoke Pollution (adverse effects)