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Epithelium Expression and Function of Retinoid Receptors in Asthma

Anne Druilhe^*,1, Jean-Marie Zahm², Laurent Benayoun^,1, Delphine El Mehdi^,1, Martine Grandsaigne¹, Marie-Christine Dombret³, Isabelle Mosnier⁴, Benoit Feger⁵, Joël Depondt⁶, Michel Aubier^1,3 and Marina Pretolani¹

¹ Inserm, U700, Université Paris 7, Paris; ³ Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Universitaire Nord Bichat-Claude Bernard, Service de Pneumologie A, Paris; ⁶ Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Universitaire Nord Bichat-Claude Bernard, Service d'Oto-Rhino-Laryngologie, Paris; ² Inserm, U514, Université Reims Champagne Ardenne, CHU Reims, Hôpital Maison Blanche, Reims; ⁴ Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Universitaire Nord Beaujon, Service d'Oto-Rhino-Laryngologie, Clichy; and ⁵ Clinique Pasteur, Brest, France

Correspondence and requests for reprints should be addressed to Marina Pretolani, Ph.D., Inserm Unité 700, Université Paris 7, Faculté de Médecine Denis Diderot, site Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France. E-mail: mpretol{at}bichat.inserm.fr

Abnormal epithelial repair to damage participates in airway remodeling in asthma by the paracrine regulation of mesenchymal cell functions. Retinoids control epithelial functions through nuclear retinoic acid receptor (RAR) and retinoid X receptor (RXR) activation, yet their expression and contribution to epithelial repair and to airway remodeling in asthma are unknown. We determined the plasma levels of retinol and the immunohistochemical expression of retinoid receptors in damaged and repaired bronchial epithelium from 9 control subjects, 10 subjects with intermittent asthma, 8 subjects with mild-to-moderate asthma, and 8 subjects with severe asthma. In addition, the effect of the retinoid receptor ligands, all-trans-retinoic acid, and 9-cis retinoic acid, on the synthesis of 38 factors potentially involved in epithelial repair and in airway remodeling was determined in human cultured airway epithelial cells and correlated with cell migration and proliferation. Circulating retinol was similar in the three patient groups. In contrast, the epithelial expression of RAR, RXR, and RXR was greater in subjects with severe asthma, as compared with patients with milder disease and to control subjects. Retinoid receptor expression correlated positively with the proportion of morphologically intact epithelium. In vitro, retinoids up-regulated the expression of the transcripts encoding transforming growth factor (TGF)-β1, metalloproteinase-9, β1-integrin, and hepatocyte growth factor receptor, and promoted wound repair and chemokinesis of human airway epithelial cells without altering proliferation. Cell treatment with an anti–TGF-β1 monoclonal antibody partially reduced retinoid-induced effects. Persistent interaction between retinoids and some of their receptors, which are overexpressed by the bronchial epithelium of individuals with severe asthma, may contribute to an abnormal repair and to airway remodeling, partly through TGF-β1 production.

Key Words: epithelium repair • airway remodeling • transforming-growth factor-β • metalloproteinase-9

CLINICAL RELEVANCE This study improves the understanding of the role played by retinoid–receptor interaction in the aberrant repair of the airway epithelium in asthma and on their link with the onset of airway remodeling.