Epithelium expression and function of retinoid receptors in asthma.
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 RARgamma, RXRalpha, and RXRgamma 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)-beta1, metalloproteinase-9, beta1-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-beta1 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-beta1 production.
Druilhe
Anne
A
Inserm Unité 700, Université Paris 7, Faculté de Médecine Denis Diderot, site Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France.
Zahm
Jean-Marie
JM
Benayoun
Laurent
L
El Mehdi
Delphine
D
Grandsaigne
Martine
M
Dombret
Marie-Christine
MC
Mosnier
Isabelle
I
Feger
Benoit
B
Depondt
Joël
J
Aubier
Michel
M
Pretolani
Marina
M
D001249:Asthma / Q000473:pathology* / Q000503:physiopathology*; D001980:Bronchi / Q000378:metabolism / Q000601:surgery; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000378:metabolism; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012044:Regression Analysis; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology; D014801:Vitamin A / Q000097:blood; D014945:Wound Healing / Q000187:drug effects
D019012:Integrin beta1; D008024:Ligands; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D016212:Transforming Growth Factor beta; D014801:Vitamin A; D014212:Tretinoin; D019859:Proto-Oncogene Proteins c-met; D020780:Matrix Metalloproteinase 9