Background: All-trans retinoic acid (ATRA) stimulates elastin synthesis by lung fibroblasts and induces alveolar regeneration in animal models of pulmonary emphysema. However, ATRA treatment has brought disappointing results in human emphysema. We hypothesized that a defect in the ATRA signalling pathway contributes to the defect of alveolar repair in the human emphysematous lung.
Methods: Fibroblasts were cultured from the lung of 10 Control and 8 Emphysema patients. Elastin mRNA was measured in those cells in the presence of incremental concentrations of ATRA. Retinoic Acid Receptors, Retinoic X Receptors and Cellular Retinoic Acid Binding Proteins (CRABP) 1 and 2 mRNAs were measured as well as the CRABP2 protein content. The effect of CRABP2 silencing on elastin expression in response to ATRA was measured in MRC5 lung fibroblasts.
Results: ATRA at 10-9M and 10-8M induced elastin mRNA expression by 182% and 126% in Control but not in Emphysema fibroblasts. RARs, RXRs and CRABP1 mRNAs were similarly expressed in Control and Emphysema fibroblasts while CRABP2 mRNA and protein were lower in Emphysema fibroblasts. CRABP2 silencing abrogated the induction of elastin expression by ATRA in MRC5 fibroblasts.
Conclusion: Pulmonary emphysema fibroblasts fail to express elastin under ATRA stimulation. CRABP2, which is necessary for elastin induction by ATRA in MRC-5 cells, is expressed at low levels in Emphysema fibroblasts. This alteration in the retinoic acid signalling pathway in lung fibroblasts may contribute to the defect of alveolar repair in human pulmonary emphysema. These results are the first demonstration of the involvement of CRABP2 in elastin expression.