Resistin-like molecule-β (RELM-β) targets airways fibroblasts to effect remodelling in asthma: from mouse to man

Summary Background RELM‐β has been implicated in airways inflammation and remodelling in murine models. Its possible functions in human airways are largely unknown. The aim was to address the hypothesis that RELM‐β plays a role in extracellular matrix deposition in asthmatic airways. Methods The effects of RELM‐β gene deficiency were studied in a model of allergen exposure in mice sensitised and challenged with Aspergillus fumigatus (Af). RELM‐β expression was investigated in bronchial biopsies from asthmatic patients. Direct regulatory effects of RELM‐β on human lung fibroblasts were examined using primary cultures and the MRC5 cell line in vitro. Results Sensitisation and challenge of wild‐type mice with Af‐induced release of RELM‐β with a time course coincident with that of procollagen in the airways. Af‐induced expression of mRNA encoding some, but not all ECM in the lung parenchyma was attenuated in RELM‐β−/− mice. RELM‐β expression was significantly increased in the bronchial submucosa of human asthmatics compared with controls, and its expression correlated positively with that of fibronectin and α‐smooth muscle actin. In addition to epithelial cells, macrophages, fibroblasts and vascular endothelial cells formed the majority of cells expressing RELM‐β in the submucosa. Exposure to RELM‐β increased TGF‐β1, TGF‐β2, collagen I, fibronectin, smooth muscle α‐actin, laminin α1, and hyaluronan and proteoglycan link protein 1 (Hapl1) production as well as proliferation by human lung fibroblasts in vitro. These changes were associated with activation of ERK1/2 in MRC5 cells. Conclusion The data are consistent with the hypothesis that elevated RELM‐β expression in asthmatic airways contributes to airways remodelling at least partly by increasing fibroblast proliferation and differentiation with resulting deposition of extracellular matrix proteins.