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

BackgroundRELM- 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- plays a role in extracellular matrix deposition in asthmatic airways. MethodsThe effects of RELM- gene deficiency were studied in a model of allergen exposure in mice sensitised and challenged with Aspergillus fumigatus (Af). RELM- expression was investigated in bronchial biopsies from asthmatic patients. Direct regulatory effects of RELM- on human lung fibroblasts were examined using primary cultures and the MRC5 cell line in vitro. ResultsSensitisation and challenge of wild-type mice with Af-induced release of RELM- 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--/- mice. RELM- expression was significantly increased in the bronchial submucosa of human asthmatics compared with controls, and its expression correlated positively with that of fibronectin and -smooth muscle actin. In addition to epithelial cells, macrophages, fibroblasts and vascular endothelial cells formed the majority of cells expressing RELM- in the submucosa. Exposure to RELM- increased TGF-1, TGF-2, collagen I, fibronectin, smooth muscle -actin, laminin 1, 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. ConclusionThe data are consistent with the hypothesis that elevated RELM- expression in asthmatic airways contributes to airways remodelling at least partly by increasing fibroblast proliferation and differentiation with resulting deposition of extracellular matrix proteins.