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

TY - JOUR

T1 - Resistin-like molecule-β (RELM-β) targets airways fibroblasts to effect remodelling in asthma

T2 - From mouse to man

AU - Fang, C. L.

AU - Yin, L. J.

AU - Sharma, S.

AU - Kierstein, S.

AU - Wu, H. F.

AU - Eid, G.

AU - Haczku, A.

AU - Corrigan, C. J.

AU - Ying, S.

PY - 2015/4/16

Y1 - 2015/4/16

N2 - 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.

AB - 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.

KW - Asthma

KW - Collagen

KW - Fibronectin

KW - RELM-β

KW - Remodelling

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=84927713505&partnerID=8YFLogxK

U2 - 10.1111/cea.12481

DO - 10.1111/cea.12481

M3 - Article

AN - SCOPUS:84927713505

SN - 0954-7894

VL - 45

SP - 940

EP - 952

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

IS - 5

ER -