Title: Resistin-like molecule-β (RELM-β) targets airways fibroblasts to effect remodelling in asthma: from mouse to man.
Authors: Fang, C L; Yin, L J; Sharma, S; Kierstein, S; Wu, H F; Eid, G; Haczku, A; Corrigan, C J; Ying, S
Published In Clin Exp Allergy, (2015 May)
Abstract: 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.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.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.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.
PubMed ID: 25545115
MeSH Terms: Actins/metabolism; Airway Remodeling*/genetics; Airway Remodeling*/immunology; Animals; Asthma/immunology; Asthma/metabolism*; Asthma/pathology*; Bronchoalveolar Lavage Fluid; Cell Proliferation; Collagen/metabolism; Disease Models, Animal; Extracellular Matrix; Fibroblasts/metabolism*; Genotype; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism*; Laminin/metabolism; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Phosphorylation; Respiratory Mucosa/immunology; Respiratory Mucosa/metabolism*; Respiratory Mucosa/pathology*; Transforming Growth Factor beta1/metabolism; Transforming Growth Factor beta2/metabolism