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Endocrinology ; 162(8)2021 08 01.
Article in English | MEDLINE | ID: mdl-33955458

ABSTRACT

Pulmonary fibrosis is an irreversible, potentially fatal disease. Adrenomedullin (AM) is a multifunctional peptide whose activity is regulated by receptor activity-modifying protein 2 (RAMP2). In the present study, we used the bleomycin (BLM)-induced mouse pulmonary fibrosis model to investigate the pathophysiological significance of the AM-RAMP2 system in the lung. In heterozygous AM knockout mice (AM+/-), hydroxyproline content and Ashcroft scores reflecting the fibrosis severity were significantly higher than in wild-type mice (WT). During the acute phase after BLM administration, FACS analysis showed significant increases in eosinophil, monocyte, and neutrophil infiltration into the lungs of AM+/-. During the chronic phase, fibrosis-related molecules were upregulated in AM+/-. Notably, nearly identical changes were observed in RAMP2+/-. AM administration reduced fibrosis severity. In the lungs of BLM-administered AM+/-, the activation level of Smad3, a receptor-activated Smad, was higher than in WT. In addition, Smad7, an antagonistic Smad, was downregulated and microRNA-21, which targets Smad7, was upregulated compared to WT. Isolated AM+/- lung fibroblasts showed less proliferation and migration capacity than WT fibroblasts. Stimulation with TGF-ß increased the numbers of α-SMA-positive myofibroblasts, which were more prominent among AM+/- cells. TGF-ß-stimulated AM+/- myofibroblasts were larger and exhibited greater contractility and extracellular matrix production than WT cells. These cells were α-SMA (+), F-actin (+), and Ki-67(-) and appeared to be nonproliferating myofibroblasts (non-p-MyoFbs), which contribute to the severity of fibrosis. Our findings suggest that in addition to suppressing inflammation, the AM-RAMP2 system ameliorates pulmonary fibrosis by suppressing TGF-ß-Smad3 signaling, microRNA-21 activity and differentiation into non-p-MyoFbs.


Subject(s)
Adrenomedullin/therapeutic use , Myofibroblasts/drug effects , Pulmonary Fibrosis/drug therapy , Receptor Activity-Modifying Protein 2/metabolism , Transforming Growth Factor beta/metabolism , Adrenomedullin/metabolism , Adrenomedullin/pharmacology , Animals , Bleomycin , Cell Differentiation/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Infusions, Intravenous , Male , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/metabolism , Myofibroblasts/metabolism , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/prevention & control , Smad7 Protein/metabolism , Transforming Growth Factor beta/pharmacology
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