Adrenomedullin Ameliorates Pulmonary Fibrosis by Regulating TGF-[beta]-Smads Signaling and Myofibroblast Differentiation

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...

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Veröffentlicht in:Endocrinology (Philadelphia) 2021-08, Vol.162 (8), p.1
Hauptverfasser: Wei, Yangxuan, Tanaka, Megumu, Sakurai, Takayuki, Kamiyoshi, Akiko, Ichikawa-Shindo, Yuka, Kawate, Hisaka, Cui, Nanqi, Kakihara, Shinji, Zhao, Yunlu, Aruga, Kohsuke, Sanjo, Hideki, Shindo, Takayuki
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Sprache:eng
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Zusammenfassung: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-[beta] increased the numbers of [alpha]-SMA-positive myofibroblasts, which were more prominent among AM+/- cells. TGF-[beta]-stimulated AM+/- myofibroblasts were larger and exhibited greater contractility and extracellular matrix production than WT cells. These cells were [alpha]-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-[beta]-Smad3 signaling, microRNA-21 activity and differentiation into non-p-MyoFbs. Key Words: adrenomedullin, RAMP2, pulmonary fibrosis. Myofibroblast, TGF-[beta], Smad, microRNA-21
ISSN:0013-7227
DOI:10.1210/endocr/bqab090