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Respiratory Research
Published in: Respiratory Research 1/2016

Open Access 01-12-2016 | Research

C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice

Authors: Toru Kimura, Takashi Nojiri, Jun Hino, Hiroshi Hosoda, Koichi Miura, Yasushi Shintani, Masayoshi Inoue, Masahiro Zenitani, Hiroyuki Takabatake, Mikiya Miyazato, Meinoshin Okumura, Kenji Kangawa

Published in: Respiratory Research | Issue 1/2016

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Abstract

Background

Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts.

Methods

C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription.

Results

CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β–induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22α, indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA.

Conclusions

These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.
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Metadata
Title
C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice
Authors
Toru Kimura
Takashi Nojiri
Jun Hino
Hiroshi Hosoda
Koichi Miura
Yasushi Shintani
Masayoshi Inoue
Masahiro Zenitani
Hiroyuki Takabatake
Mikiya Miyazato
Meinoshin Okumura
Kenji Kangawa
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2016
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-016-0335-6

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