title: Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice : ANP for pulmonary fibrosis.
abstract: Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice.
  
  
  
  Mice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-β (TGF-β) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor.
  
  
  
  ANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium-specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-β stimulation.
  
  
  
  ANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.|Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-City, Osaka, 545-8585, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan. nojiri@ri.ncvc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nojiri
authors.affiliation: Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-City, Osaka, 545-8585, Japan. kkonishi.0220@gmail.com.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Konishi
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hino
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.|Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-City, Osaka, 545-8585, Japan.
authors.forename: Yohkoh
authors.initials: Y
authors.lastname: Kyomoto
authors.affiliation: Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-City, Osaka, 545-8585, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Asai
authors.affiliation: Department of Respiratory Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-City, Osaka, 545-8585, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita-City, Osaka, 565-8565, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage*; D001761:Bleomycin; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007155:Immunologic Factors / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D001761:Bleomycin; D009320:Atrial Natriuretic Factor
keywords: Atrial natriuretic peptide; Bleomycin; Pulmonary fibrosis; Transforming growth factor-β; Vascular endothelial cell