Okamoto Atsuko, Nojiri Takashi, Konishi Kazuhisa, Tokudome Takeshi, Miura Koichi, Hosoda Hiroshi, Hino Jun, Miyazato Mikiya, Kyomoto Yohkoh, Asai Kazuhisa, Hirata Kazuto, Kangawa Kenji
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.
Respir Res. 2017 Jan 3;18(1):1. doi: 10.1186/s12931-016-0492-7.
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.
肺纤维化是一种危及生命的疾病，其特征为进行性呼吸困难和肺功能恶化。心房利钠肽（ANP）是一种源自心脏的分泌肽，在日本临床上用于治疗急性心力衰竭，对包括心脏、血管、肾脏和肺在内的各种器官具有广泛的保护作用。其治疗特性表现为通过鸟苷酸环化酶 - A（GC - A）受体介导的抗炎和抗纤维化活性。我们推测ANP对博来霉素（BLM）诱导的小鼠肺纤维化具有抗纤维化和抗炎作用。
将小鼠分为三组：正常对照组、给予载体的BLM组和给予ANP的BLM组。在给予BLM（1mg/kg）之前开始皮下给予ANP（通过渗透泵，0.5μg/kg/min）或载体，并持续至小鼠处死。在给予BLM后7天或21天，根据组织学发现和支气管肺泡灌洗液分析评估肺部的纤维化变化和炎症细胞浸润。此外，在血管内皮特异性GC - A过表达的小鼠中评估BLM诱导的纤维化和炎症。最后，使用稳定表达GC - A受体的永生化小鼠内皮细胞研究ANP对转化生长因子 - β（TGF - β）信号传导的减弱作用。
ANP显著降低了BLM给药后肺纤维化面积和肺部炎症细胞浸润。此外，在血管内皮特异性GC - A过表达的小鼠中也观察到了ANP的类似作用。在培养的小鼠内皮细胞中，ANP降低了TGF - β刺激后Smad2的磷酸化。
ANP通过血管内皮细胞对BLM诱导的肺纤维化发挥保护作用。
