Ameliorative Effect of Mepenzolate Bromide against Pulmonary Fibrosis
Ameliorative Effect of Mepenzolate Bromide against Pulmonary Fibrosis
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DOI：
10.1124/jpet.114.213009
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
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作者：
Kurotsu, Shota;Tanaka, Ken-ichiro;Mizushima, Tohru
特发性肺纤维化被认为涉及由活性氧（ROS）引起的肺损伤，其继而是异常纤维化。转化生长因子（TGF）-β 1诱导的肌成纤维细胞数量增加在这种异常纤维化中起重要作用。我们最近发现，已在临床上用于治疗胃肠道疾病的溴化甲哌唑酯（甲哌唑酯）具有降低ROS的特性。在本研究中，我们研究了甲哌唑酯对博莱霉素诱导的小鼠肺纤维化和肺功能障碍的影响。通过组织病理学评价和羟脯氨酸水平测定来评估肺纤维化的严重程度。使用计算机控制的呼吸机评估肺力学（弹性）和呼吸功能[用力肺活量（FVC）]。通过监测经皮动脉血氧饱和度（SpO（2））评价呼吸功能。博莱霉素治疗前腹腔内注射甲哌唑酯可减轻肺纤维化程度和肺力学变化，与对照组相比，FVC和SpO（2）均显著恢复。此外，即使在纤维化发生后给药，甲哌唑酯也能产生治疗效果。给予甲哌唑酯还可预防博莱霉素诱导的肺细胞死亡和炎症反应，并增加肌成纤维细胞数量。在博莱霉素治疗的情况下，美喷唑还降低NADPH氧化酶活性和活性TGF-β 1水平或增加谷胱甘肽S-转移酶（GST）活性。这些结果表明，气管内施用甲哌唑酯减少了博莱霉素诱导的小鼠肺纤维化和肺功能障碍。这些作用可能是由于该药物抑制NADPH氧化酶和TGF-β_1活性以及刺激GST活性所致。
Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-beta 1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO(2)). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO(2) compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-b1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-b1 activities and its stimulatory effect on GST.