Pulmonary hypertension (PH) associated with pulmonary fibrosis (PF) considerably worsens prognosis of interstitial lung diseases (ILD). RhoA/Rho-kinases (ROCK) pathway is implicated in high pulmonary vascular tone and pulmonary fibrosis but the effect of ROCK inhibitors on PH associated with PF is not known. We therefore aimed to determine whether long-term treatment with fasudil, a selective ROCK inhibitor, could attenuate PF and PH induced by bleomycin in mice. Male C57BL/6 mice received a single dose of intratracheal bleomycin (3.3 U/kg) to induce PF. Treatment with fasudil (30 mg kg(-1) day(-1)) was given intraperitoneally for 7, 14 or 21 days until mice underwent hemodynamic measurements. Right ventricular systolic pressure (RVSP) and RV/(LV + S) ratio were assessed. Lung inflammatory cells profiles, including macrophages, neutrophils, lymphocytes B and lymphocytes T were assessed by immunohistochemistry. Lung fibrosis was evaluated by histological and biochemical methods. Pulmonary arteriole muscularization and medial wall thickness (MWT) were evaluated by immunohistochemical staining for α-SMA. Bleomycin induced severe PF and PH in mice, associated with an increased RhoA/ROCK activity in the lung. Fasudil reduced lung inflammation and lung collagen content, and attenuated the increased RVSP, RV hypertrophy, and pulmonary vascular remodeling in bleomycin-intoxicated mice. Fasudil inhibited the increased activity of RhoA/ROCK pathway, and partly altered bleomycin-associated activation of TGF-β1/Smad pathway, via inhibition of Smad2/3 phosphorylation. The efficacy of long-term treatment with fasudil suggests that the blockade of RhoA/ROCK pathway may be a promising therapy for patients with ILD-associated PH.

译文

:与肺纤维化(PF)相关的肺动脉高压(PH)大大恶化了间质性肺疾病(ILD)的预后。 RhoA / Rho激酶(ROCK)通路与高肺血管张力和肺纤维化有关,但尚不清楚ROCK抑制剂对与PF相关的PH的影响。因此,我们旨在确定长期用选择性ROCK抑制剂法舒地尔治疗是否能减弱博来霉素诱导的小鼠的PF和PH。雄性C57BL / 6小鼠接受单剂量气管内博来霉素(3.3 U / kg)诱导PF。腹腔内给予法舒地尔(30 mg kg(-1)day(-1))治疗7、14或21天,直到小鼠接受血液动力学测量。评估右心室收缩压(RVSP)和RV /(LV S)比。通过免疫组织化学评估肺炎性细胞概况,包括巨噬细胞,嗜中性粒细胞,淋巴细胞B和淋巴细胞T。通过组织学和生化方法评估肺纤维化。通过免疫组织化学染色对α-SMA评估肺小动脉肌肉化和内侧壁厚度(MWT)。博来霉素诱导小鼠中严重的PF和PH,与肺中RhoA / ROCK活性增加有关。 Fasudil减少了博来霉素中毒小鼠的肺部炎症和肺胶原含量,并减轻了RVSP,RV肥大和肺血管重塑。 Fasudil通过抑制Smad2 / 3磷酸化来抑制RhoA / ROCK途径的活性增加,并部分改变与博莱霉素相关的TGF-β1/ Smad途径的活化。法舒地尔的长期治疗效果表明,RhoA / ROCK通路的阻断对于ILD相关性PH患者可能是一种有前途的治疗方法。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录