Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.
Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.
复制标题
DOI：
10.1111/jcmm.13206
复制
发表时间：
2017-11
影响因子：
5.3
通讯作者：
Yang CT
中科院分区：
文献类型：
--
作者：
Li LF;Kao KC;Liu YY;Lin CW;Chen NH;Lee CS;Wang CW;Yang CT
急性呼吸窘迫综合征（ARDS）患者使用机械通气（MV）可增加肺部炎症和肺纤维化。Src在ARDS纤维增生期介导转化生长因子（TGF）-β1诱导的上皮-间质转化（EMT）中至关重要。直接阻断Src的多靶点酪氨酸激酶抑制剂NATRA已被批准用于治疗特发性肺纤维化。MV、EMT和Src之间相互作用的调控机制尚不清楚。在本研究中，我们假设尼达尼布可通过抑制Src通路抑制MV增强的博来霉素诱导的EMT和肺纤维化。在施用博来霉素以模拟急性肺损伤（ALI）后5天，将野生型或Src缺陷型C57 BL/6小鼠暴露于具有室内空气的低潮气量（VT）（6 ml/kg）或高VT（30 ml/kg）MV 5小时。MV前，每日一次口服尼达尼布，剂量为30、60和100 mg/kg，持续5天。未通气的小鼠用作对照组。野生型小鼠暴露于博来霉素后，高VT MV诱导微血管通透性、TGF-β1、丙二醛、Masson三色染色、胶原1a 1基因表达、EMT（通过α-平滑肌肌动蛋白染色增加和E-钙粘蛋白染色减少的共定位确定）和肺泡上皮细胞凋亡显著增加（P < 0.05）。使用Src缺陷小鼠经口尼达尼布模拟Src信号传导的遗传下调，抑制MV增强的促纤维化介质、EMT特征、上皮凋亡细胞死亡和病理性纤维化评分（P < 0.05）。我们的数据表明，尼达尼布部分通过抑制Src通路，减少了博来霉素诱导的ALI后高VT MV增强的EMT和肺纤维化。
Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)‐β1‐induced epithelial–mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV‐augmented bleomycin‐induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild‐type or Src‐deficient were exposed to low tidal volume (VT) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non‐ventilated mice were used as control groups. Following bleomycin exposure in wild‐type mice, high VT MV induced substantial increases in microvascular permeability, TGF‐β1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α‐smooth muscle actin and decreased staining of E‐cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src‐deficient mice, dampened the MV‐augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV‐augmented EMT and pulmonary fibrosis after bleomycin‐induced ALI, partly by inhibiting the Src pathway.
登录
查看更多内容
影响因子：
5
作者：
Abdalla M;Thompson L;Gurley E;Burke S;Ujjin J;Newsome R;Somanath PR
通讯作者：
Somanath PR
DOI：
10.1164/ajrccm.160.6.9811084
发表时间：
1999-12-01
影响因子：
24.7
作者：
Armstrong, L;Thickett, DR;Millar, AB
通讯作者：
Millar, AB
影响因子：
5.8
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
通讯作者：
Roth M
DOI：
10.1183/09031936.00196412
发表时间：
2014-01
期刊：
The European respiratory journal
影响因子：
--
作者：
Burnham EL;Janssen WJ;Riches DW;Moss M;Downey GP
通讯作者：
Downey GP
影响因子：
2.9
作者：
Ichikado K;Muranaka H;Gushima Y;Kotani T;Nader HM;Fujimoto K;Johkoh T;Iwamoto N;Kawamura K;Nagano J;Fukuda K;Hirata N;Yoshinaga T;Ichiyasu H;Tsumura S;Kohrogi H;Kawaguchi A;Yoshioka M;Sakuma T;Suga M
通讯作者：
Suga M