Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF.
Nitric oxide mediates bleomycin-induced angiogenesis and pulmonary fibrosis via regulation of VEGF.
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DOI：
10.1002/jcb.25192
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发表时间：
2015-11
影响因子：
4
通讯作者：
Azad N
中科院分区：
文献类型：
--
作者：
Iyer AK;Ramesh V;Castro CA;Kaushik V;Kulkarni YM;Wright CA;Venkatadri R;Rojanasakul Y;Azad N
肺纤维化是一种以成纤维细胞增殖增加、细胞外基质沉积水平增加和血管生成增加为特征的进行性肺病。虽然血管生成介质的失调与肺纤维化有关，但涉及的特异性限速血管生成标志物及其在肺纤维化进展中的作用仍不清楚。我们证明博来霉素治疗诱导血管生成，并且使用抗VEGF抗体CBO-P11抑制中心血管生成介质VEGF显著减弱体内博来霉素诱导的肺纤维化。观察到博来霉素诱导的一氧化氮（NO）是通过PI 3 k/Akt途径调节VEGF的关键上游调节因子。血管内皮生长因子调节其他重要的血管生成蛋白，包括派-1和IL-8在博莱霉素暴露的反应。NO和VEGF活性的抑制显着减轻博莱霉素诱导的血管生成和纤维化反应。NO和VEGF是博来霉素诱导的肺纤维化的关键介质，并且可以作为对抗这种使人衰弱的疾病的重要靶点。总之，我们的数据表明，血管生成介质在博来霉素诱导的肺纤维化的发病机制中起重要作用。
Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis.