A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin-induced pulmonary fibrosis.
A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin-induced pulmonary fibrosis.
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DOI：
10.1002/pmic.201500171
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发表时间：
2016-01
期刊：
影响因子：
3.4
通讯作者：
Azad N
中科院分区：
文献类型：
--
作者：
Kulkarni YM;Dutta S;Iyer AK;Venkatadri R;Kaushik V;Ramesh V;Wright CA;Semmes OJ;Yakisich JS;Azad N
特发性肺纤维化（IPF）是一种进行性肺部疾病，大多数患者诊断后的预期寿命不到5年。IPF的分子特征不佳导致对疾病发病机制的了解不足，导致缺乏有效的治疗方法。在这项研究中，我们将基于无标记LC-MS的方法与系统生物学相结合，以确定蛋白质相互作用网络中的信号通路和调控节点，这些网络控制可能导致IPF的表型变化。对响应于博来霉素处理而调节的蛋白质的抗纤维化途径分析鉴定了PI 3 K/Akt和Wnt信号传导为最显著的促纤维化途径。对响应于血管内皮生长因子（VEGF）抑制剂（CBO-P11）治疗而调节的蛋白质的类似分析鉴定了自然杀伤细胞信号传导和PTEN信号传导为最显著的抗纤维化途径。雷帕霉素（mTOR）和细胞外信号调节激酶（ERK）的机制/哺乳动物靶被确定为促纤维化和抗纤维化反应的关键介质，其中博来霉素（BLM）治疗导致表达增加，VEGF抑制剂治疗减弱mTOR和ERK的表达。使用肺纤维化的BLM小鼠模型和VEGF抑制剂CBO-P11作为治疗措施，我们确定了一套全面的信号通路和蛋白质，有助于肺纤维化的发病机制，可以靶向治疗这种致命的疾病。
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a life expectancy of less than 5 years post diagnosis for most patients. Poor molecular characterization of IPF has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies. In this study, we have integrated a label-free LC-MS based approach with systems biology to identify signaling pathways and regulatory nodes within protein interaction networks that govern phenotypic changes that may lead to IPF. Ingenuity Pathway Analysis of proteins modulated in response to bleomycin treatment identified PI3K/Akt and Wnt signaling as the most significant profibrotic pathways. Similar analysis of proteins modulated in response to vascular endothelial growth factor (VEGF) inhibitor (CBO-P11) treatment identified natural killer cell signaling and PTEN signaling as the most significant antifibrotic pathways. Mechanistic/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) were identified to be key mediators of pro- and antifibrotic response, where bleomycin (BLM) treatment resulted in increased expression and VEGF inhibitor treatment attenuated expression of mTOR and ERK. Using a BLM mouse model of pulmonary fibrosis and VEGF inhibitor CBO-P11 as a therapeutic measure, we identified a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis that can be targeted for therapy against this fatal disease.