Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis.
Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis.
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DOI：
10.1371/journal.pone.0086536
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hardie WD
中科院分区：
文献类型：
--
作者：
Madala SK;Edukulla R;Phatak M;Schmidt S;Davidson C;Acciani TH;Korfhagen TR;Medvedovic M;Lecras TD;Wagner K;Hardie WD
肺纤维化通常由上皮损伤引发，导致肺中纤维化病变的形成，其进展损害气体交换并最终导致死亡。最近使用靶向炎症或特定分子的药物的临床试验失败了，这表明需要减弱多种途径和细胞过程以有效逆转已建立和进行性纤维化。尽管在人纤维化肺样品中已经检测到MAPK和PI3K途径的激活，但是MAPK和PI3K途径组合的体内调节的治疗益处是未知的。转基因小鼠肺上皮中TGFα的过表达导致与人类肺纤维化中发现的纤维化病变相似的纤维化病变的形成，并且我们小组先前的工作表明MAPK或PI3K通路的抑制剂可以改变纤维化的进展。在这项研究中，我们试图确定同时抑制MAPK和PI3K信号通路是否是一种更有效的治疗策略，用于建立和进行性肺纤维化。我们的研究结果表明，与单独抑制任一途径相比，抑制两种途径在减少纤维化负荷方面具有累加效应，包括降低TGFα小鼠的肺重量、胸膜厚度和肺中的总胶原蛋白。这项研究表明，抑制MEK和PI3K的组合消除与纤维化和myfibroblast积累相关的增殖变化，因此可以作为治疗人类纤维化肺病的治疗选择，其中这些途径发挥作用。
Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFα in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFα mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1165/rcmb.2006-0455oc
发表时间：
2007-09-01
影响因子：
6.4
作者：
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通讯作者：
Leikauf, George D.
影响因子：
5.8
作者：
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通讯作者：
Gentleman, Robert
影响因子：
6.2
作者：
Kis K;Liu X;Hagood JS
通讯作者：
Hagood JS
影响因子：
5
作者：
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通讯作者：
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