Dual Targeting of MEK and PI3K Pathways Attenuates Established and Progressive Pulmonary Fibrosis

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.肺纤维化（Pulmonary fibrosis）常由上皮损伤诱发，进而在肺部形成纤维化病灶，病灶进展后会损害气体交换功能，最终导致患者死亡。近期针对炎症或特定分子靶点的药物临床试验均告失败，这提示若要有效逆转已形成且处于进展中的纤维化，需要同时调控多条通路及细胞过程。尽管在人类纤维化肺组织样本中已检测到丝裂原活化蛋白激酶（MAPK）通路与磷脂酰肌醇3-激酶（PI3K）通路的激活，但联合在体调控这两条通路的治疗获益仍未明确。在转基因小鼠的肺上皮细胞中过表达转化生长因子α（TGFα），可形成与人类肺纤维化相似的纤维化病灶；本团队此前的研究显示，单独抑制MAPK或PI3K通路均可改变纤维化的进展进程。本研究旨在探究同时抑制MAPK与PI3K信号通路，是否能成为治疗已形成且进展性肺纤维化的更有效策略。研究结果显示，与单独抑制任一通路相比，同时抑制两条通路在减轻纤维化负荷方面具有叠加效应，包括降低TGFα转基因小鼠的肺重量、胸膜厚度及肺部总胶原含量。本研究证实，联合抑制丝裂原活化蛋白激酶激酶（MEK）与PI3K通路，可消除纤维化相关的增殖性改变及肌成纤维细胞聚集，因此对于此类通路发挥作用的人类纤维化肺疾病，该联合疗法可作为一种治疗选择。