Department of Anesthesiology, Weifang Medical University, Weifang, China; Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Mol Immunol. 2020 Sep;125:15-22. doi: 10.1016/j.molimm.2020.06.013. Epub 2020 Jun 30.
PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.
PIM1 是一种丝氨酸/苏氨酸蛋白激酶，参与多种生物学过程。肺纤维化（PF）是肺损伤功能障碍修复的慢性病理结果，目前尚无有效的治疗方法。在本研究中，我们研究了 PIM1 抑制是否会改善博来霉素（BLM）诱导的肺纤维化。在 BLM 诱导的肺纤维化模型中，纤维化肺组织中 PIM1 持续上调。此外，PIM1 特异性抑制剂 SMI-4a 抑制 PIM1 可改善 BLM 诱导的死亡率。此外，SMI-4a 抑制羟脯氨酸沉积并逆转上皮-间充质转化（EMT）形成，其特征在于体内 E-钙粘蛋白和α-SMA 的表达。更重要的是，发现 ZEB1/E-钙粘蛋白途径与 BLM 诱导的肺纤维化密切相关。在体外处理 A549 细胞后，PIM1 通过依赖调节转录因子 ZEB1 的活性来调节 E-钙粘蛋白的表达。在 SMI-4a 给药后体内验证了这些发现。最后，通过气管内注射递送表达 shPIM1 的腺相关病毒，以在肺泡上皮中诱导长期 PIM1 缺乏。肺组织中 AAV 介导的 PIM1 敲低减轻了 BLM 诱导的肺纤维化，表现为胶原积累减少、肺组织病理学减轻和 EMT 逆转。这些发现增强了我们对 PIM1 在 BLM 诱导的肺纤维化中的作用的理解，并表明 PIM1 抑制可能是慢性肺损伤的一种潜在治疗策略。
