Xiong Wendian, Jia Lei, Cai Yanfei, Chen Yun, Gao Mingzhu, Jin Jian, Zhu Jingyu
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China.
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China.
Immunobiology. 2023 Nov;228(6):152753. doi: 10.1016/j.imbio.2023.152753. Epub 2023 Oct 5.
Phosphatidylinositol 3-kinase delta (PI3Kδ) and gamma (PI3Kγ) are predominantly located in immune and hematopoietic cells. It is well-established that PI3Kδ/γ plays important roles in the immune system and participates in inflammation; hence, it could be a potential target for anti-inflammatory therapy. Currently, several PI3K inhibitors are used clinically to treat cancers with aberrant PI3K signaling; however, their role in treating acute respiratory inflammatory diseases has rarely been explored. Herein, we investigated the potential anti-inflammatory activities of several pharmacological PI3K inhibitors, including marketed drugs idelalisib (PI3Kδ), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K with preferential α/δ) and the clinical drug eganelisib (PI3Kγ), for treating acute lung injury (ALI). In the lipopolysaccharide-induced RAW264.7 macrophage inflammatory model, the four inhibitors significantly suppressed proinflammatory cytokine expression by inhibiting the PI3K signaling pathway. Oral administration of PI3K inhibitors markedly improved lung injury in a murine model of ALI. PI3K pathway inhibition decreased inflammatory cell infiltration and totalprotein levels, as well as reduced the expression of associated lung inflammatory factors. Collectively, all four representative PI3K inhibitors exerted prominent anti-inflammatory properties, indicating that PI3K δ and/or γ inhibition could be ideal targets to treat respiratory inflammatory diseases by reducing the inflammatory response. The findings of the current study provide a new basis for utilizing PI3K inhibitors to treat acute respiratory inflammatory diseases.
磷脂酰肌醇3激酶δ（PI3Kδ）和γ（PI3Kγ）主要位于免疫细胞和造血细胞中。PI3Kδ/γ在免疫系统中发挥重要作用并参与炎症反应，这一点已得到充分证实；因此，它可能是抗炎治疗的潜在靶点。目前，几种PI3K抑制剂已在临床上用于治疗具有异常PI3K信号传导的癌症；然而，它们在治疗急性呼吸道炎症性疾病中的作用鲜有研究。在此，我们研究了几种药理PI3K抑制剂的潜在抗炎活性，包括已上市药物idelalisib（PI3Kδ）、duvelisib（PI3Kδ/γ）和copanlisib（优先作用于α/δ的泛PI3K）以及临床药物eganelisib（PI3Kγ），用于治疗急性肺损伤（ALI）。在脂多糖诱导的RAW264.7巨噬细胞炎症模型中，这四种抑制剂通过抑制PI3K信号通路显著抑制促炎细胞因子的表达。在ALI小鼠模型中口服PI3K抑制剂可明显改善肺损伤。PI3K通路抑制可减少炎症细胞浸润和总蛋白水平，并降低相关肺炎症因子的表达。总体而言，所有四种代表性的PI3K抑制剂均具有显著的抗炎特性，表明抑制PI3Kδ和/或γ可能是通过减轻炎症反应来治疗呼吸道炎症性疾病的理想靶点。本研究结果为利用PI3K抑制剂治疗急性呼吸道炎症性疾病提供了新的依据。
