Evaluation of the anti-inflammatory effects of PI3Kδ/γ inhibitors for treating acute lung injury

Phosphatidylinositol 3-kinase delta (PI3K delta) and gamma (PI3K gamma) are predominantly located in immune and hematopoietic cells. It is well-established that PI3K delta/gamma 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 (PI3K delta), duvelisib (PI3K delta/gamma), and copanlisib (pan-PI3K with preferential alpha/delta) and the clinical drug eganelisib (PI3K gamma), 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 delta and/or gamma 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.