Purpose: Duvelisib (IPI-145), a novel targeted PI3K-δ,γ dual inhibitor is a medication used to treat hematologic malignancy. Phosphatidylinositol-3-kinase (PI3K)-δ and -γ are highly expressed in leukocytes in contrast to the other class IA PI3Ks p110α and p110β expressed ubiquitously. Theses two isoforms of PI3K plays a role in immune/ inflammatory responses in the white blood cells, although they have some distinct functions. Recent studies have demonstrated that epithelial cells (ECs) may also have primary immune functions; however, the role of PI3K- δ,γ isoforms in epithelial cell-mediated immune responses are still unclear. Methods: In this study, using LPS-induced acute lung injury animal model, we aimed to evaluate the pharmacologic effects of duvelisib on acute lung injury and to investigate the action mechanism of PI3K-δ,γ dual inhibitor focusing on MHC II-VEGFR2 epithelial expression in LPS-induced lung injury. Results: Our results showed that LPS-instilled mice showed typical features of severe lung inflammation; pulmonary neutrophilia with increases in the production of inflammatory cytokines, vascular leakage, VEGF production, and nuclear translocation of nuclear factor-κB (NF-κB) and PI3K-δ and - γ isoform activation. In addition, confocal microscopic analysis revealed that the expression of VEGFR2 and MHC II were substantially increased in LPS-stimulated lung, including the respiratory epithelium. The treatment with duvelisib substantially improved the LPS-induced pulmonary neutrophilic inflammation compared to the mice treated with vehicle only. Interestingly, the increased epithelial expression of MHC II and VEGFR2 was also reduced significantly. Conclusion: These findings suggest that PI3K-δ,γ dual inhibitor can be a promising therapeutic agent for the treatment of acute lung injury, at least in part, through the attenuation of VEGFR2-MHC II epithelial expression.