Evaluating the Anti-inflammatory Potential of JN-KI3: The Therapeutic Role of PI3Kγ-Selective Inhibitors in Asthma...

Asthma is a chronic airway inflammatory disease of the airways characterized by the involvement of numerous inflammatory cells and factors. Therefore, targeting airway inflammation is one of the crucial strategies for developing novel drugs in the treatment of asthma. Phosphoinositide 3-kinase gamma (PI3Kγ) has been demonstrated to have a significant impact on inflammation and immune responses, thus emerging as a promising therapeutic target for airway inflammatory disease, including asthma. There are few studies reporting on the therapeutic effects of PI3Kγ-selective inhibitors in asthma disease. In this study, we investigated the anti-inflammatory and therapeutic effects of PI3Kγ-selective inhibitor JN-KI3 for treating asthma by utilizing both in vivo and in vitro approaches, thereby proving that PI3Kγ-selective inhibitors could be valuable in the treatment of asthma. In RAW264.7 macrophages, JN-KI3 effectively suppressed C5a-induced Akt phosphorylation in a concentration-dependent manner, with no discernible toxicity observed in RAW264.7 cells. Furthermore, JN-KI3 can inhibit the PI3K/Akt signaling pathway in lipopolysaccharide-induced RAW264.7 cells, leading to the suppression of transcription and expression of the classical inflammatory cytokines in a concentration-dependent manner. Finally, an ovalbumin-induced murine asthma model was constructed to evaluate the initial therapeutic effect of JN-KI3 for treating asthma. Oral administration of JN-KI3 inhibited the infiltration of inflammatory cells and the expression of T-helper type 2 cytokines in bronchoalveolar lavage fluid, which was associated with the suppression of the PI3K signaling pathway. Lung tissue and immunohistochemical studies demonstrated that JN-KI3 inhibited the accumulation of inflammatory cells around the bronchus and blood vessels, as well as the secretion of mucus and excessive deposition of collagen around the airway. In addition, it reduced the infiltration of white blood cells into the lungs. In summary, JN-KI3 shows promise as a candidate for the treatment of asthma. Our study also suggests that the inhibitory effects of PI3Kγ on inflammation could offer an additional therapeutic strategy for pulmonary inflammatory diseases.