Investigation into the anti-airway inflammatory role of the PI3Kγ inhibitor JN-PK1: An in vitro and in vivo study

• Published in: International immunopharmacology 2022-10, Vol.111, p.109102-109102, Article 109102
• Main Authors: Xiong, Wendian, Jia, Lei, Liang, Junjie, Cai, Yanfei, Chen, Yun, Nie, Yunjuan, Jin, Jian, Zhu, Jingyu
• Format: Article
• Language: English
• Subjects: Asthma; Inflammation; Inflammatory airway disease; Ovalbumin; PI3Kγ inhibitor; RAW264.7 macrophage
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109102

[Display omitted] •JN-PK1 concentration and time dependently inhibited the PI3Kγ-dependent cellular C5a-induced AKT Ser473 phosphorylation in RAW264.7 macrophages.•JN-PK1 suppressed the LPS-induced pro-inflammatory cytokines expression and nitric oxide production in RAW264.7 macrophages.•Oral administration of JN-PK1 attenuated OVA-induced asthma in association with the inhibition of the PI3K signaling pathway.•JN-PK1 inhibited increases in inflammatory cell counts and reduced T-helper type 2 cytokine production in an OVA-induced asthma model. Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been proven to be a potential target for the treatment of inflammatory diseases of the airway; however, there are few reports of selective PI3Kγ inhibitors being used in the field of airway inflammation thus far. Herein, a study employing in vitro and in vivo methodologies was carried out to assess the anti-airway inflammatory effects of JN-PK1, a selective PI3Kγ inhibitor. In RAW264.7 macrophages, JN-PK1 inhibited PI3Kγ-dependent, cellular C5a-induced AKT Ser473 phosphorylation in a concentration- and time-dependent manner and had no significant effect on cell viability.Furthermore, JN-PK1 significantly suppressed LPS-induced, proinflammatory cytokine expression and nitric oxide production through inhibition of the PI3K signaling pathway in RAW264.7 cells. Then, a murine asthma model was established to evaluate the anti-airway inflammation effect of JN-PK1. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to develop an inflammatory response, fibrosis formation, and other airway changes similar to the symptomatology of asthma in humans. Oral administration of JN-PK1 remarkably attenuated OVA-induced asthma in association with the inhibition of the PI3K signaling pathway. That is to say, the oral administration significantly inhibited increases in inflammatory cell counts and reduced T-helper type 2 cytokine production in bronchoalveolar lavage fluid. Pulmonary histological studies showed that oral administration of JN-PK1 not only reduced the infiltration of inflammatory cells but also retarded airway inflammation and fibration. Taken together, JN-PK1 could be developed as a promising candidate for inflammation therapy, and our findings support some potential for therapeutic inhibition of PI3Kγ to treat inflammatory airway diseases.