CYP1B1 Inhibitor Chlorprothixene Increased Survival Rate of Cigarette Smoke-exposed Mice in Lethal IAV Infection 2253710

Abstract

Abstract Introduction Cigarette smoke (CS) exposure increases the incidence and severity of influenza A virus (IAV) infections in humans, and increases mortality in mice. Cytochrome P450 family 1 subfamily B member 1 (CYP1B1) is highly induced in CS-exposed humans, and genetic deletion in mice protects against CS-enhanced susceptibility to IAV infection. Several approved drugs inhibit CYP1B1. Repurposing them to target CYP1B1 is a translational strategy to improve influenza outcomes in smokers. Methods To test CYP1B1’s effects on survival during IAV infection, we used an in vivo mouse model. Therapeutic doses of CYP1B1 inhibitors–ticagrelor (5 mg/kg), chlorprothixene (1.3 mg/kg), and TMS (1.5 mg/kg)–were administered daily for 9 days post-infection (p.i.) in CS-exposed, IAV-infected mice. We compared survival, lung-to-body weight ratios, and immune responses between treated and untreated groups following IAV, with or without prior CS exposure. Results IAV infection survival was 36% in CS and 80% in nonsmoking (NS) mice. The CYP1B1 inhibitors ticagrelor and TMS did not improve survival in CS-exposed, IAV-infected mice (43 and 36% survival, respectively). Chlorprothixene treatment at 1.3 mg/kg increased survival to 64% in CS-exposed IAV-infected mice but not in NS IAV-infected mice (67% survival), and TMS treatment at the same dose worsened outcomes in NS IAV-infected mice (40% survival), suggesting that chlorprothixene benefits CS-exposed, IAV-infected mice. We tested 5.2 mg/kg and 0.26 mg/kg concentrations of chlorprothixene in CS-exposed, IAV infected mice. Both doses yielded lower survival rates (50% and 40%) than the 1.3 mg/kg dose. CS exposure suppressed total immune cell counts in bronchoalveolar lavage fluid (BALF). Chlorprothixene treatment restored immune cell recruitment in BALF and attenuated lung injury. Conclusion Conclusions: Our findings show treatment with chlorprothixene improved survival outcomes and decreased lung injury during IAV infection in CS-exposed mice. Funding Source Merit Review Program of the Department of Veterans Affairs, grant number I01 BX005023 to JPM, and the National Institute of General Medical Sciences, grant number P30GM149368 to JPM. Topic Categories Vaccines and Immunotherapy (VAC)