Professor University of Oklahoma Health Campus Oklahoma City, Oklahoma, United States
Disclosure(s):
Jordan P. Metcalf, MD: No financial relationships to disclose
Introduction/Rationale:
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:
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:
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.
