Abstract
Objective We aimed to understand the therapeutic potential of roflumilast to treat MHV-3 and SARS-CoV-2 lung infections, considering the anti-inflammatory effects of PDE4 inhibitors.Methods Roflumilast was administered as part of a therapeutic strategy at a dose of 1 mg/kg or 10 mg/kg or as part of a prophylactic strategy at a dose of 10 mg/kg in MHV-3-infected mice and at a dose of 10 mg/kg in SARS-CoV-2-infected mice. Lung histopathology, chemokines (CXCL-1 and CCL2), cytokines (IL-1β, IL-6, TNF, IFN-γ, IL-10 and TGFβ), neutrophil lung immunohistochemical staining (Ly6G+ cells), viral titration plaque assay, real-time PCR virus detection, and blood cell counts were examined.Results In the higher dose, treatment with roflumilast reduced lung injury in SARS-CoV-2 or MHV-3-infected mice without compromising viral clearance. In MHV-3-infected mice, the reduced lung injury was associated with decreased pulmonary chemokine levels and neutrophil accumulation in perivascular and peribronchiolar areas. However, roflumilast enhanced lung injury in MHV-3-infected mice in the prophylactic treatment strategy.Conclusion Our findings indicate that roflumilast has a time- and dose-dependent effect on reducing lung injury in betacoronavirus infection mouse models. Given the protection induced by roflumilast in inflammation, this suggests that PDE4 targeting could be a promising therapeutic avenue worth exploring.