Avaliação do efeito do inibidor seletivo de PDE, roflumilaste, e combinações na síndrome respiratória aguda grave induzida por coronavírus murino

Abstract

In 2019, a novel betacoronavirus known as SARS-CoV-2 emerged. The disease associated with SARS-CoV-2 infection, known as Corona virus disease 2019 (COVID-19), is characterized by pneumonia with pulmonary infiltrate, acute respiratory failure and sepsis, potentially resulting in severe illness and mortality. Several experimental models have been developed to investigate the pathogenesis of COVID-19 and facilitate the development of novel therapies. Infection of mice with the murine hepatitis virus (MHV), a member of the betacoronavirus genus, results in the development of an inflammatory lung disease with features similar to COVID-19, including increased inflammatory mediators, leukocyte accumulation, and lung tissue damage. In this study, our aim was to assess the effects of roflumilast, a selective phosphodiesterase 4 (PDE4) inhibitor that degrades cAMP, either alone or in combination with dexamethasone, in treating pulmonary inflammation associated with MHV-3 infection, a severe murine model of COVID, as well as MHV-A59, a mild/moderate murine model of COVID. Animals infected with MHV-3 and therapeutically treated with 10 mg/kg of roflumilast exhibited reduced lung damage and levels of CCL2 and CXCL1. Meanwhile, therapy with 1 mg/kg of roflumilast had no effect on these parameters, indicating that roflumilast has a dose-dependent effect. Adopting a prophylactic treatment strategy with roflumilast increased lung injury in MHV-3-infected mice, indicating that roflumilast has also a time-dependent effect. The combined treatment of 1 mg/kg of roflumilast and 0.1 mg/kg of dexamethasone, doses that individually do not effectively improve lung injury, reduced lung inflammation in animals infected with MHV-3. In addition, we showed that animals infected with MHV-A59 and therapeutically treated with 10 mg/kg of roflumilast had lower levels of CCL2 and CXCL1 in lung tissue and total proteins in bronchoalveolar lavage. In conclusion, we showed that treatment with roflumilast has a dose- and time-dependent effect in alleviating MHV-induced lung inflammation, and that combining roflumilast and dexamethasone has an additive or synergistic effect in alleviating lung injury associated with MHV infection.