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Objective <p>We aimed to understand the potential therapeutic and anti-inflammatory effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast in models of pulmonary infection caused by betacoronaviruses.</p> Methods <p>Mice were infected intranasally with murine hepatitis virus (MHV-3) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Roflumilast was given to MHV-3-infected mice therapeutically at doses of 1&#xa0;mg/kg or 10&#xa0;mg/kg, or prophylactically at 10&#xa0;mg/kg. In SARS-CoV-2-infected mice, roflumilast was given therapeutically at a dose of 10&#xa0;mg/kg. Lung histopathology, chemokines (CXCL-1 and CCL2), cytokines (IL-1β, IL-6, TNF, IFN-<b>γ</b>, IL-10 and TGFβ), neutrophil immunohistochemical staining (Ly6G<sup>+</sup> cells), macrophage immunofluorescence staining (F4/80<sup>+</sup> cells), viral titration plaque assay, real-time PCR virus detection, and blood cell counts were examined.</p> Results <p>Therapeutic treatment with roflumilast at 10&#xa0;mg/kg reduced lung injury in SARS-CoV-2 or MHV-3-infected mice without compromising viral clearance. In MHV-3-infected mice, reduced lung injury was associated with decreased chemokines levels, prevention of neutrophil aggregates and reduced macrophage accumulation in the lung tissue. However, the prophylactic treatment strategy with roflumilast increased lung injury in MHV-3-infected mice.</p> Conclusion <p>Our findings indicate that therapeutic treatment with roflumilast reduced lung injury in MHV-3 and SARS-CoV-2 lung infections. Given the protection induced by roflumilast in inflammation, PDE4 targeting could be a promising therapeutic avenue worth exploring following severe viral infections of the lung.</p>

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Selective phosphodiesterase 4 inhibitor roflumilast reduces inflammation and lung injury in models of betacoronavirus infection in mice

  • 期刊论文

  • 发表日期：

    2025年1月25日

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  • Vinícius Amorim Beltrami,
  • Flávia Rayssa Braga Martins,
  • Débora Gonzaga Martins,
  • Celso Martins Queiroz-Junior,
  • Franciel Batista Félix,
  • Letícia Cassiano Resende,
  • Felipe Rocha da Silva Santos,
  • Larisse de Souza Barbosa Lacerda,
  • Victor Rodrigues de Melo Costa,
  • Walison Nunes da Silva,
  • Pedro Pires Goulart Guimaraes,
  • Goulart Guimaraes,
  • Frederico Marianetti Soriani,
  • Mauro Martins Teixeira,
  • Vivian Vasconcelos Costa,
  • Vanessa Pinho

摘要

Objective

We aimed to understand the potential therapeutic and anti-inflammatory effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast in models of pulmonary infection caused by betacoronaviruses.

Methods

Mice were infected intranasally with murine hepatitis virus (MHV-3) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Roflumilast was given to MHV-3-infected mice therapeutically at doses of 1 mg/kg or 10 mg/kg, or prophylactically at 10 mg/kg. In SARS-CoV-2-infected mice, roflumilast was given therapeutically at a dose of 10 mg/kg. Lung histopathology, chemokines (CXCL-1 and CCL2), cytokines (IL-1β, IL-6, TNF, IFN-γ, IL-10 and TGFβ), neutrophil immunohistochemical staining (Ly6G+ cells), macrophage immunofluorescence staining (F4/80+ cells), viral titration plaque assay, real-time PCR virus detection, and blood cell counts were examined.

Results

Therapeutic treatment with roflumilast at 10 mg/kg reduced lung injury in SARS-CoV-2 or MHV-3-infected mice without compromising viral clearance. In MHV-3-infected mice, reduced lung injury was associated with decreased chemokines levels, prevention of neutrophil aggregates and reduced macrophage accumulation in the lung tissue. However, the prophylactic treatment strategy with roflumilast increased lung injury in MHV-3-infected mice.

Conclusion

Our findings indicate that therapeutic treatment with roflumilast reduced lung injury in MHV-3 and SARS-CoV-2 lung infections. Given the protection induced by roflumilast in inflammation, PDE4 targeting could be a promising therapeutic avenue worth exploring following severe viral infections of the lung.