Oseltamivir treatment of mice before or after mild influenza infection reduced cellular and cytokine inflammation in the lung

BACKGROUND Lung inflammation is a critical determinant of influenza infection outcomes but is seldom evaluated in animal studies of oseltamivir (OS), which have focused on viral titre and survival. OBJECTIVES To study the effects of pre- and post-infection dosing with OS on viral replication and inflammation in a mouse model of non-lethal influenza infection. METHODS BALB/c mice were infected with a laboratory-adapted H3N1 strain of influenza. In pre-dosing studies, OS was gavaged twice daily (1 and 10 mg/kg/day) from 4 hours prior to infection and continuing for 5 days (d) post-infection (p.i). In the second post-infection dosing study, dosing at 10 mg/kg/day began at 24-48 hours p.i. Mice were dissected at d3, d5 and d7 p.i. (pre-dosing study) and d5 p.i. (post-dosing study). Lung viral titres were determined by plaque assay. Bronchoalveolar lavage fluid (BALF) was collected and used for the quantitation of inflammatory cells and mediators. RESULTS Pre-infection dosing of OS reduced total cells, neutrophils and macrophages in BALF. With pre- or post-infection dosing, the pro-inflammatory mediators TNF-α, IL-1β, IL-6 and granulocyte-macrophage colony-stimulating factor, the neutrophil chemokines keratinocyte-derived chemokine and MIP-1α and the macrophage chemokine MCP-1 were reduced in BALF. Pre-dosing with 1 mg/kg OS did not reduce viral titres, while 10 mg/kg slightly reduced viral titres at d3 and d5 p.i. CONCLUSIONS Oseltamivir reduced the inflammatory response to influenza when given pre- or post-infection. This anti-inflammatory effect may contribute to the clinical benefit of OS.