Administration of etanercept protects against lethal H1N1 influenza virus infection and inhibits the immunopathologic effects associated with infection in vivo. Saline or 2.5 mg/kg of etanercept was administered i.n. to mice 2 hours after i.n. infection with 10 TCID50 of influenza virus A/FM/1/47 (H1N1). (A, B) Mice were monitored for survival and body-weight loss. Data were derived from three separate experiments, with a total of 30 mice per group (10 mice per group each time). Survival curves show data until day 14 after infection, because further mortality was not observed at later time points. (C, D) Lung/body weight and inflammation score were evaluated on day 4 after infection. Mice were weighed (grams) and euthanized. Whole lungs were harvested, weighed (grams), and the corresponding lung/body index was calculated. The scores were calculated as follows: none, 0; ≤25%, 1; 26% to 50%, 2; 51% to 75%, 3; ≥76%, 4 lung involvement. #P ≤ 0.05 compared with saline recipients. (E through H) Histopathologic analysis on day 4 after infection was carried out by three separate pathologists who were blinded to the various experimental treatments.