The Prostanoid 15-Deoxy-δ12,14-Prostaglandin-J2 Reduces Lung Inflammation and Protects Mice Against Lethal Influenza Infection

Background. Growing evidence indicates that influenza pathogenicity relates to altered immune responses and hypercytokinemia. Therefore, dampening the excessive inflammatory response induced after infection might reduce influenza morbidity and mortality. Methods. Considering this, we investigated the effect of the anti-inflammatory molecule 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) in a mouse model of lethal influenza infection. Results. Administration of 15d-PGJ(2) on day 1 after infection, but not on day 0, protected 79% of mice against lethal influenza infection. In addition, this treatment considerably reduced the morbidity associated with severe influenza infection. Our results also showed that treatment with 15d-PGJ(2) decreased influenza-induced lung inflammation, as shown by the diminished gene expression of several proinflammatory cytokines and chemokines. Unexpectedly, 15d-PGJ(2) also markedly reduced the viral load in the lungs of infected mice. This could be attributed to maintained type I interferon gene expression levels after treatment. Interestingly, pretreatment of mice with a peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonist before 15d-PGJ(2) administration completely abrogated its protective effect against influenza infection. Conclusions. Our results demonstrate for the first time that treatment of mice with 15d-PGJ(2) reduces influenza morbidity and mortality through activation of the PPAR gamma pathway. PPAR gamma agonists could thus represent a potential therapeutic avenue for influenza infections.