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-Δ(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 (PPARγ) 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 PPARγ pathway. PPARγ agonists could thus represent a potential therapeutic avenue for influenza infections.
Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de recherche clinique Étienne-Le Bel, Québec, Canada.
Alexandre
A
Cloutier
Isabelle
I
Marois
Diane
D
Cloutier
Catherine
C
Verreault
André M
AM
Cantin
Martin V
MV
Richter
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D011014:Pneumonia / Q000473:pathology* / Q000517:prevention & control; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D016019:Survival Analysis
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047495:PPAR gamma; D015230:Prostaglandin D2