IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense

To explore the mechanism of immunosuppression associated with sepsis, we de veloped a murine model of sepsis-induced Pseudomonas aeruginosa pneumonia, CD-1 mice underwent either cecal ligation and 26-gauge needle puncture (CLP ) or sham surgery, followed by the intratracheal (i.t.) administration of P , aeruginosa or saline. Survival in mice undergoing CLP followed 24 h later by the i.t. administration of saline or P, aeruginosa was 58% and 10%, res pectively, whereas 95% of animals undergoing sham surgery followed by P, ae ruginosa administration survived. Increased mortality in the CLP/P, aerugin osa group was attributable to markedly impaired lung bacterial clearance an d the early development of P, aeruginosa bacteremia, The i.t. administratio n of bacteria to CLP-. but not sham-, operated mice resulted in an impressi ve intrapulmonary accumulation of neutrophils, Furthermore, P, aeruginosa c hallenge in septic mice resulted in a relative shift toward enhanced lung I L-10 production concomitant with a trend toward decreased IL-12, The i,p,, but not i,t., administration of IL-10 Abs given just before P. aeruginosa c hallenge in septic mice significantly improved both survival and clearance of bacteria from the lungs of septic animals administered P, aeruginosa. Fi nally, alveolar macrophages isolated from animals undergoing CLP displayed a marked impairment in the ability to ingest and kill P, aeruginosa ex vivo , and this defect was partially reversed by the in vivo neutralization of I L-10, Collectively, these observations indicate that the septic response su bstantially impairs lung innate immunity to P, aeruginosa, and this effect is mediated primarily by endogenously produced IL-10.