Journal
SHOCK
Volume 28, Issue 2, Pages 186-191Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/shk.0b013e3180310982
Keywords
inflammation; TNF-alpha; IL-6; p38; NF-kappa B; macrophages
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In macrophages, peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to be important for differentiation, and it serves as a negative regulator of activation. Major trauma/injury causes a dramatic host response that disrupts cellular immune homeostasis and initiates an inflammatory cascade that predisposes the injured host to subsequent infections. In prior studies using a murine trauma model consisting of femur fracture and hemorrhage, splenic macrophages from traumatized mice had significantly enhanced LPS-induced cyclooxygenase enzyme (subtype 2) and iNOS production as well as elevated levels of inflammatory cytokines at 1 week after injury compared with uninjured controls. These up-regulated cellular responses corresponded to increased mortality when animals were challenged with LPS or Candida. In the current study, we used the injury model to determine the effect of treatment of injured mice with the endogenous PPAR gamma ligand 15-deoxy-Delta(12-,14)-PGJ2 (15d-PGJ2). It was found that in vivo 15d-PGJ2 treatment significantly reduced the levels of inflammatory mediators produced by splenic macrophages 7 days after injury. The mechanism of inhibition is dependent on PPAR gamma because concomitant treatment of animals with the PPAR gamma antagonist GW9662 reversed the inhibitory effect of 15d-PGJ2. Endogenous PPAR gamma modulated activation of LPS-induced p38 mitogen-activated protein kinase. Furthermore, treatment of injured mice with 15d-PGJ2 conferred a significant survival advantage after infectious challenge induced by cecal ligation and puncture. Thus, this PPAR gamma ligands significantly attenuate the postinjury inflammatory response and improve survival after infectious challenge.
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