Impaired activation of mitogen-activated protein kinases after XXXX .

@entity1 @entity548 @entity1435 @entity651 @entity2733 @entity881 @entity35 @entity688 @entity130
BACKGROUND: @entity1 sustaining major @entity130 are at risk of developing @entity881 . We have previously shown that resuscitated @entity548 primes for @entity651 in response to lippolysaccharide (LPS), in part by preventing upregulation of the counterinflammatory cytokine @entity688 . Because the mitogen-activated protein kinase (MAPK) family is known to participate in LPS signaling, we hypothesized that altered upstream signaling through these kinases might contribute to impaired LPS-simulated @entity688 release after shock and resuscitation. METHODS: @entity35 were bled to a mean arterial pressure of 40 mm Hg and maintained for 1 hour, then resuscitated. Alveolar macrophages were retrieved at the end of resuscitation and exposed to LPS (0.5 microg/mL). Western blotting for @entity1435 , extracellular-regulated protein kinase, and c-Jun @entity2733 -terminal kinase was performed on whole cell lysates. In some studies, the alveolar macrophages were preincubated with the @entity1435 inhibitor or the extracellular-regulated protein kinase inhibitor before LPS stimulation. @entity688 levels were measured by enzyme-linked immunosorbent assay. RESULTS: LPS caused an early activation in all members of the MAPK family, whereas antecedent shock both delayed and attenuated the LPS induction. To discern whether this reduction in LPS-stimulated MAPK activation after shock might contribute to reduced @entity688 , specific inhibitors were used. Inhibition of @entity1435 MAPK completely inhibited LPS-induced @entity688 production, whereas blockade of extracellular-regulated protein kinase pathway had no effect. CONCLUSIONS: Shock resuscitation impairs LPS-induced activation of the members of the MAPK family. For the critical counterinflammatory cytokine @entity688 , inhibition of @entity1435 activation appears to contribute to the reduced levels of this cytokine in response to LPS. This study provides in vitro evidence for altered signaling through @entity1435 MAPK, as a mechanism leading to failed upregulation of a counterinflammatory cytokine, and thus the propagation of an unrestrained proinflammatory state. Restoration of normal signaling may represent an effective strategy to reverse this effect.
