Hypothesis: Uninjured skin contributes to the elevation in circulating levels of proinflammatory cytokines seen following severe injury. Design: Male C3H/HeN mice underwent trauma, trauma-hemorrhage and resuscitation, or closed long bone fracture. Serum, skin, and liver samples were harvested at designated times after experimental treatment. Main Outcome Measures: Levels of interleukin (IL) 1β, IL-6, and tumor necrosis factor α (TNF-α) were determined in serum and skin cultures at 1,8, and 24 hours after trauma- hemorrhage. The RNA was isolated from liver and skin samples at 1, 2, 4, 8, and 24 hours from all 3 experimental groups, and gene expression of the cytokines was determined. Results: Remote (nontraumatized) skin from trauma- hemorrhage animals released significantly more IL-6 and TNF-α into culture supernatants at 1 and 24 hours and significantly more IL-Iβ at 1, 8, and 24 hours than did skin from sham animals. Serum levels of all 3 cytokines were significantly elevated at 1 and 24 hours after trauma-hemorrhage relative to sham animals. Gene expression of all 3 cytokines was detected in skin and liver following trauma-hemorrhage. Furthermore, gene expression of all 3 cytokines was detected in uninjured skin after soft tissue trauma and closed long-bone fracture. Conclusions: Proinflammatory cytokine gene expression is up-regulated in uninjured skin following trauma, trauma-hemorrhage, and long- bone fracture. This increase in gene expression correlates with increased cytokine production by cultured skin as well as increased circulating cytokine levels. These results suggest that uninjured skin may also contribute to the rise in circulating cytokine levels seen after injury.
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