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We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

The relationship between local inflammation and the subsequent systemic inflammatory response is poorly described. In a burn injury model, the dermal inflammatory response may act as an ongoing trigger for the systemic inflammatory response syndrome (SIRS) and subsequent systemic complications. We hypothesized that topical attenuation of burn wound inflammatory signaling will control the dermal inflammatory source, attenuate SIRS, and reduce acute lung injury. Mice received a 30% total body surface area burn. Subgroups were treated with specific p38 MAPK inhibitor or vehicle, which was topically applied to wounds. Topical p38 MAPK inhibition significantly reduced burn wound inflammatory signaling and subsequent systemic expression of proinflammatory cytokines and chemokines. In vitro macrophage functional assays demonstrated a significant attenuation in serum inflammatory mediators from animals receiving the topical inhibitor. Topical p38 MAPK inhibition resulted in significantly less pulmonary inflammatory response via reduction of pulmonary neutrophil sequestration, pulmonary cytokine expression, and a significant reduction in pulmonary microvascular injury and edema formation. Although dermal activating transcription factor-2, a downstream p38 MAPK target, was significantly reduced, there was no reduction in pulmonary activating transcription factor-2 expression, arguing against significant systemic absorption of the topical inhibitor. These experiments demonstrate a strong interaction between dermal inflammation and systemic inflammatory response. Attenuating local inflammatory signaling appears effective in reducing SIRS and subsequent systemic complications after burn injury.

Acute ethanol (EtOH) intoxication has been identified as a risk factor for infectious complications in trauma and burn victims. However, the mechanism of this immune dysfunction has yet to be elucidated. The monocyte/macrophage production of cytokines, in particular IL-8 and TNF-α, is critical in the regulation of the acute inflammatory response to infectious challenge. IL-8 is a potent chemoattractant and activator of neutrophils. TNF-α, a proinflammatory cytokine, initiates expression of endothelial cell surface adhesion molecules and neutrophil migration. p38, a member of the mitogen-activated protein kinases, plays an important role in mediating intracellular signal transduction in endotoxin-induced inflammatory responses. We examined the effects of LPS and ethanol on p38 activation and the corresponding IL-8 and TNF-α production in human mononuclear cells. LPS-induced IL-8 and TNF-α production was inhibited in a similar pattern by pretreatment with either EtOH or SB202190 (1 μM), a specific inhibitor of p38 kinase. Western blot analysis, using a dual phospho-specific p38 mitogen-activated protein kinase Ab, demonstrated that EtOH pretreatment inhibited LPS-induced p38 activation. These results demonstrate that alcohol suppresses the normal host immune inflammatory response to LPS. This dysregulation appears to be mediated in part via inhibition of p38 activation. Inhibition of IL-8 and TNF-α production by acute EtOH intoxication may inhibit inflammatory focused neutrophil migration and activation and may be a mechanism explaining the increased risk of trauma- and burn-related infections.