Kupffer Cell p38 Mitogen-Activated Protein Kinase Signaling Drives Postburn Hepatic Damage and Pulmonary Inflammation When Alcohol Intoxication Precedes Burn Injury

Abstract

Objective Clinical and animal studies demonstrate that alcohol intoxication at the time of injury worsens post-burn outcome. The purpose of this study was to determine the role and mechanism of Kupffer cell derangement in exacerbating post-burn end organ damage in alcohol exposed mice. Design Interventional study. Setting Research Institute. Subjects Male C57BL/6 mice. Interventions Alcohol administered 30 minutes before a 15% scald burn injury. Antecedent Kupffer cell depletion with clodronate liposomes (0.5 mg/kg). p38 mitogen-activated protein kinase (MAPK) inhibition via SB203580 (10 mg/kg). Measurements and Main Results Kupffer cells were isolated 24 hours after injury and analyzed for p38 activity and IL-6 production. Intoxicated burned mice demonstrated a 2-fold (p<0.05) elevation of Kupffer cell p38 activation relative to either insult alone and this corresponded to a 43% (p<0.05) increase in IL-6 production. Depletion of Kupffer cells attenuated hepatic damage as seen by decreases of 53% (p<0.05) in serum ALT and 74% (p<0.05) in hepatic triglycerides, as well as a 77% reduction (p<0.05) in serum IL-6 levels compared to matched controls. This mitigation of hepatic damage was associated with a 54% decrease (p<0.05) in pulmonary neutrophil infiltration and reduced alveolar wall thickening by 45% (p<0.05). In vivo p38 inhibition conferred nearly identical hepatic and pulmonary protection after the combined injury as mice depleted of Kupffer cells. Conclusions Intoxication exacerbates post-burn hepatic damage through p38-dependent IL-6 production in Kupffer cells.

Suppression of the interleukin-1β-induced inflammatory response of human Chang liver cells by acute and subacute exposure to alcohol: an in vitro study

“…However, in several burn-models, additional alcohol administration has shown adverse effects. As such, increased neutrophil infiltration, edema formation in lung tissue, and potentiated LPS-induced activation of Kupffer cells was observed upon oral alcohol gavage and burn injury ( 42 , 43 ). Systemic and adipose tissue IL-6 levels were elevated in mice undergoing single binge alcohol exposure followed by burn, while even more pronounced cytokine response was induced by episodic alcohol exposure followed by burn ( 44 ).…”

Gut Microbial Changes and their Contribution to Post-Burn Pathology

“…Ethanol exposure also alters immune responses, such as decreasing NLRP3 activation and cytokine production (70)(71)(72). Taken together, alcohol exposure at the time of burn injury potentiates end-organ damage, including the lungs, liver, and gastrointestinal tract (73)(74)(75)(76)(77).…”

Role of HIF-1α in Alcohol-Mediated Multiple Organ Dysfunction

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