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p38 mitogen-activated protein kinase inhibition attenuates burn-induced liver injury in rats
Xu-Lin Chen1, Zhao-Fan Xia, You-Xin Yu
1Department of Burns, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Anhui 230022, PR China. xulinchen@163.net
Abstract:
This study was made to evaluate the effect of SB203580, a specific p38 MAP kinase inhibitor, on burn-induced hepatic injury as well as the activation of nuclear factor (NF)-kappaB in severely burned rats. Sprague-Dawley rats were divided into three groups: (1) sham group, rats underwent sham burn; (2) burn group, rats given third-degree burns over 30% total body surface area (TBSA) and treated with vehicle plus lactated Ringer solution for resuscitation 4 ml/(kg% TBSA); and (3) burn plus SB203580 group, rats given burn injury and fluid resuscitation plus SB203580 (10 mg/kg i.v., 15 min and 12 h after burn). Hepatocellular injury (measured by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and hepatocellular function (determined by the indocyanine green dye retention rate (ICG R15)) were assessed at 24 h post-burn. Liver histologic changes were also analyzed. Burn trauma resulted in increased serum aminotransferases concentrations, decreased ICG R15, elevated serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels and hepatic TNF-alpha and IL-1beta mRNA expressions, and worsen histologic condition. The level of Nuclear Factor (kappa) inhibitor (IkappaBalpha) in liver was decreased and DNA-binding activity of Nuclear Factor-kappaB (NF-kappaB) was increased after thermal injury. p38 MAP kinase was more significantly activated in liver harvested from burn rats than from shams. SB203580 inhibited the activation of p38 MAP kinase, reduced the levels of TNF-alpha and IL-1beta, and prevented burn-mediated liver injury. Both the IkappaBalpha level and NF-kappaB activity in the liver following burns was not affected by administration with SB203580. These findings suggest that (1) p38 MAP kinase activation is one important aspect of the signaling event that may mediate the release of TNF-alpha and IL-1beta and contributes to burn-induced liver injury and (2) p38 MAP kinase does not influence the activation of NF-kappaB directly in the liver of severely burned rats.
Insights
SB203580, a p38 MAP kinase inhibitor, reduced burn-induced liver injury by decreasing inflammatory cytokines. It did not directly affect nuclear factor-kappaB activation in burned rats.
Area of Science:
- Biomedical research
- Molecular biology
- Toxicology
Background:
- Severe burns trigger significant inflammatory responses and organ damage.
- Hepatic injury is a critical complication following major thermal trauma.
- Nuclear Factor-kappaB (NF-kappaB) and p38 MAP kinase pathways are implicated in inflammatory processes.
Purpose of the Study:
- To investigate the therapeutic potential of SB203580, a p38 MAP kinase inhibitor, in mitigating burn-induced hepatic injury.
- To elucidate the role of p38 MAP kinase and NF-kappaB activation in the pathophysiology of liver damage after severe burns.
Main Methods:
- Evaluation of hepatocellular injury using serum aminotransferases (AST, ALT) and liver function tests (ICG R15) in Sprague-Dawley rats.
- Assessment of liver histology, inflammatory cytokine (TNF-alpha, IL-1beta) levels, and related gene expression post-burn.
- Pharmacological intervention with SB203580 or vehicle in burned rats, with analysis of p38 MAP kinase, IkappaBalpha, and NF-kappaB activation.
Main Results:
- Burn injury significantly increased liver injury markers, inflammatory cytokines, and p38 MAP kinase activation.
- SB203580 treatment attenuated burn-induced liver damage and reduced elevated TNF-alpha and IL-1beta levels.
- SB203580 inhibited p38 MAP kinase activation but did not alter IkappaBalpha levels or NF-kappaB DNA-binding activity in the liver.
Conclusions:
- p38 MAP kinase activation is a key mediator in the inflammatory cascade leading to burn-induced liver injury.
- SB203580 demonstrates a protective effect against hepatic damage in severe burn models.
- The protective mechanism of SB203580 appears independent of direct modulation of NF-kappaB activation in the liver.
