The p38 mitogen-activated protein kinase (MAPK) pathway is a proinflammatory signal transduction pathway for the production of cytokines and cellular response to stress, such as bacterial LPS or ischemia. We examined the effects of FR167653, a specific inhibitor of p38 MAPK, to explore the relationship between intestinal barrier damage and remote renal dysfunction. Immunohistochemical data showed the accumulation of neutrophils in the intestine after burn, and a horseradish peroxidase (HRP) tracer experiment showed burn-induced intestinal barrier damage. Our quantitative bacterial culture data demonstrated that viable bacteria reached the remote organs after burn and prevented the invading viable bacteria from using FR167653. Western blotting identified increased phosphorylation of p38 MAPK in the kidney after burn, and it may also have shown the possibility that endotoxin associated with the bacterial translocation enhances the activation of the p38 MAPK pathway. We blocked the intestinal barrier damage using FR167653, which resulted in reduced neutrophils in the intestine. FR167653 also prevented the increased phosphorylation of p38 MAPK in the kidney, which resulted in reduced neutrophils in the glomerulus and the reduction of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta mRNA in the kidneys, and, finally, prevented burn-induced renal failure. This study provides evidence for the hypothesis that the p38 MAPK pathway controls inflammatory mediators and not only improves intestinal function but also reduces remote renal failure after burn. We identified the pathophysiologic role of the p38 MAPK pathway in the development of renal failure after burn.
Hemorrhagic shock has been reported to induce renal dysfunction as a consequence of different kinds of local inflammatory response. p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction relating to the inflammatory states, and acts as an important mediator in the intracellular signal pathway for proliferation, differentiation, and production of proinflammatory cytokines such as TNF-alpha and IL-1beta. The effect of p38 MAPK on the hemorrhagic damage has not been clearly estimated as yet. In this study, our aim was to evaluate the role of p38 MAPK on the renal damage during the first 5 h after a hemorrhage using a specific inhibitor of p38 MAPK activation, FR167653. p38 MAPK activation increased immediately after a hemorrhage and decreased with time. renal mRNA expression of TNF-alpha and IL-1beta increased, renal dysfunction continued to progress, and histological inflammatory injuries were confirmed after hemorrhagic shock. With the pretreatment of FR167653, all of these hemorrhagic changes were attenuated, although the induction of the primary hypotensive state was confirmed. This study demonstrated that renal p38 MAPK is activated in hemorrhagic shock, promotes the expression of proinflammatory cytokines in the kidney, and consequently develops renal dysfunction. We concluded that p38 MAPK activation is essential in causing renal damage and that the inhibition of p38 MAPK activation blocks the development of the renal dysfunction after hemorrhagic shock.
Cardiac dysfunction is a well-known complication of hemorrhagic shock as a consequence of local inflammatory response. Several studies have indicated that p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction that is associated with the inflammatory state through the activation of proinflammatory cytokines such as TNF-alpha and IL-1beta. Whether the same applies to cardiac dysfunction after hemorrhagic shock has not been clearly determined. Therefore, in this study, the role of p38 MAPK on cardiac dysfunction after hemorrhagic shock was studied up to 5 h after a hemorrhage using FR167653, a specific inhibitor of p38 MAPK phosphorylation. The p38 MAPK phosphorylation, the cardiac mRNA expressions of TNF-alpha and IL-1beta, and intracardiac serum concentrations of each cytokine and creatine phosphokinase-MB isozyme increased after a hemorrhage. Activated neutrophil accumulation in the heart, histological inflammation-related injuries, and frequent ventricular arrhythmia were observed in the late phase after hemorrhagic shock. FR167653 inhibited these hemorrhagic changes except the induction of the primary hypotensive state. These results demonstrate that p38 MAPK phosphorylation in hemorrhagic shock plays an important role in the cardiac expression of the proinflammatory cytokines and in the development of cardiac dysfunction relative to the inflammatory responses.
After the intravenous administration of lipopolysaccharide at a dose of 3.0 mg/100 g to rats, immunoreactive sites for tumour necrosis factor (TNF) and peptide leukotrienes (LTs) were examined in the heart and lung. Immunoreaction for TNF is preferentially localized on the apical endothelial cell surface of the vessels and in lysosomes of inflammatory and interstitial cells. Lysosomes of cardiac muscle cells which undergo degeneration are also reactive. Peptide LTs in inflammatory cells give almost the same reactions as those for TNF. However, the production of peptide LTs occurs uniquely in cardiac muscle cells in the media of the pulmonary vein, although lysosomes of intracardiac muscle cells which undergo degeneration do not show immunoreactivity. These results suggest that the degeneration of cardiac muscle cells may be induced not only by endogenous TNF but also by peptide LTs which are produced in muscle cells of the venous media and are transported to the myocardium via the coronary circulation.
Two autopsy cases, where the individuals were suspected of having ingested acephate, an organophosphorous insecticide, are reported. Acephate and its active metabolite, methamidophos (MP), were analyzed in the biological fluids by GC/MS, using the salting out method with liquid-liquid extraction columns. The first case was that of a 70-year-old man whose blood acephate was 149μg/mL, and MP was 3.0μg/mL. Serum pseudocholinesterase (ChE) activity was inhibited. No remarkable finding of injury or disease was determined as the cause of his death, but acute poisoning by acephate was mostly suspected. The second case was that of a 60-year-old man. A deep gash in the left neck injured the left common carotid artery in addition to the severely ischemic state of the primary organs. His blood acephate was 46μg/mL, and MP was not detected. ChE activity was in the normal range. Hemorrhage was mainly suspected as the cause of his death. The concentrations of acephate and MP in human blood after oral ingestion are first reported here, and the acute toxic level of acephate is discussed.
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