Effect of p38 MAPK inhibition on the severity of intestinal dysfunction in suppurative peritonitis under antibacterial therapy

Abstract

BACKGROUND: Identifying new treatment strategies aimed at restoring intestinal wall integrity and preventing the development of abdominal sepsis remains a pressing issue in modern medicine.

AIM: This study aimed to examine the course of experimental peritonitis and the resulting intestinal dysfunction during etiotropic antibacterial therapy combined with pathogenetic treatment using a p38 MAPK inhibitor.

MATERIAL AND METHODS: Male Wistar rats were divided into control groups 1 and 2 and experimental groups 1, 2, and 3. All animals underwent induction of postoperative diffuse peritonitis via intraperitoneal injection of a suspension containing 10⁹ microbial bodies/mL of Escherichia coli and Bacteroides fragilis. One day after peritonitis modeling, rats in the control groups received 3 mL of saline intraperitoneally, while rats in the experimental groups received 3 mL of an aqueous solution of the p38 MAPK inhibitor (a conjugate of 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazole-5-pyridine] with poly-1-vinylimidazole). All animals received antibacterial therapy (cefoperazone + sulbactam, 47 mg/day intramuscularly) starting on day 1 post-modeling. In control group 1 and experimental group 1, the duration of antibiotic therapy was 5 days; in control group 2 and experimental groups 2 and 3, it was 10 days. Animals were euthanized on days 3, 7, 14, and 28. Peritoneal fluid underwent microbiological analysis, and intestinal wall samples were examined histologically. Statistical analysis was performed using Statistica 10 for Windows. The significance of differences between the compared samples (p values) was assessed using the Wilcoxon (W) test and the Mann–Whitney U test. Differences were considered statistically significant at p < 0.05.

RESULTS: Administration of the p38 MAPK inhibitor alongside 5-day antibiotic therapy significantly reduced the severity of intestinal dysfunction on days 3 (p_u = 0.005), 7 (p_u = 0.005), and 14 (p_u = 0.003), compared with control group 1. With 10-day antibiotic therapy, both early (group 2) and delayed (group 3) administration of the inhibitor resulted in reduced intestinal wall damage on days 14 (p_u = 0.001) and 28 (p_u = 0.003), compared with control group 2.

CONCLUSION: The p38 MAPK inhibitor attenuated the severity of destructive changes in the intestinal wall when administered alongside antibacterial therapy.

Keywords

peritonitis / enteral insufficiency / p38 mitogen-activated protein kinases (p38 MAPK) / bacterial translocation / microbiome

Funding

Правительство РФ, госзаданиеGovernment of the Russian Federation, state assignment(122022200212-6)

RIGHTS & PERMISSIONS

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