B. T. Xia1, Y. Kim1, E. Gulbins1,2, C. C. Caldwell1 1University Of Cincinnati College Of Medicine,Department Of Surgery,Cincinnati, OH, USA 2Universität Duisburg-Essen,Essen, NORTH RHINE-WESTPHALIA, Germany
Introduction: During traumatic stress and sepsis, ceramide accumulates within the lipid bilayer, due to increased acid sphingomyelinase (Asm) and decreased acid ceramidase activities. It has been demonstrated that ceramide augments the innate immune response, such as increased superoxide formation, which may damage tight junction proteins and disrupt epithelial barriers. Disruption of epithelial barriers in the intestines and lungs has been shown to lead to edema, ischemia, and organ dysfunction. We hypothesized that Asm inhibition will blunt the innate response and improve survival in a murine model of polymicrobial sepsis.
Methods: Cecal ligation and puncture (CLP) was used to induce polymicrobial sepsis. Mice were randomized to intraperitoneal injection of saline vehicle or amitriptyline (16 mg/kg) at the time of CLP. Systemic and peritoneal bacterial load, immune response, and survival were the primary endpoints.
Results: Septic mice treated with amitriptyline demonstrated improved survival compared to vehicle (p=0.03). Amitriptyline treatment resulted in decreased peritoneal neutrophil accumulation 16 hours post-CLP compared to vehicle (3.79 x106 cells/ml vs. 6.14 x106 cells/ml, p=0.03), and no changes in systemic and peritoneal bacterial burden. Of note, we did not observe changes in peritoneal neutrophil accumulation, oxidative burst, and systemic and peritoneal bacterial burden 6 hours after sepsis.
Conclusion: Amitriptyline treatment improved survival in polymicrobial sepsis and decreased neutrophil accumulation after 16 hours. We postulate that Asm inhibition may reduce epithelial exposure to activated neutrophils such that organ integrity and functionality are maintained. Future experiments will be conducted to determine neutrophil infiltration, edema, and permeability in the lung and small bowel. Altogether, we propose that ASM inhibition, in conjunction with antibiotics, is a promising therapeutic approach in the treatment of polymicrobial sepsis.