Mouse models for post-sepsis syndrome: a comparison of cecal slurry injection model versus two cecal ligation and puncture models.

Background: Sepsis survivors commonly suffer from chronic Post-Sepsis Syndrome (PSS). To understand the mechanisms of PSS, it is critical to utilize appropriate animal models. While cecal ligation and puncture (CLP) is a widely used model of sepsis, a concern exists regarding its suitability for studying long-term outcomes. Alternatively, we previously optimized a highly reproducible murine cecal slurry (CS)-injection model of sepsis. The objective of this study was to compare the suitability of CS and CLP models for investigating PSS. Methods: Male 4-month-old C57BL/6 mice were divided into 7 groups: (1) Naïve control; (2) Sham: laparotomy control; (3) CL: cecal ligation control without puncture; (4) CLP: conventional cecal ligation and puncture (21Gx2); (5) CLP-D: CLP followed by surgical removal (i.e., debridement) of the ligated distal cecum; (6) CS: cecal slurry injection; and (7) vehicle injection control for CS. All mice except for Naïve, received repeated antibiotics and fluid resuscitation starting at 12 h after infection or the control procedure. Blood samples were collected at 6 h and 1-month for IL-6 ELISA. A month later, all mice were euthanized, and qRT-PCR was performed to assess IL-6 gene expression in several tissues including the cecum. Results: Equivalent sepsis severity was confirmed in the sepsis groups (CS, CLP, and CLP-D) by similar survival rates (73-78%) and acute 6 h-plasma IL-6 levels (63.3-159.6 pg./mL). A month later, large abscesses, deformed necrotic tissues, and aberrant adhesions were frequently present in and around the cecum of CL, CLP, and CLP-D mice. Elevated levels of plasma IL-6 (>25 pg./mL) 1-month after sepsis induction were observed in both the CL and CLP groups and also in the CLP-D group to a lesser degree. Strong IL-6 gene expression was found only in the ligated distal cecum from the CLP and CL groups. The cecum abnormality and high levels of plasma IL-6 were completely absent in the CS group. Conclusion: The CLP model is accompanied with abnormal cecum which persistently produces IL-6. The CLP-D model with debridement reduces such problems to some extent but not completely. Because such experimental artifacts are absent in the CS model, this model appears to be better suited for studying PSS.