Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient β₂-microgloblin knockout mice

Abstract

Our previous studies showed that beta(2)-microglobulin knockout mice treated with anti-asialoGM1 (beta2MKO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia, and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild-type mice and whether beta2MKO/alphaAsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury after CLP in wild-type mice and that beta2MKO/alphaAsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and beta2MKO/alphaAsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately after CLP to decrease the impact of systemic infection in our model. Treatment of wild-type and beta2MKO/alphaAsGM1 mice with imipenem decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and had significant hypothermia, metabolic acidosis, and high plasma concentrations of the cytokines interleukin-6, macrophage inflammatory protein-2, and keratinocyte-derived chemokine. beta2MKO/alphaAsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. beta2MKO/alphaAsGM1 mice had less hypothermia, decreased metabolic acidosis, and lower cytokine concentrations at 18 h after CLP compared with wild-type mice. These results suggest that infection is not the major cause of mortality for wild-type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. beta2MKO/alphaAsGM1 mice appear resistant to these early, non-infection-related causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.

A3adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis

“…Several studies demonstrated that bacterial translocation is an important initiating mechanism for the induction of systemic inflammation and organ injury after CLP as removal of the cecal contents or treatment with powerful antibiotics reduce mortality and organ dysfunction (12,13). We showed in the present study that high bacterial counts were observed in blood and peritoneal cavity (Fig.…”

NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis

“…Our studies using ␤ 2 -microglobulin knockout mice show decreased systemic inflammation, less cardiovascular dysfunction, and improved survival after CLP, compared with wildtype controls (11)(12)(13). However, ␤ 2 -microglobulin knockout mice have multiple immunological defects in addition to NKT cell deficiency (14,15).…”

Why Antibiotic Treatment Is Not Enough for Sepsis Resolution: an Evaluation in an Experimental Animal Model

“…In addition, the inclusion of antibiotics in these experimental animal models has varied tremendously with regard to the type of antibiotic, dose, route, and even dosing schedule. Some studies demonstrated improved outcomes (16,17,30,31) or a delay in mortality (32) after CLP in the presence of antibiotics, whereas other studies did not show an improved survival rate (33). Thus, the efficacy of antibiotic treatment in an experimental murine model remains unclear.…”

“…In the present study, we evaluated systematically the contribution of antibiotics in an acute model of sepsis induced by CLP. We used imipenem as the antibiotic of choice for its broad spectrum, covering most enteric organisms, and because it was previously used in various studies (16,17,(30)(31)(32)(33). We did not observe any improvement in survival after CLP by using a variety of antibiotic treatment protocols, including periprocedural, preprocedural, multiple-interval-dosing postprocedural, and even intracecal protocols.…”