Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 290, Issue 2, Pages G277-G284Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00338.2005
Keywords
cecal ischemia; peritonitis; inflammation; CD8(+) T cells; natural killer cells; beta(2)-microglobulin knockout mice treated with anti-asialoGM1
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Funding
- NIGMS NIH HHS [R01 GM-66885] Funding Source: Medline
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Our previous studies showed that beta(2)-microglobulin knockout mice treated with anti-asialoGM1 (beta 2MKO/alpha AsGM1 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 beta 2MKO/alpha AsGM1 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 beta 2MKO/alpha AsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and beta 2MKO/alpha AsGM1 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 beta 2MKO/alpha AsGM1 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. beta 2MKO/alpha AsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. beta 2MKO/alpha AsGM1 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. beta 2MKO/alpha AsGM1 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.
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