title: Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury.
abstract: CD8 knockout mice depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (CD8KO/alphaAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential sources of injury include bacterial dissemination, cecal ischemia, and translocation of bacterial toxins. We treated wild-type and CD8KO/alphaAsGM1 mice with imipenem after CLP to decrease bacterial dissemination. Additional mice were subjected to cecal ligation without puncture of the cecal wall or cecal ligation and removal of cecal contents. Imipenem treatment 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 exhibited significant hypothermia, metabolic acidosis, and high plasma cytokine concentrations. Wild-type mice subjected to cecal ligation without puncture also died, despite very low bacterial counts in blood, but wild-type mice subjected to cecal ligation and washout of cecal contents survived. In CD8KO/alphaAsGM1 mice subjected to CLP, imipenem treatment increased survival from 50% to 100%. After cecal ligation without puncture, long-term survival was 80-90% in CD8KO/alphaAsGM1 mice. Hypothermia, metabolic acidosis, and cytokine production were attenuated in CD8KO/alphaAsGM1 mice compared with wild-type controls. These results indicate that bacterial dissemination is not a major source of injury in wild-type mice after CLP, but the presence of gut flora in the cecal lumen is required for induction of systemic inflammation after cecal injury. CD8KO/alphaAsGM1 mice are resistant to the systemic manifestations of cecal injury.
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas 77555-0591, USA.
authors.forename: Victor T
authors.initials: VT
authors.lastname: Enoh
authors.forename: Chad D
authors.initials: CD
authors.lastname: Fairchild
authors.forename: Cheng Y
authors.initials: CY
authors.lastname: Lin
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Varma
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D000007:Abdominal Injuries / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001424:Bacterial Infections; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002432:Cecum / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000276:immunology*; D005260:Female; D015378:Imipenem / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000209:etiology / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D016827:CD8 Antigens; D016207:Cytokines; D015378:Imipenem