title: Cecal ligation and puncture-induced impairment of innate immune function does not occur in the absence of caspase-1.
abstract: Mice that have been subjected to cecal ligation and puncture (CLP) have an impaired ability to clear a subsequent Pseudomonas aeruginosa challenge compared with that of sham CLP controls. We hypothesized that this outcome is dependent upon a caspase-1 mechanism and tested this hypothesis by measuring caspase-1 after CLP and by measuring clearance of a bacterial challenge in caspase-1-deficient mice after CLP. Wild-type mice subjected to CLP had increased caspase-1 activity as well as increased IL-1β and increased IL-18 production in splenocytes stimulated with heat-killed Pseudomonas and had increased plasma concentrations of IL-1β and IL-18 and impaired clearance of a P. aeruginosa challenge compared with sham controls. Healthy, uninjured caspase-1(-\-) mice did not differ from wild-type mice in their ability to clear a Pseudomonas challenge. However, unlike wild-type mice, caspase-1(-/-) mice subjected to CLP had no impairment of bacterial clearance of the Pseudomonas challenge, suggesting that caspase-1 induction after CLP played a role in impairment of bacterial clearance. This was further substantiated by the use of a specific caspase-1 inhibitor, Ac-YVAD-CMK. Wild-type mice treated with Ac-YVAD-CMK (10 mg/kg s.c. twice daily, initiated at time of CLP) did not have impaired clearance of a Pseudomonas challenge compared with that of sham mice and had significantly improved bacterial clearance compared with that of untreated CLP mice. Increased caspase-1 expression and activity after CLP injury appears to contribute to diminished innate immune function.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555-0591, USA. edmurphe@utmb.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Murphey
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D002432:Cecum / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D011677:Punctures / Q000009:adverse effects; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000382:microbiology
chemical_list: D020170:Caspase 1