title: Early trauma-hemorrhage-induced splenic and thymic apoptosis is gut-mediated and toll-like receptor 4-dependent.
abstract: Immune depression after trauma-hemorrhage has been implicated as an important factor in the pathogenesis of sepsis and septic-organ failure. Although recent studies have implicated immune-cell apoptosis as an important factor in the evolution of this posttrauma immune-suppressed state, neither the initial triggers that induce this response nor the cellular pathways through which these triggering pathways act have been fully defined. Thus, the current study tests the hypothesis that acute splenic and thymic immune-cell apoptosis developing after trauma-hemorrhagic shock (T/HS) is due to gut-derived factors carried in intestinal lymph and that this T/HS lymph-induced immune depressed state is mediated through Toll-like receptor 4 (TLR4). The first set of experiments documented that T/HS caused both thymic and splenic immune-cell apoptosis as measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase-3 immunohistochemistry and that this increase in apoptosis was totally abrogated by mesenteric lymph duct ligation. In subsequent experiments, mesenteric lymph collected from animals subjected to T/HS or trauma-sham shock were injected into TLR4-deficient (TLR4mut) mice or their wild-type (WT) littermates. Trauma-hemorrhagic shock, but not trauma-sham shock, lymph caused splenic apoptosis in the WT mice. However, the TLR4mut mice were resistant to T/HS lymph-induced splenic apoptosis. Furthermore, the WT, but not the TLR4mut mice developed splenic apoptosis after actual T/HS. In conclusion, gut-derived factors appear to initiate a sequence of events that leads to an acute increase in splenic and thymic immune-cell apoptosis, and this process is TLR4-dependent.
authors.affiliation: Department of Surgery, UMDNJ-New Jersey Medical School, Newark, New Jersey 07101, USA. tiesigr@umdnj.edu
authors.forename: Gregory
authors.initials: G
authors.lastname: Tiesi
authors.forename: Diego
authors.initials: D
authors.lastname: Reino
authors.forename: Leonard
authors.initials: L
authors.lastname: Mason
authors.forename: David
authors.initials: D
authors.lastname: Palange
authors.forename: Jacquelyn N
authors.initials: JN
authors.lastname: Tomaio
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D007422:Intestines / Q000276:immunology*; D008196:Lymph / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000276:immunology* / Q000473:pathology; D012774:Shock, Traumatic / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D034421:Sus scrofa; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4
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