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  • Title: Toll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock.
    Author: Prince JM, Levy RM, Yang R, Mollen KP, Fink MP, Vodovotz Y, Billiar TR.
    Journal: J Am Coll Surg; 2006 Mar; 202(3):407-17. PubMed ID: 16500244.
    Abstract:
    BACKGROUND: Hemorrhagic shock and resuscitation (HS/R) activates inflammatory pathways leading to organ injury after trauma. Toll-like receptors (TLRs), such as TLR4, are required for activation of proinflammatory cellular signaling pathways in response to microbial products, but can also recognize endogenous molecules released from damaged tissues. Using mouse strains deficient in TLR4 protein or signaling, we hypothesized that TLR4 would be important for development of systemic inflammation and hepatic injury after HS/R. We sought to determine the role of lipolysaccharide through use of CD14-/- mice. STUDY DESIGN: TLR4-mutant (C[3H]/HeJ), TLR4-deficient (TLR4-/-), CD14-/-, TLR2-/- mice and wild-type (WT) controls were subjected to HS/R or sham procedure (Sham). At 6.5 hours, mice were euthanized for determination of serum interleukin (IL)-6, IL-10, and alanine aminotransferase concentrations. Hepatic nuclear factor-kappaB DNA-binding (electrophoretic mobility shift assay) and tumor necrosis factor, IL-10, and inducible nitric oxide synthase mRNA expression (semiquantitative reverse transcriptase-polymerase chain reaction) were determined. RESULTS: Relative to sham, TLR4-competent (C[3H]/HeOuJ) mice exhibited a significant increase in serum alanine aminotransferase, IL-6, and IL-10 after HS/R (p < 0.05). TLR4-mutant (C[3H]/HeJ) mice were protected from HS/R-induced hepatocellular injury and had lower circulating IL-6 and IL-10 levels than WT (p < 0.05). Similarly, TLR4-/- mice had lower circulating IL-6 and IL-10 levels than WT after HS/R (p < 0.05). Hepatic nuclear factor-kappaB activation and tumor necrosis factor, IL-10, and inducible nitric oxide synthase mRNA expression were lower in TLR4-mutant compared with TLR4-competent mice after HS/R. In contrast, serum ALT concentrations were comparable between CD14-/- and TLR2-/- mice and their WT counterparts after HS/R. CONCLUSIONS: These results suggest that TLR4, but not TLR2, signaling is required for initiation of the systemic inflammatory response and development of hepatocellular injury after HS/R. Lack of involvement of CD14 argues for a lipolysaccharide-independent role for TLR4 in this process.
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