Figure 1.

Toll-like receptor 4 (TLR4) drives systemic inflammation and end-organ damage in a mouse model of hemorrhagic shock (HS) and trauma (HS/T). Wild-type (WT), TLR4^−/−, MyD88^−/−, or Trif^−/− B6 mice were subjected to HS/T. IL-6 and ALT plasma levels were measured 6 h after the onset of HS/T as described in Section “Materials and Methods” (A,B). In separate experiments, the selective anti-mouse TLR4 Ab 1A6 or its isotype control (W6/32 Ab) was administered intravenously 30 min prior to the initiation of the HS and the levels of IL-6 and ALT were measured at 3, 6, and 20 h after the onset of HS/T (C,D). Panels (A,C) show IL-6 plasma levels, (B,D) show ALT plasma levels, (E,F) show IL-6 and ALT plasma levels after 6 h following the initiation of HS/T in the following cell-specific TLR4^−/− B6 mouse strains: Albumin-Cre × TLR4^loxP/loxP (Alb-Cre), CD11c-Cre × TLR4^loxP/loxP (CD11c-Cre), and Lyz-Cre × TLR4^loxP/loxP (Lyz-Cre). WT and TLR4^loxP/loxP (FloxP) mice were used as controls. Panels (G,H) show IL-6 and ALT plasma levels in lethally irradiated WT B6 mice reconstituted with bone marrow cells from CD11c-diphtheria toxin (DT) receptor (DTR) B6 mice or CD11c-TLR4^−/− B6 mice at 6 h after HS/T. WT B6 mice were used as controls [(A,B,E,F) *P < 0.05, analyzed by Mann–Whitney Rank Sum Test; (C) P = 0.050, (D) *P < 0.001, analyzed by two-way ANOVA; (G,H) *P < 0.001, analyzed by Student’s t-test (n = 6–15 animals/experimental condition)].