Figure 6.
Type 1 IFN signaling and HMGB1 mediates TF-dependent coagulopathy in endotoxemia through PS exposure. (A) Quantitative analysis SD-IVM images of thrombin and platelet fluorescence intensity within the liver microcirculation from endotoxemic mice expressing normal or low levels of TF (4 mg/kg of LPS for 6 hours). (B) Plasma levels of TAT complexes and PAI-1 in saline- and LPS-challenged normal or low levels of TF mice (0.4 mg/kg of LPS for 7 hours + 10 mg/kg of LPS for 8 hours). (C) Mice were injected with liposome-clodronate and liposome–phosphate-buffered saline before LPS injection (0.4 mg/kg of LPS for 7 hours + 10 mg/kg of LPS for 8 hours). Plasma concentrations of TAT and PAI-1 were measured. (D-E) TF protein detected by western blot in the lungs, livers, and spleens from WT, IFN-α/βR1 KO, TRIF KO, Hmgb1fl/fl, and Hmgb1fl/fl Alb-cre+ mice that were challenged with LPS. (F-G) Quantitative analysis of TF protein and messenger RNA (mRNA) (liver) expression. Values are given as fold increase over unstimulated controls. (H) The correction between TF protein in liver detected by using enzyme-linked immunosorbent assay and plasma concentrations of TAT. (I) Quantitative analysis of PS exposure in peripheral leukocytes and splenocytes from endotoxemic WT mice by using FlowJo software. (J-K) WT mice were injected with or without recombinant MFG-E8 (rMFG-E8; 160 μg/kg) 2 hours before administration of 10 mg/kg of LPS (TAT and PAI-1) or 4 mg/kg of LPS (SD-IVM). Plasma levels of TAT complexes and PAI-1 (J) and quantitative analysis of thrombin and platelet fluorescence intensity within the liver microcirculation (K). (L-M) Flow cytometric analysis of PS exposure labeled by fluorescein isothiocyanate (FITC)–AnnexinV in peripheral leukocytes and splenocytes from mice of indicated genotypes. Representative images of PS exposure in splenocytes (L). Quantitative analysis of PS exposure in peripheral leukocytes and splenocytes (M). Data are shown as mean ± standard error of the mean. *P < .05; **P < .01; ***P < .001. N = 3 to 12 mice per group. NS, not significant.

Type 1 IFN signaling and HMGB1 mediates TF-dependent coagulopathy in endotoxemia through PS exposure. (A) Quantitative analysis SD-IVM images of thrombin and platelet fluorescence intensity within the liver microcirculation from endotoxemic mice expressing normal or low levels of TF (4 mg/kg of LPS for 6 hours). (B) Plasma levels of TAT complexes and PAI-1 in saline- and LPS-challenged normal or low levels of TF mice (0.4 mg/kg of LPS for 7 hours + 10 mg/kg of LPS for 8 hours). (C) Mice were injected with liposome-clodronate and liposome–phosphate-buffered saline before LPS injection (0.4 mg/kg of LPS for 7 hours + 10 mg/kg of LPS for 8 hours). Plasma concentrations of TAT and PAI-1 were measured. (D-E) TF protein detected by western blot in the lungs, livers, and spleens from WT, IFN-α/βR1 KO, TRIF KO, Hmgb1fl/fl, and Hmgb1fl/fl Alb-cre+ mice that were challenged with LPS. (F-G) Quantitative analysis of TF protein and messenger RNA (mRNA) (liver) expression. Values are given as fold increase over unstimulated controls. (H) The correction between TF protein in liver detected by using enzyme-linked immunosorbent assay and plasma concentrations of TAT. (I) Quantitative analysis of PS exposure in peripheral leukocytes and splenocytes from endotoxemic WT mice by using FlowJo software. (J-K) WT mice were injected with or without recombinant MFG-E8 (rMFG-E8; 160 μg/kg) 2 hours before administration of 10 mg/kg of LPS (TAT and PAI-1) or 4 mg/kg of LPS (SD-IVM). Plasma levels of TAT complexes and PAI-1 (J) and quantitative analysis of thrombin and platelet fluorescence intensity within the liver microcirculation (K). (L-M) Flow cytometric analysis of PS exposure labeled by fluorescein isothiocyanate (FITC)–AnnexinV in peripheral leukocytes and splenocytes from mice of indicated genotypes. Representative images of PS exposure in splenocytes (L). Quantitative analysis of PS exposure in peripheral leukocytes and splenocytes (M). Data are shown as mean ± standard error of the mean. *P < .05; **P < .01; ***P < .001. N = 3 to 12 mice per group. NS, not significant.

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