Loss of the endogenous aPC-PAR1 signaling pathway sensitizes mice to increased vascular leakage and lethality in sublethal LPS challenge. (A) Wild-type (WT), PAR1^−/−, Sphk1^−/−, S1P3^−/−, TM^Pro, or TM^Pro/PAR1^−/− mice were challenged with low dose, 3.5 mg/kg LPS and, where indicated, received anti-PC TVM1 antibody at 10 hours after LPS administration (n = 8-12; P < .01 survival difference between challenged WT and Sphk1^−/−, PAR1^−/−, TM^Pro, or TM^Pro/PAR1^−/−). (B) Vascular permeability in lung, kidney, and spleen, and plasma levels of IL1β and TAT were determined at 18 hours after 3.5-mg/kg LPS challenge. Where indicated, treatments were given 10 hours after LPS challenge (mean ± SD; n = 3–5 mice/group; * indicates different from LPS-treated WT, P < .001; # indicates different from anti-PC TVM1-treated PAR1^−/− or Sphk1^−/− LPS-challenged groups, P < .005 by ANOVA). (C) Representative views of lower right lung lobes after Evans blue injections and perfusion. Scale bar equals 5 mm.