OBJECTIVE:Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems. METHODS AND RESULTS: To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-alpha2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both P<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-alpha1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release. CONCLUSIONS: These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during human endotoxemia.
RCT Entities:
OBJECTIVE:Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems. METHODS AND RESULTS: To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-alpha2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both P<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-alpha1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release. CONCLUSIONS: These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during humanendotoxemia.
Authors: A Sato; C Nishida; K Sato-Kusubata; M Ishihara; Y Tashiro; I Gritli; H Shimazu; S Munakata; H Yagita; K Okumura; Y Tsuda; Y Okada; A Tojo; H Nakauchi; S Takahashi; B Heissig; K Hattori Journal: Leukemia Date: 2014-05-05 Impact factor: 11.528
Authors: Sarah K Baker; Zu-Lin Chen; Erin H Norris; Alexey S Revenko; A Robert MacLeod; Sidney Strickland Journal: Proc Natl Acad Sci U S A Date: 2018-09-25 Impact factor: 11.205
Authors: Philip C Spinella; Kimberly A Thomas; Isaiah R Turnbull; Anja Fuchs; Kelly Bochicchio; Douglas Schuerer; Stacey Reese; Adrian A Coleoglou Centeno; Christopher B Horn; Jack Baty; Susan M Shea; M Adam Meledeo; Anthony E Pusateri; Jerrold H Levy; Andrew P Cap; Grant V Bochicchio Journal: Front Immunol Date: 2020-09-08 Impact factor: 7.561