title: Pro-Coagulant Endothelial Dysfunction Results from EHEC Shiga Toxins and Host Damage-Associated Molecular Patterns.
abstract: Hemolytic uremic syndrome (HUS) from enterohemorrhagic Escherichia coli infection is a leading cause of kidney failure in otherwise healthy U.S. children. The bacterial Shiga toxins (Stx) induce the characteristic coagulopathy of HUS, but the damage to toxin-receptor expressing cells and organ injury due to ischemia likely also releases inflammatory damage-associated molecular patterns (DAMPs), which may exacerbate injury along with the toxins. To examine this, human aortic and renal glomerular cell anti-coagulant and barrier functions were studied after in vitro challenge with Stx1, Stx2, and DAMPs. There was significant loss of surface anti-coagulant protein C pathway molecules, increased expression of pro-thrombotic PAR1 and reduced protein C activation capability by 15-27%. Histones nearly completely prevented the activated protein C protection of endothelial cells from thrombin-induced permeability. In mice, lethal Stx2 challenge elevated plasma HMGB1 (day 2, 321 ± 118%; p < 0.01) and extracellular histones (day 3, 158 ± 62%; p < 0.01). Mice colonized with Stx2-expressing Citrobacter rodentium developed increased HMGB1 (day 5, 155 ± 55%; p < 0.01) and histones (day 3, 378 ± 188%; p < 0.01). Anti-histone antibody reduced both DAMPs to baseline, but was not sufficient to improve survival outcome or kidney function. Together, these data suggest a potential role Stx to produce DAMPs, and DAMPs to produce endothelial injury and a pro-thrombotic environment.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA , USA.
authors.forename: Chad L
authors.initials: CL
authors.lastname: Mayer
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA , USA.
authors.forename: Caitlin S L
authors.initials: CS
authors.lastname: Parello
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA , USA.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA , USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kurosawa
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA , USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stearns-Kurosawa
keywords: Shiga toxin 1; Shiga toxin 2; damage-associated molecular patterns; endothelial cells; hemolytic uremic syndrome; protein C; thrombotic microangiopathy