title: Heparin-binding protein is important for vascular leak in sepsis.
abstract: BACKGROUND
  Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability.
  
  
  METHODS
  Association between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice.
  
  
  RESULTS
  Following adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO2/FiO2) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects.
  
  
  CONCLUSIONS
  HBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.
authors.affiliation: Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden.|Department of Clinical Sciences Lund, Lund University, Lund, Sweden.|Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Bentzer
authors.affiliation: Department of Infectious Diseases, University of Lund and Skåne University Hospital, Getingevägen, Lund, SE-221 85, Sweden.|Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jane
authors.initials: J
authors.lastname: Fisher
authors.affiliation: Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: HyeJin Julia
authors.initials: HJ
authors.lastname: Kong
authors.affiliation: Department of Infectious Diseases, University of Lund and Skåne University Hospital, Getingevägen, Lund, SE-221 85, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.affiliation: Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.affiliation: Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: Department of Infectious Diseases, University of Lund and Skåne University Hospital, Getingevägen, Lund, SE-221 85, Sweden. adam.linder@med.lu.se.|Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. adam.linder@med.lu.se.
authors.forename: Adam
authors.initials: A
authors.lastname: Linder
keywords: Acute respiratory distress syndrome; Heparin-binding protein (HBP); Permeability; Septic shock; Vascular leak