title: Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?
abstract: BACKGROUND
  Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions.
  
  
  METHODS
  Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c.
  
  
  RESULTS
  Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP.
  
  
  CONCLUSIONS
  ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.
authors.affiliation: Department of Anaesthesiology, Surgical Services and Intensive Care, Karolinska University Hospital, Solna, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: B P
authors.initials: BP
authors.lastname: Persson
authors.forename: H
authors.initials: H
authors.lastname: Halldorsdottir
authors.forename: L
authors.initials: L
authors.lastname: Lindbom
authors.forename: P
authors.initials: P
authors.lastname: Rossi
authors.forename: H
authors.initials: H
authors.lastname: Herwald
authors.forename: E
authors.initials: E
authors.lastname: Weitzberg
authors.forename: A
authors.initials: A
authors.lastname: Oldner
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000097:blood*; D001798:Blood Proteins; D019559:Capillary Leak Syndrome / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000097:blood* / Q000502:physiology; D019446:Endotoxemia / Q000150:complications*; D004731:Endotoxins / Q000633:toxicity; D015633:Extravascular Lung Water / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation; D007262:Infusions, Intravenous; D007958:Leukocyte Count; D008297:Male; D018375:Neutrophil Activation; D011654:Pulmonary Edema / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D011725:Pyridines / Q000627:therapeutic use*; D011897:Random Allocation; D044023:Receptor, Endothelin B / Q000819:agonists; D034421:Sus scrofa; D013552:Swine; D013777:Tetrazoles / Q000627:therapeutic use*; D014757:Viper Venoms / Q000008:administration & dosage / Q000633:toxicity
chemical_list: C062991:AZU1 protein, human; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004731:Endotoxins; D011725:Pyridines; D044023:Receptor, Endothelin B; D013777:Tetrazoles; D014757:Viper Venoms; C057354:sarafotoxins s6; C120582:tezosentan; C044101:endotoxin, Escherichia coli