title: Human serum albumin improves endothelial dysfunction and survival during experimental endotoxemia: concentration-dependent properties.
abstract: OBJECTIVE
  The mechanisms by which human serum albumin might protect against sepsis-induced organ dysfunction and improve survival are not elucidated. The present study was designed to assess the effects of two concentrations of human serum albumin on endotoxin-induced mortality as well as on endothelial and organ dysfunctions in both mouse and cell models.
  
  
  METHODS
  Prospective, randomized, controlled experimental study.
  
  
  METHODS
  University research laboratories.
  
  
  METHODS
  Swiss mice (n = 10-15/group) were injected with either lipopolysaccharide or vehicle. Four and 12 hrs later, mice were infused or not with human serum albumin HSA (4% or 20%, 10 mL/kg) or normal saline (0.9% NaCl, 30 mL/kg). Human uterine vein endothelial cells were exposed to both lipopolysaccharide and tumor necrosis factor-α during 8 hrs in the presence or absence of human serum albumin (4% or 20%).
  
  
  RESULTS
  Mice survival, reactivity of mesenteric arteries, and Western blot protein analysis were assessed. Circulating endothelin-1, gluthatione, gluthatione disulfide, and creatinine plasma levels were measured. Nitric oxide production, oxidative, and nitrosative stresses were also measured in situ in endothelial cells. Human serum albumin 4%, but not human serum albumin 20% or normal saline solution, improved survival time of endotoxemic mice. Furthermore, human serum albumin 4% activated endothelial nitric oxide synthase and restored lipopolysaccharide-impaired flow-dependent endothelial dilation in mesenteric arteries. This was associated with a downregulation of nuclear factor κB and an upregulation of nuclear respiratory factor-2 and heme oxygenase-1. Human serum albumin 4% reduced lipopolysaccharide-induced renal dysfunction, enhanced endothelin-1 production and glutathione plasmatic levels, whereas human serum albumin 20% increased gluthatione disulfide. Furthermore, human serum albumin 4% but not 20% blunted lipopolysaccharide-tumor necrosis factor-α-induced oxidative and nitrosative stresses in endothelial cells and increased their gluthatione levels.
  
  
  CONCLUSIONS
  The present data confirm a protective effect of 4% human serum albumin treatment both on mice survival and endothelial dysfunction by inhibiting inflammatory and oxidative stress pathways induced by endotoxins. Conversely, higher concentrations of human serum albumin were detrimental suggesting a dose-dependent effect.
authors.affiliation: Service de réanimation médicale, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Kremer
authors.forename: Céline
authors.initials: C
authors.lastname: Baron-Menguy
authors.forename: Angela
authors.initials: A
authors.lastname: Tesse
authors.forename: Yves
authors.initials: Y
authors.lastname: Gallois
authors.forename: Alain
authors.initials: A
authors.lastname: Mercat
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.forename: Pierre
authors.initials: P
authors.lastname: Asfar
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D019446:Endotoxemia / Q000188:drug therapy / Q000503:physiopathology*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D012709:Serum Albumin / Q000008:administration & dosage*; D014471:Umbilical Veins / Q000187:drug effects / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D012709:Serum Albumin