title: Influence of heme-based solutions on stress protein expression and organ failure after hemorrhagic shock.
abstract: OBJECTIVE
  Hemoglobin-based oxygen carriers (e.g., diaspirin-cross-linked hemoglobin [DCLHb] and hemoglobin glutamer-200 [HbG]) may have potential in the treatment of hemorrhagic shock. The nitric oxide scavenging and direct vasoconstrictive side effects of free hemoglobin of currently available preparations may increase organ injury after shock in contrast to non-oxygen-carrying heme solutions (e.g., hemin arginate [HAR]). However, both classes of substances might induce the protective enzyme heme oxygenase (HO)-1, particularly in the liver. The aim of the study was to assess the role of pretreatment with DCLHb, HbG, or HAR on HO-1 expression and organ injury after hemorrhagic shock.
  
  
  METHODS
  Prospective controlled laboratory study.
  
  
  METHODS
  Animal research laboratory at a university hospital.
  
  
  METHODS
  Male Sprague-Dawley rats (200-300 g body weight, n = 5-12/group).
  
  
  METHODS
  Twenty-four hours after different doses of DCLHb, HbG (each 1, 2, or 3 g/kg of body weight), or HAR (5, 25, or 75 mg/kg of body weight), the protein expression of HO-1 and heat shock protein-70 in liver, kidney, heart, lungs, and aorta was determined. Twenty-four hours after pretreatment with DCLHb, HbG, or HAR, rats were subjected to hemorrhage (mean arterial blood pressure, 35-40 mm Hg for 1 or 2 hrs)/resuscitation (5 or 4 hrs, respectively). Animals treated with Ringer's solution (30 mL/kg of body weight) served as controls. In additional experiments, HO activity was blocked with tin mesoporphyrin-IX.
  
  
  RESULTS
  DCLHb, HbG, and HAR dose-dependently induced HO-1 protein but not heat shock protein-70. Pretreatment with DCLHb or HbG shortened the onset of decompensation in shock (DCLHb, 40 +/- 11 mins; HbG, 36 +/- 4 mins) compared with vehicle (68 +/- 4 mins, p < .05) and HAR pretreatment (81 +/- 7 mins, p < .05). High doses of DCLHb pretreatment increased mortality (2 hrs of shock, 80%; p < .05 vs. vehicle or HAR). Pretreatment with HAR led to higher shed blood volumes (p < .05) and higher hepatocellular ATP levels (2 hrs of shock, p < .05 vs. DCLHb and HbG). Blockade of HO activity by tin mesoporphyrin-IX abolished the protection mediated by HAR.
  
  
  CONCLUSIONS
  Although DCLHb, HbG, and HAR induce HO-1 in the absence of an unspecific stress response, only HAR pretreatment protects against shock-induced organ failure. Although the underlying mechanisms of positive HAR priming are not completely understood, the induction of HO-1 expression and the lack of nitric oxide scavenging through HAR may play an important role.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Kubulus
authors.forename: Hauke
authors.initials: H
authors.lastname: Rensing
authors.forename: Markus
authors.initials: M
authors.lastname: Paxian
authors.forename: Jan-Tobias
authors.initials: JT
authors.lastname: Thierbach
authors.forename: Tanja
authors.initials: T
authors.lastname: Meisel
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Inge
authors.initials: I
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D001802:Blood Substitutes / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects* / Q000378:metabolism; D051547:Heme Oxygenase-1; D006427:Hemin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006454:Hemoglobins / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017093:Liver Failure / Q000503:physiopathology; D008297:Male; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D001802:Blood Substitutes; D018840:HSP70 Heat-Shock Proteins; D006454:Hemoglobins; C402601:hemoglobin glutamer-200; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin