title: Inhaled Carbon Monoxide Protects against the Development of Shock and Mitochondrial Injury following Hemorrhage and Resuscitation.
abstract: OBJECTIVE
  Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation.
  
  
  RESULTS
  Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25-500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100-500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets).
  
  
  CONCLUSIONS
  These preclinical studies suggest that inhaled CO can be a protective therapy in HS/R; however, further clinical studies are warranted.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America; The Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Hernando
authors.initials: H
authors.lastname: Gomez
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kautza
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Escobar
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Nassour
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Luciano
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Botero
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gordon
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinez
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Andre
authors.initials: A
authors.lastname: Holder
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Ogundele
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America; The Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Rosengart
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Pinsky
authors.affiliation: Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, United States of America; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: VA Pittsburgh Healthcare System, Pittsburgh, PA, United States of America; The Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, PA, United States of America; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000517:prevention & control* / Q000628:therapy; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019344:Lactic Acid; D002248:Carbon Monoxide; D000255:Adenosine Triphosphate