title: Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice.
abstract: BACKGROUND
  Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it's biochemical mechanisms and effects on inflammatory reactions.
  
  
  METHODS
  Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured.
  
  
  RESULTS
  HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3(rd) and 6(th) hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines.
  
  
  CONCLUSIONS
  Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany. nora.jahn@medizin.uni-leipzig.de.
authors.forename: Nora
authors.initials: N
authors.lastname: Jahn
authors.affiliation: Department of Anaesthesiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Centre, Amsterdam, The Netherlands. regis.lamberts@gmail.com.
authors.forename: Regis R
authors.initials: RR
authors.lastname: Lamberts
authors.affiliation: Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg, Germany. Cornelius.Busch@med.uni-heidelberg.de.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Busch
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany. theresa.voelker@medizin.uni-leipzig.de.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Voelker
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany. thilo.busch@medizin.uni-leipzig.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Busch
authors.affiliation: Department of Clinical Chemistry, Neurological Laboratory and Biobank, VU University Medical Centre, Amsterdam, The Netherlands. MJA.Koel-Simmelink@vumc.nl.
authors.forename: Marleen J A
authors.initials: MJ
authors.lastname: Koel-Simmelink
authors.affiliation: Department of Clinical Chemistry, Neurological Laboratory and Biobank, VU University Medical Centre, Amsterdam, The Netherlands. c.teunissen@vumc.nl.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: Department of Anaesthesiology, Universitätsklinikum, Münster, Germany. dr.d.oswald@googlemail.com.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Oswald
authors.affiliation: Department of Anaesthesiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Centre, Amsterdam, The Netherlands. S.Loer@vumc.nl.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Loer
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany. udo.kaisers@medizin.uni-leipzig.de.
authors.forename: Udo X
authors.initials: UX
authors.lastname: Kaisers
authors.affiliation: Department of Anaesthesia and Intensive Care Medicine, Sankt Gertrauden-Krankenhaus, Berlin, Germany. Joerg.Weimann@sankt-gertrauden.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Weimann
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002248:Carbon Monoxide / Q000008:administration & dosage*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; C440499:lipopolysaccharide, Escherichia coli O111 B4; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse