title: Reactive oxygen species scavengers attenuate endotoxin-induced impairment of hypoxic pulmonary vasoconstriction in mice.
abstract: BACKGROUND
  Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are implicated in the pathogenesis of sepsis-induced lung injury. The authors investigated whether treatment with scavengers of ROS prevents impairment of HPV in mice challenged with endotoxin.
  
  
  METHODS
  The pulmonary vasoconstrictor response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg Escherichia coli endotoxin. In some mice, challenge with saline solution or endotoxin was followed after 1 h with intraperitoneal or intratracheal administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase activity and nitric oxide synthase-2 gene expression were measured in lung tissues.
  
  
  RESULTS
  The LMBO increased left pulmonary vascular resistance by 106 +/- 24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P< 0.05 endotoxin-challenged mice). Intratracheal administration of ROS scavengers 1 h after endotoxin challenge was equally effective but required lower doses than systemic treatment. Administration of the ROS scavengers 22 h after endotoxin challenge did not restore HPV.
  
  
  CONCLUSIONS
  Administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge in mice prevented the impairment of HPV after LMBO. Early therapy with ROS scavengers, either systemically or by inhalation, may provide a means to preserve HPV in sepsis-associated acute lung injury.
authors.affiliation: Department of Anesthesia and Critical Care, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: Hemanth A
authors.initials: HA
authors.lastname: Baboolal
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Roman
authors.initials: R
authors.lastname: Ullrich
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawai
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000502:physiology*; D004731:Endotoxins / Q000633:toxicity*; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000517:prevention & control; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D004731:Endotoxins; D005029:Ethylenediamines; D009942:Organometallic Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); C044101:endotoxin, Escherichia coli; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000111:Acetylcysteine