title: Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury.
abstract: OBJECTIVE
  Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation.
  
  
  METHODS
  Prospective, randomized, controlled, experimental animals study.
  
  
  METHODS
  Investigational intensive care unit at university hospital.
  
  
  METHODS
  Adult female sheep.
  
  
  METHODS
  Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline.
  
  
  RESULTS
  Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology.
  
  
  CONCLUSIONS
  The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA. peenkhba@utmb.edu
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Rhykka
authors.initials: R
authors.lastname: Connelly
authors.forename: Jianpu
authors.initials: J
authors.lastname: Wang
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Nakano
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Atsumori
authors.initials: A
authors.lastname: Hamahata
authors.forename: Eszter
authors.initials: E
authors.lastname: Horvath
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: Stefan
authors.initials: S
authors.lastname: Jaroch
authors.forename: Peter
authors.initials: P
authors.lastname: Hölscher
authors.forename: Margrit
authors.initials: M
authors.lastname: Hillmann
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schmalstieg
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D002056:Burns / Q000150:complications; D004195:Disease Models, Animal; D005260:Female; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000627:therapeutic use*; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications
chemical_list: D010078:Oxazines; C534917:ZK 234238; D052248:Nitric Oxide Synthase Type I