Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury.
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.
Enkhbaatar
Perenlei
P
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA. peenkhba@utmb.edu
Connelly
Rhykka
R
Wang
Jianpu
J
Nakano
Yoshimitsu
Y
Lange
Matthias
M
Hamahata
Atsumori
A
Horvath
Eszter
E
Szabo
Csaba
C
Jaroch
Stefan
S
Hölscher
Peter
P
Hillmann
Margrit
M
Traber
Lillian D
LD
Schmalstieg
Frank C
FC
Herndon
David N
DN
Traber
Daniel L
DL
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
D010078:Oxazines; C534917:ZK 234238; D052248:Nitric Oxide Synthase Type I