Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury

Perenlei Enkhbaatar, Rhykka Connelly, Jianpu Wang, Yoshimitsu Nakano, Matthias Lange, Atsumori Hamahata, Eszter Horvath, Csaba Szabo, Stefan Jaroch, Peter Hölscher, Margrit Hillmann, Lillian D. Traber, Frank C. Schmalstieg, David N. Herndon, Daniel L. Traber

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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. DESIGN:: Prospective, randomized, controlled, experimental animals study. SETTING:: Investigational intensive care unit at university hospital. SUBJECTS:: Adult female sheep. INTERVENTIONS:: 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°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 μg/kg/hr. Sham and control groups received same amount of saline. MEASUREMENTS AND MAIN 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.

Original languageEnglish (US)
Pages (from-to)208-214
Number of pages7
JournalCritical care medicine
Issue number1
StatePublished - Jan 2009


  • Acute lung injury
  • Burn
  • Neuronal nitric oxide synthase
  • Smoke

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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