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 Herndon, Daniel L. Traber

Research output: Contribution to journalArticle

20 Citations (Scopus)

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. 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
Volume37
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Nitric Oxide Synthase Type I
Acute Lung Injury
Sheep
Smoke Inhalation Injury
Halothane
Smoke
Lung
Wounds and Injuries
Nitric Oxide
Inhalation Burns
Anesthesia
Pulmonary Gas Exchange
Lung Compliance
Skin
Adult Respiratory Distress Syndrome
Pulmonary Edema
Mechanical Ventilators
Ambulatory Surgical Procedures
Interleukin-8
Intensive Care Units

Keywords

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

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Enkhbaatar, P., Connelly, R., Wang, J., Nakano, Y., Lange, M., Hamahata, A., ... Traber, D. L. (2009). Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury. Critical Care Medicine, 37(1), 208-214. https://doi.org/10.1097/CCM.0b013e318193226a

Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury. / Enkhbaatar, Perenlei; Connelly, Rhykka; Wang, Jianpu; Nakano, Yoshimitsu; Lange, Matthias; Hamahata, Atsumori; Horvath, Eszter; Szabo, Csaba; Jaroch, Stefan; Hölscher, Peter; Hillmann, Margrit; Traber, Lillian D.; Schmalstieg, Frank C.; Herndon, David; Traber, Daniel L.

In: Critical Care Medicine, Vol. 37, No. 1, 01.2009, p. 208-214.

Research output: Contribution to journalArticle

Enkhbaatar, P, Connelly, R, Wang, J, Nakano, Y, Lange, M, Hamahata, A, Horvath, E, Szabo, C, Jaroch, S, Hölscher, P, Hillmann, M, Traber, LD, Schmalstieg, FC, Herndon, D & Traber, DL 2009, 'Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury', Critical Care Medicine, vol. 37, no. 1, pp. 208-214. https://doi.org/10.1097/CCM.0b013e318193226a
Enkhbaatar, Perenlei ; Connelly, Rhykka ; Wang, Jianpu ; Nakano, Yoshimitsu ; Lange, Matthias ; Hamahata, Atsumori ; Horvath, Eszter ; Szabo, Csaba ; Jaroch, Stefan ; Hölscher, Peter ; Hillmann, Margrit ; Traber, Lillian D. ; Schmalstieg, Frank C. ; Herndon, David ; Traber, Daniel L. / Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury. In: Critical Care Medicine. 2009 ; Vol. 37, No. 1. pp. 208-214.
@article{c6f65e9688924d489d3492f28f33324b,
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. 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.",
keywords = "Acute lung injury, Burn, Neuronal nitric oxide synthase, Smoke",
author = "Perenlei Enkhbaatar and Rhykka Connelly and Jianpu Wang and Yoshimitsu Nakano and Matthias Lange and Atsumori Hamahata and Eszter Horvath and Csaba Szabo and Stefan Jaroch and Peter H{\"o}lscher and Margrit Hillmann and Traber, {Lillian D.} and Schmalstieg, {Frank C.} and David Herndon and Traber, {Daniel L.}",
year = "2009",
month = "1",
doi = "10.1097/CCM.0b013e318193226a",
language = "English (US)",
volume = "37",
pages = "208--214",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury

AU - Enkhbaatar, Perenlei

AU - Connelly, Rhykka

AU - Wang, Jianpu

AU - Nakano, Yoshimitsu

AU - Lange, Matthias

AU - Hamahata, Atsumori

AU - Horvath, Eszter

AU - Szabo, Csaba

AU - Jaroch, Stefan

AU - Hölscher, Peter

AU - Hillmann, Margrit

AU - Traber, Lillian D.

AU - Schmalstieg, Frank C.

AU - Herndon, David

AU - Traber, Daniel L.

PY - 2009/1

Y1 - 2009/1

N2 - 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.

AB - 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.

KW - Acute lung injury

KW - Burn

KW - Neuronal nitric oxide synthase

KW - Smoke

UR - http://www.scopus.com/inward/record.url?scp=59649113862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59649113862&partnerID=8YFLogxK

U2 - 10.1097/CCM.0b013e318193226a

DO - 10.1097/CCM.0b013e318193226a

M3 - Article

VL - 37

SP - 208

EP - 214

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 1

ER -