Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury

Fiona D. Saunders, Martin Westphal, Perenlei Enkhbaatar, Jianpu Wang, Konrad Pazdrak, Yoshimitsu Nakano, Atsumori Hamahata, Collette C. Jonkam, Matthias Lange, Rhykka L. Connelly, Gabriela A. Kulp, Robert A. Cox, Hal K. Hawkins, Frank C. Schmalstieg, Eszter Horvath, Csaba Szabo, Lillian D. Traber, Elbert Whorton, David Herndon, Daniel L. Traber

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the pathophysiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number3
DOIs
StatePublished - Mar 2010

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Nitric Oxide Synthase Type I
Lung Injury
Sheep
Smoke Inhalation Injury
Lung
Wounds and Injuries
Peroxynitrous Acid
Poly(ADP-ribose) Polymerases
Acute Lung Injury
Airway Obstruction
Nitrites
Malondialdehyde
Interleukin-8
Nitrates
Peroxidase
Nitric Oxide
Oxidative Stress
Gases
Inflammation
Control Groups

Keywords

  • Acute lung injury
  • Pathogenesis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury. / Saunders, Fiona D.; Westphal, Martin; Enkhbaatar, Perenlei; Wang, Jianpu; Pazdrak, Konrad; Nakano, Yoshimitsu; Hamahata, Atsumori; Jonkam, Collette C.; Lange, Matthias; Connelly, Rhykka L.; Kulp, Gabriela A.; Cox, Robert A.; Hawkins, Hal K.; Schmalstieg, Frank C.; Horvath, Eszter; Szabo, Csaba; Traber, Lillian D.; Whorton, Elbert; Herndon, David; Traber, Daniel L.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 298, No. 3, 03.2010.

Research output: Contribution to journalArticle

Saunders, FD, Westphal, M, Enkhbaatar, P, Wang, J, Pazdrak, K, Nakano, Y, Hamahata, A, Jonkam, CC, Lange, M, Connelly, RL, Kulp, GA, Cox, RA, Hawkins, HK, Schmalstieg, FC, Horvath, E, Szabo, C, Traber, LD, Whorton, E, Herndon, D & Traber, DL 2010, 'Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 298, no. 3. https://doi.org/10.1152/ajplung.00147.2009
Saunders, Fiona D. ; Westphal, Martin ; Enkhbaatar, Perenlei ; Wang, Jianpu ; Pazdrak, Konrad ; Nakano, Yoshimitsu ; Hamahata, Atsumori ; Jonkam, Collette C. ; Lange, Matthias ; Connelly, Rhykka L. ; Kulp, Gabriela A. ; Cox, Robert A. ; Hawkins, Hal K. ; Schmalstieg, Frank C. ; Horvath, Eszter ; Szabo, Csaba ; Traber, Lillian D. ; Whorton, Elbert ; Herndon, David ; Traber, Daniel L. / Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010 ; Vol. 298, No. 3.
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AU - Pazdrak, Konrad

AU - Nakano, Yoshimitsu

AU - Hamahata, Atsumori

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AU - Connelly, Rhykka L.

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AU - Cox, Robert A.

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