Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury

Matthias Lange, Csaba Szabo, Perenlei Enkhbaatar, Rhykka Connelly, Eszter Horvath, Atsumori Hamahata, Robert A. Cox, Aimalohi Esechie, Yoshimitsu Nakano, Lillian D. Traber, David Herndon, Daniel L. Traber

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO-). ONOO- exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO- decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injuryrelated increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO-, were prevented by INO-4885, providing evidence for the neutralization of ONOO - action by the compound. Burn and smoke injury induced a significant drop in arterial PO2-to-inspired O2 fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO- decomposition catalyst. In conclusion, the current study suggests that ONOO- plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO- decomposition catalyst may represent a potential treatment option for this injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume300
Issue number2
DOIs
StatePublished - Feb 2011

Fingerprint

Smoke Inhalation Injury
Peroxynitrous Acid
Lung
Sheep
Smoke
Vascular Endothelial Growth Factor A
Poly Adenosine Diphosphate Ribose
Reactive Nitrogen Species
Poly(ADP-ribose) Polymerases
Acute Lung Injury
Body Surface Area
Wounds and Injuries
Lung Injury
Lymph
Pulmonary Edema
Interleukin-8
Superoxides
Nitric Oxide
Proteins
Lipids

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Peroxynitrite
  • poly(ADP-ribose)
  • Sheep
  • Vascular endothelial growth factor

ASJC Scopus subject areas

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

Cite this

Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury. / Lange, Matthias; Szabo, Csaba; Enkhbaatar, Perenlei; Connelly, Rhykka; Horvath, Eszter; Hamahata, Atsumori; Cox, Robert A.; Esechie, Aimalohi; Nakano, Yoshimitsu; Traber, Lillian D.; Herndon, David; Traber, Daniel L.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 300, No. 2, 02.2011.

Research output: Contribution to journalArticle

Lange, Matthias ; Szabo, Csaba ; Enkhbaatar, Perenlei ; Connelly, Rhykka ; Horvath, Eszter ; Hamahata, Atsumori ; Cox, Robert A. ; Esechie, Aimalohi ; Nakano, Yoshimitsu ; Traber, Lillian D. ; Herndon, David ; Traber, Daniel L. / Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011 ; Vol. 300, No. 2.
@article{ea51dee5bc4d4410a5c94f94549c4b4e,
title = "Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury",
abstract = "During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO-). ONOO- exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO- decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40{\%} total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injuryrelated increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO-, were prevented by INO-4885, providing evidence for the neutralization of ONOO - action by the compound. Burn and smoke injury induced a significant drop in arterial PO2-to-inspired O2 fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO- decomposition catalyst. In conclusion, the current study suggests that ONOO- plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO- decomposition catalyst may represent a potential treatment option for this injury.",
keywords = "Acute lung injury, Acute respiratory distress syndrome, Peroxynitrite, poly(ADP-ribose), Sheep, Vascular endothelial growth factor",
author = "Matthias Lange and Csaba Szabo and Perenlei Enkhbaatar and Rhykka Connelly and Eszter Horvath and Atsumori Hamahata and Cox, {Robert A.} and Aimalohi Esechie and Yoshimitsu Nakano and Traber, {Lillian D.} and David Herndon and Traber, {Daniel L.}",
year = "2011",
month = "2",
doi = "10.1152/ajplung.00277.2010",
language = "English (US)",
volume = "300",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury

AU - Lange, Matthias

AU - Szabo, Csaba

AU - Enkhbaatar, Perenlei

AU - Connelly, Rhykka

AU - Horvath, Eszter

AU - Hamahata, Atsumori

AU - Cox, Robert A.

AU - Esechie, Aimalohi

AU - Nakano, Yoshimitsu

AU - Traber, Lillian D.

AU - Herndon, David

AU - Traber, Daniel L.

PY - 2011/2

Y1 - 2011/2

N2 - During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO-). ONOO- exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO- decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injuryrelated increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO-, were prevented by INO-4885, providing evidence for the neutralization of ONOO - action by the compound. Burn and smoke injury induced a significant drop in arterial PO2-to-inspired O2 fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO- decomposition catalyst. In conclusion, the current study suggests that ONOO- plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO- decomposition catalyst may represent a potential treatment option for this injury.

AB - During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO-). ONOO- exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO- decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injuryrelated increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO-, were prevented by INO-4885, providing evidence for the neutralization of ONOO - action by the compound. Burn and smoke injury induced a significant drop in arterial PO2-to-inspired O2 fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO- decomposition catalyst. In conclusion, the current study suggests that ONOO- plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO- decomposition catalyst may represent a potential treatment option for this injury.

KW - Acute lung injury

KW - Acute respiratory distress syndrome

KW - Peroxynitrite

KW - poly(ADP-ribose)

KW - Sheep

KW - Vascular endothelial growth factor

UR - http://www.scopus.com/inward/record.url?scp=79551531104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551531104&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00277.2010

DO - 10.1152/ajplung.00277.2010

M3 - Article

VL - 300

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 2

ER -