Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways

Raja Elie E Abdulnour, Xinqi Peng, Jay H. Finigan, Eugenia J. Han, Emile J. Hasan, Konstantin G. Birukov, Sekhar P. Reddy, James E. Watkins, Usamah S. Kayyali, Joe GN Garcia, Rubin M. Tuder, Paul M. Hassoun

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Xanthine oxidoreductase (XOR) plays a prominent role in acute lung injury because of its ability to generate reactive oxygen species. We investigated the role of XOR in ventilator-induced lung injury (VILI). Male C57BL/6J mice were assigned to spontaneous ventilation (sham) or mechanical ventilation (MV) with low (7 ml/kg) and high tidal volume (20 ml/kg) for 2 h after which lung XOR activity and expression were measured and the effect of the specific XOR inhibitor allopurinol on pulmonary vascular leakage was examined. In separate experiments, rat pulmonary microvascular endothelial cells (RPMECs) were exposed to cyclic stretch (5% and 18% elongation, 20 cycles/min) for 2 h before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 h of MV without changes in XOR expression. There was evidence of p38 MAP kinase, ERK1/2, and ERK5 phosphorylation, but no change in JNK phosphorylation. Evans blue dye extravasation and bronchoalveolar lavage protein concentration were significantly increased in response to MV, changes that were significantly attenuated by pretreatment with allopurinol. Cyclic stretch of RPMECs also caused MAP kinase phosphorylation and a 1.7-fold increase in XOR activity, which was completely abrogated by pretreatment of the cells with specific MAP kinase inhibitors. We conclude that XOR enzymatic activity is significantly increased by mechanical stress via activation of p38 MAP kinase and ERK and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume291
Issue number3
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Xanthine Dehydrogenase
Mechanical Stress
Phosphotransferases
Lung
Ventilator-Induced Lung Injury
Artificial Respiration
Allopurinol
Phosphorylation
p38 Mitogen-Activated Protein Kinases
Endothelial Cells
Evans Blue
Acute Lung Injury
Mitogen-Activated Protein Kinase 1
Tidal Volume
Bronchoalveolar Lavage
Pulmonary Edema
Inbred C57BL Mouse
Blood Vessels
Ventilation
Reactive Oxygen Species

Keywords

  • Acute lung injury
  • Mechanical ventilation
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways. / Abdulnour, Raja Elie E; Peng, Xinqi; Finigan, Jay H.; Han, Eugenia J.; Hasan, Emile J.; Birukov, Konstantin G.; Reddy, Sekhar P.; Watkins, James E.; Kayyali, Usamah S.; Garcia, Joe GN; Tuder, Rubin M.; Hassoun, Paul M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 291, No. 3, 2006.

Research output: Contribution to journalArticle

Abdulnour, REE, Peng, X, Finigan, JH, Han, EJ, Hasan, EJ, Birukov, KG, Reddy, SP, Watkins, JE, Kayyali, US, Garcia, JGN, Tuder, RM & Hassoun, PM 2006, 'Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 291, no. 3. https://doi.org/10.1152/ajplung.00453.2005
Abdulnour, Raja Elie E ; Peng, Xinqi ; Finigan, Jay H. ; Han, Eugenia J. ; Hasan, Emile J. ; Birukov, Konstantin G. ; Reddy, Sekhar P. ; Watkins, James E. ; Kayyali, Usamah S. ; Garcia, Joe GN ; Tuder, Rubin M. ; Hassoun, Paul M. / Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2006 ; Vol. 291, No. 3.
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AU - Hasan, Emile J.

AU - Birukov, Konstantin G.

AU - Reddy, Sekhar P.

AU - Watkins, James E.

AU - Kayyali, Usamah S.

AU - Garcia, Joe GN

AU - Tuder, Rubin M.

AU - Hassoun, Paul M.

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N2 - Xanthine oxidoreductase (XOR) plays a prominent role in acute lung injury because of its ability to generate reactive oxygen species. We investigated the role of XOR in ventilator-induced lung injury (VILI). Male C57BL/6J mice were assigned to spontaneous ventilation (sham) or mechanical ventilation (MV) with low (7 ml/kg) and high tidal volume (20 ml/kg) for 2 h after which lung XOR activity and expression were measured and the effect of the specific XOR inhibitor allopurinol on pulmonary vascular leakage was examined. In separate experiments, rat pulmonary microvascular endothelial cells (RPMECs) were exposed to cyclic stretch (5% and 18% elongation, 20 cycles/min) for 2 h before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 h of MV without changes in XOR expression. There was evidence of p38 MAP kinase, ERK1/2, and ERK5 phosphorylation, but no change in JNK phosphorylation. Evans blue dye extravasation and bronchoalveolar lavage protein concentration were significantly increased in response to MV, changes that were significantly attenuated by pretreatment with allopurinol. Cyclic stretch of RPMECs also caused MAP kinase phosphorylation and a 1.7-fold increase in XOR activity, which was completely abrogated by pretreatment of the cells with specific MAP kinase inhibitors. We conclude that XOR enzymatic activity is significantly increased by mechanical stress via activation of p38 MAP kinase and ERK and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.

AB - Xanthine oxidoreductase (XOR) plays a prominent role in acute lung injury because of its ability to generate reactive oxygen species. We investigated the role of XOR in ventilator-induced lung injury (VILI). Male C57BL/6J mice were assigned to spontaneous ventilation (sham) or mechanical ventilation (MV) with low (7 ml/kg) and high tidal volume (20 ml/kg) for 2 h after which lung XOR activity and expression were measured and the effect of the specific XOR inhibitor allopurinol on pulmonary vascular leakage was examined. In separate experiments, rat pulmonary microvascular endothelial cells (RPMECs) were exposed to cyclic stretch (5% and 18% elongation, 20 cycles/min) for 2 h before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 h of MV without changes in XOR expression. There was evidence of p38 MAP kinase, ERK1/2, and ERK5 phosphorylation, but no change in JNK phosphorylation. Evans blue dye extravasation and bronchoalveolar lavage protein concentration were significantly increased in response to MV, changes that were significantly attenuated by pretreatment with allopurinol. Cyclic stretch of RPMECs also caused MAP kinase phosphorylation and a 1.7-fold increase in XOR activity, which was completely abrogated by pretreatment of the cells with specific MAP kinase inhibitors. We conclude that XOR enzymatic activity is significantly increased by mechanical stress via activation of p38 MAP kinase and ERK and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.

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