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1 Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States
2 Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland, United States
3 Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States
4 Medicine, Tufts University School of Medicine, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: phassoun{at}jhmi.edu.
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 (LVT, 7ml/kg) and high tidal volume (HVT, 20ml/kg) for 2 hrs 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 hrs before intracellular XOR activity measurement. Lung XOR activity was significantly increased at 2 hrs 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 (EBD) 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 MAPK and ERK, and plays a critical role in the pathogenesis of pulmonary edema associated with VILI.
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