Role of neutrophils in xanthine/xanthine oxidase-induced oxidant injury in isolated rabbit lungs

Departments of 1 Anesthesiology and 2 Internal Medicine, and 3 Cell and Molecular Biology Program, Saint Louis University School of Medicine, St. Louis, Missouri 63110 Reactive oxygen species have been shown to play an important role in the pathogenesis of lung injury. This study was designed to clarify the role of intrapulmonary neutrophils in the development of xanthine/xanthine oxidase (X/XO)-induced lung injury in isolated buffer-perfused rabbit lungs. We measured microvascular fluid filtration coefficient ( K f ) and wet-to-dry weight ratio to assess lung injury. X/XO induced a significant increase in K f and wet-to-dry weight ratio in neutrophil-replete lungs, whereas the lung injury was attenuated in neutrophil-depleted lungs. A neutrophil elastase inhibitor, ONO-5046, also attenuated the lung injury. In addition, X/XO induced a transient pulmonary arterial pressure (P pa ) increase. The thromboxane inhibitor OKY-046 attenuated the P pa increase but did not alter the increase in permeability. Neutrophil depletion reduced the K f increase but had no effect on the P pa increase. These results suggest that intrapulmonary neutrophils activated by X/XO play a major role in development of the lung injury, that neutrophil elastase is involved in the injury, and that the X/XO-induced vasoconstriction is independent of intrapulmonary neutrophils. permeability; neutrophil elastase; perfused lungs