Hypoxanthine and Oxygen Induced Lung Injury: A Possible Basic Mechanism of Tissue Damage?

Abstract

Summaryoxygen exposure with simultaneous intravenous hypoxanthine infusion. Lung injury was induced in young rats by a continuous infusion of hypoxanthine intravenously and breathing 100% oxygen for 48 h (group 1). Control animals were rats infused glucose and MATERIALS AND METHODSbreathing 100% oxygen (group 2), rats infused hypoxanthine in room air (group 3), and untreated rats (group 4). In group 1 rats interstitial and alveolar edema was found with a tendency toward marked margination of polymorphonuclear neutrophils in small vessels (P < 0.025 compared with group 2). The main elastase inhibitor alphal-antitrypsin (a-1-PI) was significantly elevated in group 1; 2-, 3-and 5-fold, respectively, when compared with groups 2, 3, and 4. The surfactant phopholipids from alveolar lavage were normal in all groups. The protein-rich fraction of the lavage fluid from group I rats inactivated, however, the surface properties of lung surfactant. Minimum surface tension in group 1 rats was 14.5 dyn/cm compared with 7.0 dyn/cm in group 2, 2.9 dyn/cm in group 3 and 3.5 dyn/cm in group 4 (P < 0.05, group 1 and 2 versus 4). We conclude that the combination of hypoxanthine and high levels of oxygen causes lung injury, possibly via free oxygen radicals. We discuss the possibility that these findings demonstrate a basic pathogenetic mechanism for the hypoxic-hyperoxic insult and can contribute to the understanding of pathogenesis of a variety of diseases both in pediatrics and adult medicine. AbbreviationFree oxygen radicals have been shown to destroy cell membranes by lipid peroxidation (3, 8, 1 1, 2 1). It has been suggested that such radicals play an important role in the pathogenesis of the acute and chronic lung damage among patients treated with oxygen. Many authors have, however, suggested that oxygen must be combined with other more or less unknown factors, before injury occurs ( 14,27).Recently, it has been shown that the hypoxanthine/xanthine oxidase system generates free radicals (7), and that this system potently induces inflammatory changes both in the hamster cheek pouch (22) and the rat lung (16). Further, it has, by now, been well established that hypoxanthine accumulates in tissues (33), plasma (30,32,34,35), and other body fluids (12,23,25) during hypoxia. When high concentrations of oxygen are administered to the hypoxic patient, large amounts of free radicals may be produced by the hypoxanthine/xanthine oxidase system. We, therefore, have raised the question whether the combination of hypoxanthine and oxygen is more damaging than high oxygen alone to the lung. In the present study we evaluated this by investigating experimentally the effect on the rat lung to 100% Young female rats of the Wistar strain, weighing 170-230 g, were used. Four groups were investigated. Group 1, rats infused continuously with 5 mM hypoxanthine dissolved in 5% glucose and exposed to 98-100% oxygen (n = 10). Group 2, rats infused continuously with 5% glucose and exposed to 98-100% oxygen (n = 9). Group 3, rats infused continuously wit...

Chronic Lung Disease: The Role of Oxidative Stress

“…A series of experimental studies have shown that the free radical-generating system, hypoxanthine-xanthine oxidase, can damage the lung [7,[21][22][23]. These experimental data are supported by the results of Russell and Cooke [24] showing that premature infants who subsequently developed CLD had higher plasma hypoxanthine levels at birth than those who did not develop CLD.…”

“…A new momentum in the search for the pathogenetic mechanism(s) of this condition occurred, however, when the hypothesis was introduced that oxygen free radicals may play a significant role in its development [6,7], and further that CLD is only one facet of the so-called oxygen radical disease of the newborn infant [8]. This new concept has made it clear that hyperoxia is only one possible factor contributing to oxidative stress.…”

Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

“…To test this hypothesis we performed an experiment in which young rats were infused intravenously with hypoxanthine while breathing 100% oxygen for 48 h. Compared with control animals breathing 100% oxygen and infused with glucose, or animals infused with hypoxanthine but breathing room air, we found hemorrhage and edema in the lungs (105). In lung lavage there was a many-fold increase in protein content.…”

Reactive Oxygen Metabolites Produce Pulmonary Vasoconstriction in Young Pigs

“…Oxygen-derived free radicals play an important role in experimentally induced hypoxic-reoxygenation injury (4,5), and may be responsible for both hypoxic and hyperoxic aspects of pulmonary damage (6)(7)(8). One source of oxidant genertion in the lungs may be the Hx-XO system (6).…”