ABSTRACT:Animal studies have shown that induction of cytochrome P450 (CYP) in the lung by oxygen exposure may result in the release of free radical oxidants and arachidonic acid metabolites, which can cause lung injury that is reduced by treatment with cimetidine, a CYP inhibitor. To determine whether cimetidine would reduce lung injury in human infants at risk for chronic lung disease, we conducted a randomized clinical trial in which we administered either cimetidine or a placebo for 10 d beginning Ͻ24 h after birth to 84 newborn infants weighing Յ1250 g who were receiving O 2 and mechanical ventilation. Cimetidine had no significant effect on severity of respiratory insufficiency assessed at 10 d postnatal age. F 2 -isoprostane levels (a marker of oxidant injury) in tracheal aspirates were significantly higher in the cimetidine group at 4 d and at 10 d. There were no significant differences between the groups in tracheal aspirate levels of inflammatory markers (leukotriene B 4 , IL-8, and nucleated cell count) or arachidonic acid metabolites. We conclude that cimetidine does not reduce lung injury in newborn premature infants receiving O 2 and mechanical ventilation. It is possible that cimetidine was not an adequate CYP inhibitor in this context. (Pediatr Res 59: 795-800, 2006) C imetidine, a cytochrome P450 (CYP) inhibitor as well as an H 2 blocker, prevents the severe pulmonary gas exchange failure that occurs in newborn lambs after 72 h of breathing 95% oxygen (1). It is postulated that this beneficial effect occurs as a result of the inhibitory action of this drug on CYP metabolism in the lung, since this enzyme system, which is induced by oxygen exposure, can be a source of free radical oxidants and specific metabolites of arachidonic acid that have the potential to cause lung injury (2).There is a variety of in vivo evidence to support the concept of CYP mediated oxidant injury. For example, survival of newborn rats in 100% O 2 is significantly decreased by treatment with 3-methylcholanthrene, an inducer of the 1A1 isoform of CYP in the lung (3). Treatment with IL-1, which prolongs the survival of rats exposed to lethal concentrations of O 2 , also results in a significant decrease in pulmonary CYP, a decrease of CYP 2B1 isoform mRNA, and a significant decrease in superoxide anion generation from isolated pulmonary microsomes (4). In a rabbit model of lung reperfusion injury, CYP inhibitors (including cimetidine) markedly decrease lung edema and prevent the reperfusion-related increase in lung microvascular permeability (5). In an isolated perfused rat heart model, cimetidine and other CYP inhibitors confer a dose-dependent reduction in myocardial damage following ischemia and reperfusion, an effect attributed to suppression of reactive oxygen species production (6). Carbon tetrachloride liver injury is known to be mediated by a CYPcatalyzed reaction that produces free radicals. In rats exposed to carbon tetrachloride, inhibition of CYP has been shown to decrease hepatic lipid peroxidation (7). There a...
We determined if surfactant treatment effect can be enhanced by mechanical volume recruitment during surfactant administration by measuring functional residual capacity, tidal volume, the alveolar portion of tidal volume, dynamic compliance of the respiratory system, a/A ratio, and PaCO2 by measuring before and after surfactant administration to rabbits with lung injury induced by airway lavage. There was improvement in all lung function indices when surfactant was given with volume recruitment, but when surfactant was given without volume recruitment, the only index to show significant improvement was a/A ratio of oxygenation. These results support the hypothesis that mechanical recruitment of terminal airspaces from a previously unventilated compartment will enhance the effectiveness of surfactant replacement by facilitating the distribution of instilled surfactant to this compartment.
Cytochrome P450 (CYP) inhibition with cimetidine reduces hyperoxic lung injury in young lambs. Nitric oxide (NO), also a CYP inhibitor, has been shown to either aggravate or protect against oxidant stress depending on experimental context. The objective of this study was to determine whether NO, like cimetidine, would protect young lambs against hyperoxic lung injury, and whether its effect was associated with CYP inhibition. Three groups of lambs were studied: 1) room air exposure, 2) Ͼ95% O 2 , and 3) Ͼ95% O 2 plus inhaled NO. After 72 h, hyperoxia alone resulted in a significant increase in arterial PCO 2 and number of polymorphonuclear leukocytes in bronchoalveolar lavage (BAL), and a significant decrease in arterial/alveolar O 2 tension (a/A). The addition of inhaled NO significantly decreased the hypercarbia and BAL polymorphonuclear cellular response associated with hyperoxia but had no beneficial effect on a/A ratio. There were no significant differences in F 2 -isoprostanes or isofurans (markers of lipid peroxidation) measured in BAL or lung tissue among study groups. No intergroup differences were detected in BAL epoxyeicosatrienoic acid levels (index of CYP activity). The results of this study indicate that hypercarbia and inflammation accompanying hyperoxic lung injury in young lambs can be attenuated by inhaled NO. However, this study provides no direct evidence that NO is inhibiting CYPmediated oxidant lung injury. (Pediatr Res 59: 142-146, 2006) P revious work has shown that administration of a CYP inhibitor, cimetidine, would reduce hyperoxic lung injury in young lambs (1). In that work, lambs that breathed high oxygen concentrations exhibited impaired gas exchange (elevated PCO 2 and lower than expected PO 2 ) and evidence of an increase in pulmonary vascular permeability as indicated by a marked increase in lung lymph flow and protein clearance after 72-74 h of continuous hyperoxia. These effects of hyperoxia were attenuated by the administration of cimetidine before beginning high oxygen exposure. In further studies (2), oxygen breathing significantly increased lung CYP1A1 mRNA levels in vivo, and this increase preceded the increase in isozyme activity. Oxygen exposure also promptly increased CYP1A1 mRNA levels in cultured lamb lung microvascular endothelial cells in these studies. As a monooxygenase, the catalytic activity of CYP is accompanied by the production and release of free radicals (3), and there is a variety of evidence linking CYP to oxidant lung injury (4). Also, the products of arachidonic acid metabolism catalyzed by the CYP system have biologic actions that could cause or aggravate lung injury (5). Taken together, these findings are consistent with the hypothesis that the CYP system in the lung provides a source of damaging oxygen free radicals and catalyzes the production of certain arachidonic acid metabolites which may cause or aggravate lung injury.NO, an agent that mediates a wide variety of biologic actions, is used clinically as a vasodilator in the management ...
A multiple-breath nitrogen washout system designed to measure lung volume in mechanically ventilated infants was validated by assessing three performance criteria: 1) accuracy of lung volume measurements in the presence of an endotracheal tube leak was assessed by comparing the measurements of functional residual capacity (FRC) in a mechanical lung model with and without airway leak; 2) in vivo accuracy was assessed in rabbits by comparing FRC measurements obtained by this system with measurements obtained by helium dilution; and 3) in vivo precision was assessed by analyzing measurements of FRC obtained in replicate measurements at different times in ventilator-dependent premature infants with hyaline membrane disease. The average difference between the measurements of FRC in a mechanical lung model with airway leak and without leak was 3.0 +/- 9.4% (mean +/- SD, P > 0.2), and no difference was greater than 20%. There was a significant correlation between the measurements of FRC in rabbits by nitrogen washout and by helium dilution (r = 0.93, P < 0.0001), and 65.4% of the paired measurements were within 20% of their average. The 95% limits of agreement within pairs of measurements by the two techniques ranged from -4.0 to + 6.5 mL/kg. FRC measured by helium dilution was slightly higher (1.3 +/- 2.7 mL/kg, P < 0.01) than FRC measured by nitrogen washout, and positive end-expiratory pressure was a significant predictor of this difference (P < 0.0001). The regression between the individual FRC measurements obtained in premature infants and the average of the other replicates was significant (r2 > 0.98, P < 0.0001). The coefficient of variation was 12.3%. These findings provide further validation of this multiple-breath nitrogen washout system for measuring FRC in premature infants during mechanical ventilation.
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