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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Experimental studies reveal that inhaled nitric oxide (NO) can prevent, worsen, or have no effect on lung injury in the setting of ischemia-reperfusion (I-R). We tested the hypothesis that these disparate effects could be related to differences in the timing of administration and/or concentration of inhaled NO during I-R. Isolated rat lungs were subjected to 1-h periods of ischemia followed by 1-h periods of blood reperfusion. We investigated the effects of NO (30 ppm) given during ischemia, NO (30 or 80 ppm) begun immediately at reperfusion, or NO (30 ppm) given 15 min after the beginning of reperfusion, on total pulmonary vascular resistance (PVR), the coefficient of filtration (Kfc), the lung wet/dry weight ratio (W/D) of lung tissue, and lung myeloperoxidase activity (MPO). A control group did not receive NO. NO given during ischemia had no effect on Kfc or MPO, but decreased PVR. NO (30 ppm) during reperfusion (early or delayed) decreased PVR, W/D, Kfc, and MPO. NO at 80 ppm decreased PVR and MPO but not W/D or Kfc. In conclusion, NO at 30 ppm, given immediately or in a delayed fashion during reperfusion, attenuates I-R-induced lung injury. NO at 30 ppm given during ischemia or at 80 ppm during reperfusion is not protective.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Lung ischemia-reperfusion (I-R) leads to increased microvascular permeability and sequestration of polymorphonuclear neutrophils (PMNs) in the lung, dysfunction of the pulmonary endothelium, and pulmonary hypertension (1). Increasingly, ischemia and reperfusion are being recognized as two separate events that have a distinct pathophysiology, and each of which can independently cause damage (4). During ischemia, hypoxic stress initiates the conversion of xanthine dehydrogenase to xanthine oxidase, and promotes the catabolism of adenosine triphosphate (ATP) to yield hypoxanthine. When oxygen is reintroduced at the time of reperfusion, it reacts with hypoxanthine and xanthine oxidase to produce a burst of superoxide and hydrogen peroxide (4). This is generally seen as the initial proinflammatory event that leads to early endothelial injury and the activation and adhesion of PMNs to endothelial cells in I-R injury (5). PMNs can then augment the lung injury by releasing reactive oxygen species and cytotoxic enzymes in close proximity to the endothelium (3). The sequestration of PMNs is a central feature in nearly all models of I-R injury.
Nitric oxide (NO) appears to be a key modulator in I-R injury. Endogenous NO levels plummet rapidly after reperfusion (6, 7), and exogenous NO has been reported to be protective in many models of I-R injury (8). Studies in our laboratory have shown that inhaled NO, given during reperfusion, attenuates I-R-induced lung injury, endothelial dysfunction, and PMN accumulation in isolated piglet lungs and in intact pigs following lung transplantation (8, 9). In addition, many studies have demonstrated beneficial effects of NO or NO donors in other models of pulmonary, cardiac, renal, or mesenteric I-R injury (10).
Several mechanisms might account for this beneficial effect: NO inhibits xanthine oxidase (15), quenches superoxide radicals, prevents neutrophil activation and adherence to the endothelium (16, 17) and platelet aggregation (18), mediates vasodilation, and maintains endothelial homeostasis (19). Nevertheless, the use of exogenous NO during I-R remains controversial, mainly because NO can combine with superoxide to form highly toxic peroxynitrite (20, 21), which could explain the deleterious effect of NO or incomplete protection with NO reported in some studies (22, 23). Such interaction has been reported in lungs (24), heart (25), and endothelial cells (21). Peroxynitrite catalyzes membrane peroxidation, reacts with metals to form toxic nitrosylating species, and oxidizes sulfhydryl groups on cellular proteins (20, 21). The timing of administration and dosage of NO remain issues of importance, because it has been suggested that delaying NO inhalation after the initial burst of radical oxygen species at early reperfusion (22, 12), or reducing the concentration of NO (8, 9), might abrogate the potentially deleterious effects of its use. Therefore, we designed the present study to investigate the effect of different concentrations and timings of administration of inhaled NO on lung function in experimental I-R lung injury. Using a model of I-R injury in an ex vivo, blood-perfused, isolated rat-lung preparation (26), we gave inhaled NO during different periods and at varying concentrations, following which we studied endothelial permeability, pulmonary vascular resistance, and PMN sequestration.
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INTRODUCTION
METHODS
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DISCUSSION
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All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health.
Isolated Perfused Rat Lung Preparation
Thirty male Sprague-Dawley rats (250 to 300 g body weight; Iffa Credo, Paris, France) were anesthetized with thiopental sodium (50 mg/kg intraperitoneally), tracheostomized, and ventilated. After sternotomy and median pericardotomy, a polyethylene cannula was inserted into the pulmonary artery (PA) through the right ventricle. A second cannula was placed in the left atrium through a mid-left-ventricular incision. The heart-lung preparation was then dissected free and suspended in a Statham force-displacement transducer that was put into a thermostated and humidified chamber to monitor weight changes. The lungs were then ventilated with a Harvard rodent ventilator (Model 680; South Natick, MA) at 60 breaths/min, a VT of 2.5 ml, and a positive end-expiratory pressure (PEEP) of 2 cm H2O. Ventilation was performed with a humidified, warmed gas mixture (20% O2/5% CO2/75% N2). Lungs were perfused via the PA cannula with 30 ml heparinized blood obtained from two donor rats. Blood was recirculated with a peristaltic pump (Ismatec; Bioblock, Paris, France) at a flow rate of 0.04 ml/g body weight/min. Pulmonary effluent blood was collected in a plastic reservoir through the cannula placed in the left atrium.
Hemodynamic Measurements
Pulmonary artery pressure (Ppa), pulmonary venous pressure (Ppv),
and airway pressure were continuously monitored with P23 ID transducers (Statham, Paris, France) connected to an amplifier (Model M52;
Telco, Paris, France). Pulmonary capillary pressure (Ppc) was measured with the double occlusion method (14, 26). A cannulating probe
(Model 1517-025, Statham) connected to an electromagnetic flowmeter
(Model 2201, Statham) was placed in series with the perfusing circuit
for continuous pulmonary blood flow (Q) monitoring. Flow and pressure signals were recorded on a multichannel chart recorder (ED69;
Alco, Paris, France). Zone 3 conditions (arterial > venous > alveolar
pressures) were maintained throughout all experiments. Total pulmonary vascular resistance was calculated as: PVR = (Ppa 
Ppv)/Q.
Determination of the coefficient of filtration. The coefficient of filtration (Kfc), used as an index of endothelial permeability to fluid, was measured with the isogravimetric method (14, 26). After an isogravimetric period of 30 min, Ppv was rapidly increased by 8 cm H2O for 15 min by raising the outflow end of the left atrial cannula. The increase in lung weight was recorded. A characteristic rapid weight gain due to vascular filling was followed by a slower rate of weight gain reflecting filtration of fluid into the pulmonary interstitium. The rate of slow weight change (dW/dt) was determined through linear regression of the log10-transformed weight changes per minute. The initial rate of weight gain was calculated by extrapolating dW/dt to Time 0. Kfc was calculated by dividing dW/dt at Time 0 by the change in Ppc that occurred after venous outflow pressure was increased, normalized for the baseline wet lung weight, and expressed as ml/min/cm H2O/100 g lung tissue. Baseline wet lung weight was estimated by measuring the weight of the heart, mediastinal tissue, and lungs at the beginning of the experiment and subtracting the weight of the extrapulmonary tissue at the end of the experiment.
Myeloperoxidase (MPO) Activity
At the end of each experiment, lungs were flushed with normal saline at a low flow of 5 ml/min for 5 min. The right lung was then snap- frozen in liquid nitrogen for MPO determination according to the method described by Mullane and colleagues (27). Briefly, lung tissue was homogenized in 10% (wt/vol) hexadecyltrimethyl ammonium bromide phosphate buffer, using a Polytron homogenizer (Kinematica, Lucerne, Switzerland). The homogenate was sonicated, frozen, thawed, and centrifuged. Supernatant was assayed spectrophotometrically for MPO activity.
Wet-dry Weight Ratio
Lungs excised at the end of the experiment were weighed for determination of the final wet lung weight. The left lung was weighed separately and stored in an oven at 60° C. The left lung was weighed daily until the dry weight was stable for longer than 5 d, to allow determination of the wet/dry (W/D) weight ratio.
Gas Preparation
NO was purchased from CFPO Inc. (Paris, France) as a mixture of 450 ppm in pure nitrogen. NO (30 or 80 ppm) was mixed with the inspired gas mixture and the resulting mixture was stored in a balloon. The concentrations of NO and NO2 were measured in the balloon with an electrochemical method (NOxbox; Bedfont Scientific Ltd., Upchurch, UK). NO2 concentrations remained under 2 ppm.
Specific Protocol
Five groups (n = 6 each) were studied. A control group, a group to which NO (30 ppm) was given only during ischemia (NO-30-I), a group in which NO at 30 ppm was started immediately at the beginning of reperfusion (NO-30-R), a group in which NO at 80 ppm was started immediately at the beginning of reperfusion (NO-80-R), and a group in which NO administration (30 ppm) was delayed and started only after 15 min of reperfusion (NO-30-DR). The cumulative doses of NO were approximately 11 nmol in the NO-30-I and NO-30-R groups, 9 nmol in the NO-30-DR group, and 29 nmol in the NO-80-R group. After being placed in the thermostated and humidified chamber, the lungs were allowed to equilibrate for 30 min and made isogravimetric by adjusting Ppv. Baseline values for Ppa, Ppv, and Ppc were then measured. Perfusion was then interrupted, and the lungs were maintained in the humidified chamber at a temperature of 37° C for 60 min (warm ischemia). Ventilation was continued throughout the ischemia period, with a humidified, warmed gas mixture of N2 with or without addition of NO (30 ppm). At the end of the ischemia period, after the arterial and venous cannulas were clamped, the recirculating blood was discarded and the external circuit was flushed with saline. New fresh blood was then obtained from two donor rats and the lungs were reventilated with 20% O2/5% CO2/75% N2 with or without NO and reperfused for a period of 60 min under isogravimetric conditions during which Ppa, Ppv, Ppc, and Kfc were measured. The hematocrit was adjusted to 28% at the beginning of each reperfusion period (baseline/reperfusion) by adding saline.
Statistical Analysis
All results are expressed as mean ± SEM. Baseline and final measurements of hemodynamic variables were compared through the nonparametric Kruskal-Wallis test, followed by the Mann-Whitney test to compare Kfc, lung MPO activity and W/D ratio values in the different groups. Significance was set at p < 0.05.
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Hemodynamic Variables
Baseline measurements of Ppa, Ppv, Ppc, and PVR were similar in all groups (Figure 1). After I-R, Ppc values did not differ in the five groups. After I-R, percent increases in PVR above the respective baseline values were higher (p < 0.05) in the control group than in the other groups (72 ± 22% in the control versus 34.7 ± 7% in the NO-30-I, 34.4 ± 7% in the NO-30-R, 35.1 ± 10% in the NO-30-DR, and 10.7 ± 3% in the NO-80-R groups). After I-R, PVR did not differ from baseline in the NO-80-R group, and was lower than in the four other groups, indicating that inhaled NO at 80 ppm prevented the reperfusion-induced increase in PVR.
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p < 0.05 versus control group after ischemia-reperfusion, 
p < 0.05 versus NO-30-I, NO-30-R, and NO-30-DR groups
after ischemia-reperfusion.
Pulmonary Edema and Endothelial Permeability
The W/D ratio and Kfc were significantly (p < 0.05) decreased in both groups treated with NO30 ppm during reperfusion (NO-30-R and NO-30-DR), as compared with the control, NO-30-I, and NO-80-R groups (Figures 2 and 3). The W/D ratio and Kfc in the NO-30-I and NO-80-R groups did not differ from those of the control group.
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PMN Sequestration
MPO activity was significantly reduced only when inhaled NO (30 ppm) was given during reperfusion (NO-30-R and NO-30-DR), and not during ischemia (Figure 4). A higher dose of NO during reperfusion (80 ppm) resulted in a further decrease in MPO than did a dose of 30 ppm.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The results of the present study that inhaled NO at 30 ppm, given immediately or in a delayed fashion during reperfusion, prevented I-R-induced lung injury. A higher dose (80 ppm), of NO, started immediately at reperfusion, was not protective, although it further decreased pulmonary hypertension and PMN sequestration. Inhaled NO at 30 ppm administered during ischemia was not beneficial.
An increase in pulmonary microvascular permeability, which in our study was assessed on the basis of Kfc and W/D, is the main consequence of lung endothelial I-R injury. Kfc values after I-R in the control group of animals in our study were very close to values measured in our previous study (26) (i.e., a 100% increase as compared with values measured under baseline conditions). Since the PMN-endothelium interaction is the central mechanism in I-R-induced lung endothelial injury (3, 26), the lung sequestration of PMNs was assessed in the present study by measuring the lung MPO content (27).
Inhaled NO has been proposed to prevent I-R injury by maintaining endothelial cell function and decreasing PMN adhesion to endothelial cells. However, concerns have emerged about potential toxic side effects of NO, stemming from the production of highly toxic peroxynitrite and hydroxyl anion when exogenous NO encounters superoxide generated during reperfusion (20, 21). Yet predictions about therapeutic or toxic effects of inhaled NO in lung I-R are limited by incomplete knowledge of its optimal concentrations and timing of administration.
Timing of NO Administration: Ischemia Versus Reperfusion
In the setting of lung ischemia, inhaled NO is theoretically attractive because it can be delivered in the pulmonary endothelial cells even after cessation of cardiac activity. In support of buttressing the NO pathway during ischemia, a recent study (23) compared a cyclic guanosine monophosphate (cGMP) analogue given during ischemia with inhaled NO (65 ppm) administered during reperfusion after rat-lung transplantation. The authors concluded that the former treatment was more beneficial because it bypassed the reactive oxygen species-producing step. Previous studies also indicated that administration prior to injury of the NO-precursor L-arginine (38), NO-donors (10), or inhaled NO (29) reduced lung damage after I-R. Another study, in renal I-R, demonstrated that NO was most beneficial when given during early ischemia (12). Conversely, a recent report indicated that NO is more beneficial during reperfusion than during ischemia in rat small-bowel transplantation (30). The present study confirms these latter findings: inhaled NO at 30 ppm during ischemia was not protective, whereas the same dose given during reperfusion was. The protection (reduced W/D, and Kfc) occurs through inhibition of PMN accumulation, rather than through a vasoactive effect, since NO only partially prevented pulmonary hypertension. Moreover, NO at 30 ppm during ischemia similarly reduced PVR, but had no protective effect on PMN sequestration in or I-R injury to the lung. This observation is consistent with earlier reports indicating that NO limits PMN-induced lung injury via mechanisms unrelated to direct vasodilatation (11, 12, 31). Additionally, our findings confirm several reports that L-arginine or inhaled NO was beneficial when used during reperfusion in experimental models of lung I-R (7, 22).
Delayed versus Immediate Administration of NO During Reperfusion, and NO at 80 ppm versus 30 ppm
In a recent study (22), early administration of inhaled NO at 80 ppm during reperfusion worsened postischemic reperfusion lung injury. Delaying NO inhalation until 10 min after reperfusion, or blockade with superoxide dismutase, avoided the toxicity, which was thus thought to occur from a harmful interaction between NO and superoxide during early reperfusion. Another study showed that early administration of inhaled NO at 65 ppm during reperfusion had no protective effect in experimental lung transplantation (23). Our present results, as well as those in our previous study (8), indicate that starting inhaled NO at lower concentrations (30 or 10 ppm) immediately at reperfusion or after 15 min does not result in toxic effects; rather, similar protective effects were observed with both approaches. A possible explanation for this apparent discrepancy is the concentration of inhaled NO. In our study, higher-dose (80 ppm) inhaled NO started immediately at reperfusion resulted in a further inhibition of I-R-induced pulmonary hypertension and PMN sequestration, whereas no concomitant protection against microvascular permeability was observed. These results suggest that administration of NO at 80 ppm as compared with 30 ppm was associated with increased production of toxic peroxynitrates, which abrogated the beneficial effects of the further inhibition of PMN accumulation in the lung. All of these observations illustrate the delicate balance between the beneficial and toxic effects of inhaled NO as a function of the concentrations used.
The present study has some limitations in relation to the species of animal and the isolated lung preparation used. However, the clinical implications of our findings may be important. Inhaled NO given at a concentration of 30 ppm or lower during reperfusion, as recently recommended for therapeutic use (32, 33), can be of benefit in the prevention of I-R-induced lung injury. Conversely, higher concentrations of 60 to 80 ppm, which may be needed in some patients with severe pulmonary hypertension (33), should not be offered in the setting of lung I-R because they may either not prevent or even worsen lung injury.
In conclusion, our study demonstrated that inhaled NO, given at 30 ppm during early reperfusion or in a delayed manner, results in prevention of I-R-induced microvascular injury in an isolated, blood-perfused rat-lung model. The mechanisms for this are likely to involve PMN inhibition rather than vasodilation. Inhaled NO at 30 ppm during ischemia was ineffective. Higher-dose (80 ppm) inhaled NO during reperfusion prevents I-R-induced PMN accumulation and vasoconstriction, but is not protective against the I-R induced increase in endothelial permeability.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Philippe Hervé, M.D., Centre Chirurgical Marie-Lannelongue, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France.
(Received in original form August 6, 1996 and in revised form March 10, 1997).
Acknowledgments: Supported by grants from the Association Francaise de Lutte contre la Mucoviscidose (AFLM) and the Etablissement Français des Greffes (EFG).
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References |
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INTRODUCTION
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 J Cranshaw, M J D Griffiths, and T W Evans The pulmonary physician in critical care c 9: Non-ventilatory strategies in ARDS Thorax, September 1, 2002; 57(9): 823 - 829. [Abstract] [Full Text] [PDF]
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 M. R. Karamsetty and J. R. Klinger NO: More Than Just a Vasodilator in Lung Transplantation Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 1 - 5. [Full Text] [PDF]
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H. SCHUTTE, K. MAYER, H. BURGER, M. WITZENRATH, T. GESSLER, W. SEEGER, and F. GRIMMINGER Endogenous Nitric Oxide Synthesis and Vascular Leakage in Ischemic-Reperfused Rabbit Lungs Am. J. Respir. Crit. Care Med., August 1, 2001; 164(3): 412 - 418. [Abstract] [Full Text] [PDF]
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 S. M. Fiser, J. T. Cope, I. L. Kron, A. K. Kaza, S. M. Long, J. A. Kern, and C. G. Tribble Aerosolized prostacyclin (epoprostenol) as an alternative to inhaled nitric oxide for patients with reperfusion injury after lung transplantation J. Thorac. Cardiovasc. Surg., May 1, 2001; 121(5): 981 - 982. [Full Text] [PDF]
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 H. Schutte, M. Witzenrath, K. Mayer, N. Weissmann, A. Schell, S. Rosseau, W. Seeger, and F. Grimminger The PDE inhibitor zaprinast enhances NO-mediated protection against vascular leakage in reperfused lungs Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L496 - L502. [Abstract] [Full Text] [PDF]
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D. M. Payen Is Nitric Oxide Inhalation a ""Cosmetic"" Therapy in Acute Respiratory Distress Syndrome? Am. J. Respir. Crit. Care Med., May 1, 1998; 157(5): 1361 - 1362. [Full Text] [PDF]
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