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Ann Thorac Surg 1995;60:1169-1175
© 1995 The Society of Thoracic Surgeons
Section of Thoracic Surgery and Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan
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Abstract |
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Methods. Rats underwent thoracotomy, with clamps used to create left lung ischemia. After 90 minutes of ischemia, clamps were released, permitting reperfusion for either 30 minutes or 4 hours. Additional animals received inhaled •NO via the ventilator to determine its effects on reperfusion injury.
Results. Lung injury, measured by increased vascular permeability using iodine-125–labeled bovine serum albumin leakage, was significantly increased in ischemic-reperfused animals compared with time-matched shams not undergoing ischemia. Inhaled •NO delivered at the start of reperfusion worsened injury at 30 minutes but was protective at 4 hours. The increased injury could be avoided either by delaying •NO for 10 minutes or by treating the animals with superoxide dismutase before reperfusion. •NO reversed postischemic pulmonary hypoperfusion at 4 hours, as measured by labeled microspheres. Lung neutrophil content was significantly reduced at 4 hours in •NO-treated animals.
Conclusions. •NO is toxic early in reperfusion, due to its interaction with superoxide, but is protective at 4 hours of reperfusion, due to reversal of postischemic lung hypoperfusion and reduction of lung neutrophil sequestration.
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Introduction |
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The use of lung transplantation as therapy for end-stage lung disease has made a strong resurgence since the late 1980s. However, difficulties in maintaining optimal graft function continue to compromise patient outcome. Lung dysfunction during the intraoperative or early postoperative period caused by technical difficulties or lung reperfusion injury threatens graft viability as well as patient survival [1]. Furthermore, there is evidence that significant reperfusion injury predicts a worse outcome for long-term graft survival [2]. An important factor in reperfusion injury may be dysfunction of the pulmonary vascular endothelium, as manifested by pulmonary hypertension and increased vascular permeability, resulting in pulmonary edema and impaired gas exchange. The recent identification of nitric oxide (•NO) as endothelium-derived relaxing factor [3, 4] has resulted in much research regarding the contribution of endogenous •NO to processes involved in the maintenance of vascular endothelial integrity.
Driven by the finding that inhaled •NO is a potent pulmonary vasodilator, its application in clinical settings has been rapidly employed. A major attraction is its pulmonary selectivity due to inactivation by hemoglobin in the circulation [5, 6]. Inhaled •NO has been used in treating pulmonary hypertension after surgical correction of congenital cardiac defects [7], for primary pulmonary hypertension in the newborn [8, 9], and for adults undergoing cardiac operations [10]. It has also been of value in the reversal of pulmonary hypertension secondary to hypercapnia [5, 11, 12]. There has been at least one report dealing with the use of inhaled •NO in the treatment of postoperative graft dysfunction after lung transplantation [13].
In the midst of clinical successes using inhaled •NO, there have been isolated reports of deleterious effects associated with its use [14, 15]. These mixed results point out the need for careful consideration of the spectrum of activity of •NO. The vascular relaxing properties of •NO are due primarily to the activities of constitutive •NO synthase, an endothelial-derived, calcium-dependent enzyme, which is a low level producer of •NO [3]. Nitric oxide is also produced as an inflammatory mediator by the inducible form of •NO synthase, a macrophage-derived, calcium independent enzyme, which is a high output producer of •NO [16]. In contrast to the beneficial effects of inhaled •NO in settings of abnormally high pulmonary vascular resistance, some models of lung injury have pointed out the toxic effects of endogenously produced •NO in inflammation [17].
We have previously described an in vivo rat lung model of ischemia-reperfusion demonstrating a bimodal pattern of injury with peaks at 30 minutes and 4 hours of reperfusion [18]. Using this model, we sought to determine the effects of inhaled •NO on lung ischemia-reperfusion injury. We attempted to identify causes for both beneficial and toxic effects of inhaled •NO to provide some insight into strategies for the rational use of inhaled •NO in reperfusion lung injury.
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Material and Methods |
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The animals were placed on their right sides, and a left anterolateral thoracotomy via the fifth interspace was carried out. The left pulmonary hilum was stripped of all neural, vascular, lymphatic, and connective tissue, thereby skeletonizing the left bronchus, pulmonary artery, and pulmonary vein. The inferior pulmonary ligament was divided as it entered the hilum. All dissection was carried out under an operating microscope. Each animal received 50 units of heparin in saline solution intravenously (total volume 500 µL) via the penile vein.
After we waited 5 minutes for circulation of the heparin, the left pulmonary artery, bronchus, and pulmonary vein were sequentially occluded with noncrushing microvascular clamps. The lungs were kept moist with intermittent application of warm normal saline solution, and the wounds were kept covered with plastic film to prevent excessive fluid loss. Periods of ischemia were held constant at 90 minutes (see Table 1
for a description of all groups used in these experiments).
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Lung Permeability Assessment
To quantitate injury to the lung as a result of ischemia and reperfusion, lung permeability was measured in the following manner. Iodine-125–labeled bovine serum albumin, prepared by a standard chloramine-T method, was diluted to approximately 3 to 5 µCi/mL in 1% bovine serum albumin/phosphate-buffered saline solution. Eight hundred thousand counts per minute of 125I-bovine serum albumin was then bought to a final volume of 500 µL in phosphate-buffered saline solution for injection. At the time of unclamping of the hilar structures, or at the comparable time in the sham animals, the mix was then injected into the animal via the penile vein. Immediately before sacrifice, 1 mL of blood was drawn from the inferior vena cava for counting. After the animal was sacrificed and the pulmonary vasculature was flushed, the left lung was excised for counting. Each lung specimen was weighed, and the lungs and blood were counted separately in a gamma counter. All results are expressed as counts per minute ratio of 1 g of lung tissue per milliliter of blood (permeability index). This ratio provided a reliable measure of microvascular permeability as a marker for lung injury (see Table 1
for a summary of groups used for permeability comparisons).
Nitric Oxide Intervention
Nitric oxide, 240 ppm in N2 (Airco Gas and Gear, Ann Arbor, MI), was provided via the ventilator with supplemental oxygen (60%) at a concentration of 80 ppm either immediately with the start of reperfusion (Groups E and F) or beginning 10 minutes after the start of reperfusion (Groups G and H). The nitric oxide was then continued for the duration of the reperfusion time course, either 30 minutes (Groups E and G) or 4 hours (Groups F and H). Injury was assessed as for standard model, described above.
Superoxide Dismutase Treatment
A subset of animals undergoing 90 minutes of ischemia and 30 minutes of reperfusion with early delivery of •NO (group I, n = 4) also received 10,000 units of superoxide dismutase (from bovine erythrocytes) in 50 µL of saline solution via penile vein injection immediately before the start of reperfusion. These animals were evaluated for lung injury using 125I-bovine serum albumin as described above.
Microsphere Analysis of Relative Pulmonary Flow
Chromium-51–labeled microspheres (NEN-DuPont, Boston, MA) were used to determine the effect of left lung ischemia-reperfusion on relative pulmonary flow. Animals not undergoing the ischemia-reperfusion protocol were evaluated for relative pulmonary flow comparing the left lung with the middle and lower lobes of the right lung (chosen because of an approximately equal lung mass). Normal rats (group J, n = 4) were anesthetized, intubated, and placed on the ventilator in a supine position. They were then injected via the inferior vena cava with approximately 1 µCi of 51Cr-labeled microspheres (mean diameter, 15 µm) in 500 mL of normal saline solution with 0.02% Tween-20 (Bio-Rad, Hercules, CA) as a detergent. After 5 minutes, the rats were sacrificed as above (lungs flushed via right ventricle with 10 mL of saline solution). The left lungs and middle and lower lobes of the right lung were harvested separately and counted in a gamma counter. The ratio of microsphere sequestration was then recorded as representing the ratio of pulmonary blood flow to these lung segments (flow ratio = 51Cr counts/min of left lung/counts/min of middle and lower lobes right lung). To assess whether the effect of inhaled •NO on lung reperfusion injury could in part be explained by a reversal of postischemic hypoperfusion, animals undergoing the ischemia-reperfusion protocol were also subjected to pulmonary flow measurements using microspheres. Four groups of animals were used: 30 minutes (group K) or 4 hours (group L) of reperfusion with supplemental oxygen alone, and 30 minutes (group M) or 4 hours (group N) of reperfusion with inhaled •NO (early) added via the ventilator (n = 4 for each group). Five minutes before the end of the reperfusion period and with the animals completely supine, radiolabeled microspheres were injected via the inferior vena cava. At sacrifice the lungs were flushed as described above and the left lung and middle and lower lobes of the right lung were counted separately in a gamma counter.
Myeloperoxidase Assay
Myeloperoxidase assay was used to compare the relative neutrophil sequestration in lung tissue of experimental animals. Myeloperoxidase, an enzyme found primarily within neutrophils, has been shown to be a sensitive marker for quantifying neutrophil content in tissue. The procedure was adapted from a published method for quantitating neutrophils using myeloperoxidase as a marker [19]. We have previously found neutrophils to be important for the development of reperfusion injury at the 4-hour time point, with no significant neutrophil sequestration or contribution to injury at the 30-minute time point [18]. Therefore, animals undergoing the ischemia-reperfusion protocol with 90 minutes of ischemia and 4 hours of reperfusion either with supplemental oxygen alone (group O) or with delayed •NO (group P, n = 4 each) were sacrificed as described above at the end of the reperfusion period. Left (ischemic-reperfused) lungs were then removed, frozen in liquid nitrogen, and stored at -80°C until the assay was performed. Lung samples were homogenized in 3 mL of 0.5% hexadecyltrimethylammonium bromide, 5 mmol/L ethylenediaminetetraacetic acid in 50 mmol/L potassium phosphate buffer, pH 6.0. Samples were sonicated to disrupt the granules and solubilize the myeloperoxidase in the hexadecyltrimethylammonium bromide. Samples were then centrifuged at 2,300 g for 30 minutes at 4°C. Assay buffer comprised 0.0005% H2O2, 0.167 mg/mL o-dianisidine dihydrochloride in 100 mmol/L potassium phosphate buffer, pH 6.0. Fifty microliters of each sample was mixed into 1.45 mL of assay buffer at room temperature, and the change in absorbance at 460 nm over 1 minute was recorded. Results are expressed as relative change in absorbance per minute at 460 nm.
Statistical Analysis
All data are presented as mean ± standard error of the mean. All comparisons except for myeloperoxidase data were made using a one-way analysis of variance, with Tukey's procedure used to determine significant differences between groups at individual time points. Comparisons between groups on myeloperoxidase data were made using a two-tailed, unpaired Student's t test. Statistical significance for all tests was set at p less than 0.05.
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Results |
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). At 4 hours of reperfusion there was also substantial injury with permeability indices of 0.358 ± 0.035 counts/min of 1 g tissue per mL blood in the positive control animals (group B) compared with 0.102 ± 0.009 counts/min of 1 g tissue per mL blood for the time-matched sham animals (group D; p < 0.01) (see Fig 1).
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We hypothesized that the increase in injury might be due to an interaction of nitric oxide with endogenously produced superoxide anion. The production of superoxide upon reperfusion is thought to be very short lived, disappearing within minutes. To test this, we gave animals undergoing the identical protocol with 30 minutes of reperfusion •NO delayed for 10 minutes after the start of reperfusion (group G, n = 4). These animals demonstrated a mean permeability index of 0.095 ± 0.013 counts/min of 1 g tissue per mL blood, a 45% reduction in injury compared with positive control animals (group A, p < 0.05) (see Fig 1). This demonstrated the importance of the timing of •NO delivery in determining beneficial or deleterious effects.
To further substantiate the role of interaction with superoxide anions in the early reperfusion period, additional animals (n = 4) undergoing the ischemia-reperfusion protocol with early delivery of •NO also received 10,000 units of superoxide dismutase intravenously immediately before the start of reperfusion to remove endogenously produced superoxide (group I). These animals had a mean permeability index of 0.137 ± 0.033 counts/min of 1 g tissue per mL blood, a 21% reduction in injury compared with positive control animals (group A; p = not significant). However, this is a reduction in injury of 71% (p < 0.01) compared with animals receiving early nitric oxide but not superoxide dismutase (group E) (see Fig 1), supporting the theory that increased injury with early •NO was due to its interaction with superoxide anion.
Four-Hour Nitric Oxide Intervention
Evaluation of the effect of inhaled •NO later in the reperfusion time course was undertaken as well. Animals undergoing ischemia and 4 hours of reperfusion (n = 5) received •NO beginning 10 minutes after the start of reperfusion (group H). These animals had a mean permeability index of 0.172 ± 0.012 counts/min of 1 g tissue per mL blood, a reduction in lung injury of 52% (p < 0.01) compared with positive control animals (group B) (see Fig 1). To determine whether the timing of •NO delivery would critically affect the outcome at 4 hours of reperfusion (as had been seen at 30 minutes), we performed the identical protocol in a limited number of animals (n = 2), but with early delivery of •NO (group F). These animals had a mean permeability index of 0.143 ± 0.028 counts/min of 1 g tissue per mL blood, not significantly different from that of animals receiving delayed •NO (group H) (see Fig 1). Because there was no observable difference using this permutation, no additional animals were used. In contrast to reperfusion injury at 30 minutes, the timing of •NO delivery had no bearing on the outcome at 4 hours, suggesting that other factors are involved in lung injury over longer reperfusion times.
Microsphere Studies
The ratio of pulmonary blood flow (measured by 51Cr counts per minute) of the left lung versus middle and lower lobes of the right lung in normal animals (group J) was 0.84 ± 0.05 (Fig 2). In animals undergoing 90 minutes of ischemia and 30 minutes of reperfusion with supplemental oxygen but not •NO (group K, n = 4), the mean ratio of left (ischemic lung) to right pulmonary flow was 0.61 ± 0.02, a reduction in relative flow to the ischemic lung to 73% of normal lung values (p < 0.01) (see Fig 2). After 4 hours of reperfusion (group L, n = 4), the mean flow ratio had increased to 0.70 ± 0.03, 83% of normal values (p = not significant) (see Fig 2). Animals undergoing ischemia-reperfusion with early delivery of •NO were evaluated for relative pulmonary flow. At 30 minutes of reperfusion (group M, n = 4) relative flow to the ischemic lung was reduced to 0.53 ± 0.05, significantly lower than that in normal animals (group K; p < 0.01) but not significantly different from that in animals undergoing reperfusion in the absence of inhaled •NO (group L) (see Fig 2). After 4 hours of reperfusion, animals receiving inhaled •NO (group N, n = 4) had a mean relative flow to the ischemic lung of 0.88 ± 0.04, not significantly different from that of normal animals (group J) but significantly better (p < 0.05) than that of positive control animals (group M) (see Fig 2). This demonstrated the vasodilating effects of inhaled •NO on postischemic hypoperfusion at 4 hours but not at 30 minutes of reperfusion.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Inhaled •NO, a potent and selective pulmonary vasodilator, has recently been introduced as an intervention in conditions associated with acute increases in pulmonary vascular resistance. As such, it has been shown in many instances to dramatically improve pulmonary flow. In addition, there is good evidence that •NO may also have effects both on the recruitment and function of neutrophils. Despite widespread success with its application, many instances of adverse effects have led to concern regarding its safety. We speculated that inhaled •NO may be beneficial in alleviating lung reperfusion injury, based on its pulmonary vasodilating properties and ability to reduce neutrophil mediated injury. Given this, we also sought to determine possible mechanisms for deleterious effects associated with its use.
The delivery of inhaled •NO at the start of reperfusion markedly worsened injury at 30 minutes. Evidence that this increase in injury was due to an interaction with endogenously produced superoxide was provided by our ability to eliminate the increase either by pretreating the animal with superoxide dismutase or by delaying the delivery of •NO for 10 minutes, after the early burst of superoxide production had passed. With the delayed delivery of inhaled •NO, reperfusion injury was improved compared with animals ventilated with oxygen alone.
Lung injury at 4 hours of reperfusion was improved with either early or delayed delivery of inhaled •NO. Due to the pulmonary vasodilating properties of •NO, the postischemic hypoperfusion seen as a result of reperfusion injury was eliminated at 4 hours. Neutrophils, known from our previous studies to play a significant role in the reperfusion injury at this time point, were significantly reduced in the reperfused lung in animals receiving early •NO. These factors combined to alleviate this phase of lung reperfusion injury.
Experimental evidence for a harmful interaction between •NO and superoxide has been demonstrated in other systems as well. Nitric oxide and superoxide can combine to form peroxynitrite anion, which upon further reaction can generate hydroxyl anion [20], both of which have potent oxidizing capabilities. Peroxynitrite produced in this fashion can contribute to cytotoxicity by inducing membrane lipid peroxidation and nitrosylation [21] and by oxidizing sulfhydryl groups on cellular proteins [22].
Further support for the role of superoxide mediation of •NO toxicity early in the reperfusion period comes from our observation that the effects can also be avoided by delaying the administration of •NO for 10 minutes after the start of reperfusion. It has been demonstrated in human vascular endothelial cells that xanthine oxidase is the primary source of superoxide production after ischemia, with hypoxanthine generated during the ischemic period serving as the principal substrate [23]. As oxygen becomes available at the start of reperfusion, the relatively large supply of xanthine oxidase creates a burst of superoxide anion production, with resultant tissue injury. As reperfusion continues, superoxide production declines within minutes. Under these conditions, damaging interactions between superoxide and •NO would be most likely during the earliest phases of reperfusion, and would cease to be of major importance a few minutes after the start of reperfusion. Consequently, by delaying the delivery of •NO, much of the interaction with superoxide can be avoided.
Pulmonary macrophages are also known to be a significant source of released superoxide through the action of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase, although the extent to which these cells contribute to superoxide generation in ischemic and reperfused rat lungs is unknown. The respiratory burst activity of macrophages is important in their role as a line of defense against inhaled pathogens. Inhibiting superoxide with superoxide dismutase has been shown to be of benefit in reducing injury in lung reperfusion models [24], similar to what is found in this model.
Examining the results at 4 hours of reperfusion in our model demonstrated the beneficial effects of inhaled •NO on lung reperfusion injury. There was clear reduction in lung vascular permeability, measured by the accumulation of 125I-bovine serum albumin in •NO-treated lungs, compared with animals not receiving inhaled •NO. This beneficial effect persisted whether the •NO was delivered at the start of reperfusion or delayed for 10 minutes. This suggests that the acute reperfusion injury seen in this model is probably completely reversible, and is related more to endothelial dysfunction than to permanent damage as a result of the reperfusion. As an explanation for the reduction in reperfusion injury at this time point, we found that the use of inhaled •NO improved the relative blood perfusion in the ischemic lung at the end of 4 hours, converting flow to essentially normal levels, significantly better than in ischemic lungs undergoing 4 hours of reperfusion without added •NO. This phenomenon of postischemic hypoperfusion after an initial hyperemic period is well known in other models of ischemia and has been demonstrated in lung reperfusion as well [25]. The mechanism for this finding may be in part a failure of endothelial •NO production during periods of postischemic reperfusion, such that exogenously administered •NO corrects the defect in pulmonary vascular relaxation and normalizes flow.
We also found that the neutrophil accumulation in lungs at 4 hours of reperfusion was less in •NO-treated animals than in animals undergoing ventilation without added •NO. This observation may relate to studies demonstrating that •NO is important in regulating adhesion of neutrophils to endothelium [26]. Nitric oxide decreases the adhesive interaction between neutrophils and endothelial cells. Conversely, direct exposure of neutrophils to L-arginine analogues, which are inhibitors of •NO production, increases the expression of the adhesion molecule CD11/CD18 as determined by flow cytometry. It has also been reported that •NO may have a direct effect on the ability of neutrophils to generate superoxide anion through inhibition of the membrane components of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase [27]. This may result in a decreased ability of neutrophils to exert damaging effects on tissues.
This series of experiments provides an explanation for the beneficial effects of •NO in lung reperfusion injury as well as for deleterious effects associated with its use. Inhaled •NO demonstrated clearly beneficial effects on lung injury, provided that the toxic interactions with superoxide were avoided. Inhaled •NO can act as a selective pulmonary vasodilator, as an inhibitor to neutrophil-mediated lung injury, and as a bronchodilator [28]. Nitric oxide can also act as a mediator of inflammation, both directly and through its interaction with superoxide anions. This may be important, as we have demonstrated, in settings of high level superoxide production, such as in early reperfusion. Because superoxide and •NO have both been incriminated in cytotoxicity mechanisms by leukocytes in settings of inflammation, inhaled •NO may result in an exacerbation of already present mediators of lung injury.
Despite the potential toxicities associated with the administration of inhaled •NO, the therapeutic gain that may be realized through the mechanisms described above suggests that it may prove useful in the clinical setting. Reperfusion injury in the setting of lung transplantation, although not generally fatal, contributes to early graft dysfunction and may predispose to the early appearance of rejection or to long-term bronchiolitis obliterans. Given the relatively poor long-term prognosis for lung transplant patients compared with the success with other solid organs, insights into the early development of rejection may improve overall outcome. The use of inhaled •NO during the reperfusion period may minimize the effects of reperfusion injury, keeping in mind the toxic effects associated with its delivery in the early phase. A clear understanding of the chemistry and physiology related to •NO therapy will help ensure that treatment follows a rational plan, and that problems generated by its use will be minimized.
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Acknowledgments |
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Opinions and conclusions in this article are those of the authors and are not intended to represent the official position of the Department of Defense, United States Air Force, or any other government agency.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Deeb, University of Michigan Hospitals, 1500 E. Medical Center Dr, 2124F Taubman Center TC/0344, Ann Arbor, MI 48109.
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