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Ann Thorac Surg 1999;67:194-199
© 1999 The Society of Thoracic Surgeons

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Original Articles

Reduced ischemia–reperfusion injury with rolipram in rat cadaver lung donors: effect of cyclic adenosine monophosphate

^a Division of Cardiothoracic Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

Address reprint requests to Dr Egan, University of North Carolina, CB 7065, 108 Burnett-Womack Bldg, Chapel Hill, NC 27599-7065
e-mail: ltxtme{at}med.unc.edu

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

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Background. The perfusion of rat lungs retrieved from cadavers with a solution containing isoproterenol has been shown to ameliorate the ischemia–reperfusion injury seen in lungs retrieved after death, and this protective effect parallels increases in tissue cyclic adenosine monophosphate levels. In this study, we investigated the effect of rolipram, a phosphodiesterase inhibitor, on capillary permeability and lung cyclic adenosine monophosphate levels in lungs retrieved from circulation-arrested rats.

Methods. Using an isolated perfused lung circuit, we retrieved lungs from circulation-arrested donor rats either ventilated with 100% oxygen or not ventilated for varying postmortem times. The lungs were reperfused with or without rolipram (2 µmol/L). The capillary filtration coefficient and wet to dry weight ratio, indicators of pulmonary vascular integrity, were determined, and tissue levels of adenine nucleotides and cyclic adenosine monophosphate were measured by high-performance liquid chromatography.

Results. The capillary filtration coefficient was significantly reduced in nonventilated cadaver lungs reperfused with rolipram 120 minutes after death (p < 0.05). Oxygen ventilation or reperfusion with rolipram had a similar effect on the capillary filtration coefficient. Cyclic adenosine monophosphate levels were significantly higher in rolipram-reperfused lungs retrieved 120 minutes after death in both oxygen-ventilated (p < 0.01) and nonventilated (p < 0.01) lungs.

Conclusions. In lungs from nonventilated, circulation-arrested donors, reperfusion with rolipram reduces the ischemia–reperfusion injury that may be due to intracellular cyclic adenosine monophosphate. Alteration of perfusate may have an impact on capillary leak caused by antecedent ischemia. Thus, rolipram may be a useful adjunct in the preservation of donor lungs retrieved after death.

	Introduction

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Lung transplantation is an effective palliative therapy for a variety of end-stage lung diseases. Nevertheless, potential recipients far outnumber the availability of donor organs. This shortage of donor lungs prompted our laboratory to investigate the use of lungs retrieved from circulation-arrested cadavers [1]. Previous experiments support the hypothesis that the lung may remain viable after circulatory arrest and death for a period of time sufficient to allow retrieval for transplantation. Studies demonstrating postmortem parenchymal cell viability in rat lungs ventilated with oxygen for 4 hours after death [2], ultrastructural evidence of preserved cellular integrity [3], and marked attenuation in the time-dependent decrement of lung high-energy phosphate stores in cadaveric rat lungs ventilated with oxygen [4] provide support for the hypothesis that the lung remains viable for a significant time interval after death.

Using an isolated perfused rat lung model, we studied the degree and time course of ischemia–reperfusion injury assessed by the capillary filtration coefficient (K_fc), wet to dry weight ratio, adenine nucleotide levels, and cell viability [5]. The effect of oxygen ventilation of the nonperfused cadaver lung was investigated at varying time intervals. In this study, lungs ventilated for 1 hour after death had normal K_fc values, implying preserved microvascular integrity. Also, loss of adenine nucleotides with increasing ischemic time correlated with increasing K_fc values, suggesting a relation between vascular permeability and adenine nucleotide levels.

Numerous studies have suggested that increased levels of 3',5'-cyclic adenosine monophosphate (cAMP) can prevent or attenuate the increased microvascular permeability associated with the ischemia–reperfusion lung insult [6–10]. Siebert and associates [8] and Adkins and colleagues [9] used various pharmacologic agents, including a cAMP analogue, that reduced microvascular permeability and increased cAMP levels. Similarly, phosphodiesterase inhibitors, such as aminophylline, pentoxifylline, and rolipram, have been shown to ameliorate ischemia–reperfusion injury [6, 11–14].

Using an isolated perfused rat lung model, we recently investigated the effects of reperfusion with isoproterenol on ischemia–reperfusion injury in cadaveric donor lungs retrieved from rats at varying postmortem time intervals [15]. Increased capillary permeability of lungs retrieved from circulation-arrested donors was ameliorated up to 120 minutes after death if the lungs were reperfused with an isoproterenol-containing solution. This effect was associated with increased cAMP levels measured in whole lung tissue.

Rolipram, an isozyme-selective cAMP phosphodiesterase inhibitor (type IV), should prevent breakdown of cAMP and thus may increase cAMP levels in lung tissue. To further define the role of cAMP in the maintenance of capillary integrity in lungs retrieved from non–heart-beating donors, we studied the use of rolipram in the isolated perfused rat lung model. We hypothesized that reperfusion of lungs retrieved from non–heart-beating donors with rolipram should exhibit a reduction in ischemia–reperfusion injury, manifested by a reduction in K_fc. Thus, we anticipated results similar to those seen with reperfusion with isoproterenol. We further hypothesized that a reduction in K_fc would be associated with increased tissue levels of cAMP.

	Material and methods

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Isolated perfused lung circuit
Details of the experimental protocol have been described previously [5]. In brief, male Sprague-Dawley rats weighing 250 to 450 g were anesthetized by intraperitoneal injection of pentobarbital sodium (20 mg/kg) (Abbott Laboratories, Chicago, IL). A small transverse laparotomy incision was made, and heparin (600 units) (Elkins-Sinn, Cherry Hill, NJ) was injected intrahepatically. The trachea was cannulated, and the rat was euthanized with an intrahepatic injection of pentobarbital sodium (30 mg/kg). Cardiac arrest was confirmed, and the laparotomy incision was closed. The rat was then either ventilated (Harvard rodent ventilator model 683; Harvard Apparatus Co, Millis, MA) with 100% oxygen at 60 breaths/minute, a tidal volume of 4 mL, and a positive end-expiratory pressure of 2 cm H₂O, or not ventilated. The heart–lung block was left in situ to simulate the cadaveric donor as closely as possible.

Lungs were retrieved through sternotomy immediately (controls) or after varying intervals (between 30 and 120 minutes) after death. The main pulmonary artery and the left atrium were cannulated through right and left ventriculotomies, respectively. The heart–lung block was removed and suspended from a force-displacement transducer (model FT03; Grass Instruments, Quincy, MA) into a humidified chamber to monitor weight changes. The lungs were ventilated with 5% carbon dioxide, 20% oxygen, 75% nitrogen at the same ventilator settings described previously. The lungs were reperfused with a peristaltic pump (Minipuls 3; Gilson Medical Electronics, Middleton, WI) at a constant flow rate of 0.03 mL · g^-1 · min. The reperfusate was a modified Earle’s balanced salt solution containing 0.21% sodium bicarbonate and 4% bovine serum albumin (Sigma Chemical Co, St. Louis, MO). The reperfusate was further modified by the addition of rolipram (2 µmol/L) (Biomol, Plymouth Meeting, PA), depending on the study group. The initial 75 mL of effluent perfusate was discarded to ensure removal of residual red and white blood cells and plasma before maintaining recirculation. The perfusate temperature was maintained between 35° and 38.5°C using a water-jacketed reservoir. The pH was continually monitored with a pH probe (Accumet; Fisher Scientific, Pittsburgh, PA) placed in the venous reservoir and maintained near 7.40 using dilute hydrochloric acid or sodium bicarbonate, as necessary.

Pressure transducers (Cope Laboratories, Lakewood, CO) were positioned at the hila of the lungs, zeroed to atmospheric pressure, and calibrated with a mercury manometer. Pulmonary artery, pulmonary venous, and peak inspiratory airway pressures were measured continuously. All pressure measurements and weight changes were amplified (Hewlett-Packard 8805D, Mountain View, CA) and then analyzed with a special computer software package developed for our laboratory. Data were recorded and displayed on a Macintosh II Fx computer.

Measurement of pulmonary capillary pressure
Pulmonary capillary pressure was estimated by the double-occlusion technique [16], by which simultaneous occlusion of arterial and venous cannulas results in equilibration of pulmonary artery and pulmonary venous pressures to the same pressure. This equilibrated pressure equals the pulmonary capillary pressure and also reflects the capillary pressure when the lung is not isogravimetric.

Capillary filtration coefficient
Calculation of K_fc has been described previously [17, 18]. Briefly, after the lungs reached an isogravimetric state, the venous reservoir was rapidly elevated to increase pulmonary venous pressure by 6 to 8 cm H₂O for 15 minutes. The increase in lung weight was recorded over time (dWT/dt). The initial 3- to 5-minute period of weight gain represents vascular distension and recruitment and is not a reflection of capillary permeability. The dWt/dt between minutes 6 and 15 represents increased transvascular fluid flux secondary to increased capillary permeability, and this later dWt/dt was analyzed by using linear regression of the log₁₀-weight changes per minute. The initial rate of weight gain was calculated by extrapolation of dWt/dt to time 0, using Excel 5.0.

The Starling equation describes the role of K_fc in transvascular fluid flux [19]:

where Jv is the transvascular fluid flux; Pc and Pi are hydrostatic pressures in the capillary and interstitium, respectively; c and i are osmotic pressures in the capillary and interstitium, respectively; and o is the osmotic reflection coefficient. At the extrapolated time 0, both Pc and Jv are elevated to new steady states before the remaining factors can be affected. Over the relatively short time period of this experiment, changes in the osmotic pressures in the interstitium are assumed to be negligible, so that K_fc can be calculated by the equation

where K_fc was calculated by dividing dWt/dt at time 0 by the change in pulmonary capillary pressure that occurred after pulmonary venous pressure elevation. K_fc was normalized using baseline wet lung weight and expressed as mL · min^-1 · cm H₂O^-1 · 100 g lung tissue^-1.

Wet to dry weight ratios
At the completion of the experiment, the upper lobe of the right lung was excised and immediately weighed. It was then dried in an oven at 60°C for 48 hours and reweighed. The remaining lung was partitioned, flash-frozen in liquid nitrogen, and stored at -70°C.

High-performance liquid chromatography
Tissue samples previously retrieved from the right lung for high-performance liquid chromatography were pulverized by using a liquid nitrogen–cooled Bessman pulverizer and then homogenized with ice-cold 0.6 N perchloric acid (2 to 8 mL/g tissue) using a tissue tearer (Biospec Products, Bartlesville, OK) at 30,000 rpm for 30 seconds. After centrifugation for 2 minutes at 10,000 rpm, the supernatant was removed and neutralized with cold 1 mol/L potassium phosphate dibasic (pH 12) to achieve a pH of 6.8. The supernatant was separated from precipitated salt by repeat centrifugation for 2 minutes at 10,000 rpm. The remaining solution was passed through a 0.45-mm acrodisc filter.

Adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and cAMP concentrations were determined by high-performance liquid chromatography using an LKB Bromma apparatus (LKB-Produkter AB, Bromma, Sweden). A partisil 10 SAX Whatman column (Whatman Inc, Clifton, NJ) in 0.25 mol/L potassium phosphate monobasic (pH 6.5) at a flow rate of 1.5 mL/min was used to separate and quantify ATP and ADP levels. An EQC 5u S C18 column (Whatman Inc) in 0.25 mol/L ammonium phosphate monobasic (pH 4.5) at a flow rate of 2.0 mL/min was used to measure cAMP and AMP levels. For each assay, 50 to 100 µL of solution was injected into the high-performance liquid chromatographic system. Chromatograms were analyzed on an IBM 486 DX 33 MHz computer with Peak Simple Software. Standard curves were made by performing serial dilutions for ATP, ADP, AMP, and cAMP (Sigma Chemical Co).

Specific protocol
Seventy-eight pairs of lungs were divided into 13 groups, with six lungs in each group (Table 1). No 30-minute postmortem oxygen ventilation groups with rolipram were studied because lungs retrieved 30 minutes after death with oxygen ventilation had K_fc values similar to those of controls.

Statistics
All results are expressed as mean ± standard error. Comparisons between groups were made using analysis of variance with a Bonferroni post hoc test for multiple comparisons. Differences were significant when p was less than 0.05. Linear correlations were obtained using simple regression analysis on Excel 5.0 and expressed as r values (Pearson product moment).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Capillary filtration coefficient
Changes in K_fc are shown in Figure 1. The K_fc was elevated with increasing postmortem ischemic time in both non–rolipram-perfused and rolipram-perfused groups. As reported previously [5], the increase in K_fc was delayed until 1 hour after death in cadaveric donor lungs ventilated with oxygen (without rolipram reperfusion) compared with nonventilated rat lungs. Reperfusion with rolipram had no effect on K_fc of lungs ventilated with oxygen, but K_fc was reduced at all time points in nonventilated lungs reperfused with rolipram. The K_fc values with rolipram were approximately 50% of baseline values without rolipram and reached statistical significance at 30 and 120 minutes (p < 0.05).

View larger version (21K): [in this window] [in a new window]   Fig 1. Capillary filtration coefficient (Kfc) related to postmortem ischemic time interval for each group (n = 6 per group). Data are presented as mean ± standard error. (NV = no ventilation; O2 = oxygen ventilation; Roli = rolipram, 2 µmol/L; * = p < 0.05 rolipram versus control; # = p = 0.055 rolipram versus control.)

Wet to dry weight ratios
As pulmonary capillary permeability increases with increasing postmortem times, the wet to dry weight ratio increases (Fig 2). Wet to dry weight ratios correlated with K_fc for the group as a whole (r = 0.79) because of the relation in non–rolipram-perfused lungs (r = 0.91). However, in the rolipram-perfused group, correlation was poor (r = 0.31). In addition, rolipram reperfusion did not result in a reduced wet to dry weight ratio compared with non–rolipram-perfused lungs at the same postmortem time.

View larger version (25K): [in this window] [in a new window]   Fig 2. Wet to dry (W/D) weight ratios as related to postmortem ischemic time interval for each group (n = 6 per group). Data are presented as mean ± standard error. No benefit was found with rolipram (Roli) (2 µmol/L) or oxygen ventilation (O2) at similar postmortem time intervals. (NV = no ventilation.)

View larger version (23K): [in this window] [in a new window]   Fig 3. Lung tissue cAMP levels are shown after reperfusion with and without rolipram (Roli) (2 µmol/L) for each postmortem ischemic time interval. Data are presented as mean ± standard error. (NV = no ventilation; O2 = oxygen ventilation; * = p < 0.05 rolipram versus control.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

We are particularly interested in pulmonary capillary function after a period of warm ischemia to better appreciate mechanisms of endothelial dysfunction that might be apparent before any period of cold storage. To simulate the clinical scenario, additional experiments will be necessary to study the impact of hypothermic perfusion after warm ischemia. We have previously demonstrated that an additional 4 hours of hypothermic storage, after 4 hours of warm ischemia, did not adversely affect lung cell viability [21].

We have chosen to administer heparin in donors before death so that we can assess the impact of ischemia alone on capillary function. In the clinical scenario of lung retrieval from non–heart-beating donors, it may be possible to administer heparin in potential donors after death by intracardiac injection of heparin and a brief period of cardiopulmonary resuscitation.

Using the isolated perfused rat lung model, our laboratory first studied the time course and extent of ischemia–reperfusion injury by measuring K_fc at varying durations of in situ warm ischemia. Oxygen ventilation appeared to preserve microvascular integrity up to 1 hour of postmortem ischemia, as evidenced by normal K_fc and wet to dry lung weight ratios. However, after 120 minutes of ischemia, preharvest ventilation had no demonstrable beneficial effect on permeability [5].

Pharmacologic therapies that increase cAMP levels may reduce capillary permeability [6–14]. In models of lung injury, cAMP may exert beneficial effects by a variety of mechanisms. Tighter intercellular junctions may enhance barrier properties [7, 8]. Pulmonary vascular endothelial cells contain actomyosin myofibrils with contractile properties [22]. Agents that cause actomyosin relaxation lead to cell flattening, with increased intercellular apposition and subsequent decreased permeability [7, 22]. Cellular cAMP levels also affect the release and function of various cytokines, the tumor necrosis factor-–related expression of endothelial thrombomodulin, and the expression of leukocyte adhesion molecules [23]. In addition, alveolar epithelial cells respond to increased cAMP levels by activating ionic transport systems that may result in a shift of edema fluid from the airspace to the interstitium [8].

We previously studied an isoproterenol-enhanced reperfusate in non–heart-beating donor rat lungs using the isolated perfused circuit [15]. Isoproterenol attenuated the ischemia–reperfusion injury, as measured by K_fc, up to 120 minutes after death. This beneficial affect was associated with markedly elevated cAMP levels. Reduction in capillary permeability was observed only in nonventilated cadaver lungs. Postmortem ventilation was beneficial, but the effect of oxygen and isoproterenol reperfusion was not synergistic.

In the present model, rolipram at a concentration of 2 µmol/L appears to attenuate the increase in capillary permeability associated with postmortem ischemia in nonventilated cadaver lungs. This beneficial effect was observed only in nonventilated cadaver lungs. We were not able to demonstrate an increase in cAMP levels above control levels using rolipram at any time point, whereas cAMP levels were increased threefold to fivefold with isoproterenol [15]. In the current study, rolipram appeared to attenuate the decrease of cAMP in lung tissue that occurs after death. It is conceivable that our method of measuring cAMP is not sufficiently sensitive to distinguish subtle differences in cAMP. It is also conceivable that phosphodiesterase inhibition with rolipram may provide for more cAMP at specific sites of action in the endothelial cell without an appreciable increase in total amounts of cAMP extracted from whole tissue. Finally, it is conceivable that the beneficial effect of rolipram in our model is unrelated to alterations in cAMP.

Reperfusion of lungs with a rolipram-containing solution after retrieval from non–heart-beating rat donors attenuated the increased capillary permeability in animals not ventilated before harvest. We did not observe a corresponding reduction in the wet to dry weight ratio in lungs retrieved 30 or 60 minutes after death, but this ratio is a more crude measure of capillary function. The wet to dry weight ratio was lower in nonventilated cadaver lungs retrieved 120 minutes after circulatory arrest when reperfused with rolipram but was not statistically significant (p = 0.086). Future studies using this model will focus on the possible synergistic effect of cAMP-enhancing agents with other strategies to reduce reperfusion injury. Improved understanding of ischemia–reperfusion injury may facilitate the use of non–heart-beating donors for human lung transplantation.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark S. Bleiweis David R. Jones Thomas M. Egan Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bleiweis, M. S. Articles by Egan, T. M. Search for Related Content PubMed PubMed Citation Articles by Bleiweis, M. S. Articles by Egan, T. M.