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Ann Thorac Surg 1999;67:798-803
© 1999 The Society of Thoracic Surgeons

Original Articles

Theophylline improves functional recovery of isolated rat lungs after hypothermic preservation

Roland L. Featherstone, PhDa, Frank J. Kelly, PhDa, David J. Chambers, PhDb

a Cardiovascular Research, The Rayne Institute, St. Thomas’ Hospital, London, England, UK
b Cardiac Surgical Research, The Rayne Institute, St. Thomas’ Hospital, London, England, UK

Accepted for publication August 11, 1998.

Address reprint requests to Dr Featherstone, Cardiovascular Research, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, England
e-mail: rfeather{at}rayne.umds.ac.uk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Raising intracellular cyclic adenosine monophosphate levels protects lungs from ischemia-reperfusion injury. We hypothesized that the phosphodiesterase inhibitor theophylline would protect lungs during storage.

Methods. Rat lungs were perfused with modified bicarbonate buffer mixed with rat blood (4:1 vol/vol) (37°C) and ventilated (80 breaths/min). After 20 minutes of perfusion during which vascular resistance and airway compliance were measured, lungs were flushed with and then immersed in bicarbonate buffer (4°C) alone or containing theophylline (30 to 1,000 µmol/L). After 6 hours of storage, lung function was reassessed during 40 minutes of reperfusion.

Results. Lungs stored in the presence of theophylline had improved lung function on reperfusion. After 40 minutes of reperfusion, pulmonary compliance was 0.008 ± 0.004 mL/cm H2O, 0.022 ± 0.010, 0.037 ± 0.007, 0.044 ± 0.006, and 0.073 ± 0.003 mL/cm H2O, and vascular resistance was 3.84 ± 0.40 cm H2O · min · mL-1, 3.64 ± 0.78, 2.12 ± 0.35, 2.22 ± 0.25, and 1.90 ± 0.38 cm H2O · min · mL-1 in lungs stored in the presence of 0, 30, 100, 300, or 1,000 µmol/L theophylline, respectively. Similar improvements were obtained for wet to dry weight ratio and gas exchange.

Conclusions. Theophylline merits investigation as a potentially beneficial addition to solutions for the flushing and storage of human lungs for transplantation.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Lung transplantation is the accepted therapy for end-stage pulmonary disease. However, severe graft dysfunction occurs in 10% to 20% of recipients in the immediate postoperative period [1] and often is associated with prolonged intensive care and increased mortality. This primary graft failure accounts for 12% to 14% of early postoperative deaths. Consequently, strategies are required to reduce postischemic lung damage.

Raising the intracellular cyclic adenosine monophosphate (cAMP) concentration has been shown to protect against ischemia-reperfusion injury in the lungs [2]. The xanthine derivatives are a class of drugs that raises intracellular cAMP levels by phosphodiesterase inhibition [3]. Of these, pentoxifylline has been shown to protect isolated rat lungs against human neutrophil–mediated injury [4] and ischemia-reperfusion injury [5] and to reduce lung allograft reperfusion injury in dogs [6, 7]. This agent has a relatively broad spectrum of action, and its beneficial effects have been suggested to be due to its ability to protect endothelial function [8], induce vasodilation [7], or inhibit neutrophil and monocyte activation [5]. Interestingly, pentoxifylline appears to exert important antiinflammatory activity even when added to a cell-free flush solution [7].

Because existing studies with pentoxifylline added to flush solutions or storage solutions or both in long-term hypothermic ischemia [6, 7, 9] have used a single, relatively high dose (570 to 720 µmol/L), these investigations have not contributed to an understanding of the mechanism of the beneficial effects of xanthine derivatives. Theophylline, like pentoxifylline, is a clinically employed xanthine derivative. Whereas pentoxifylline is generally used for peripheral vascular disease, theophylline is more widely employed for asthma because of its bronchodilative and putative antiinflammatory effects. We therefore hypothesized that theophylline, by virtue of its phosphodiesterase inhibitory properties, would protect rat lungs during storage. To examine this, we investigated the dose–response relationship for the protective effect of theophylline in an isolated rat lung preparation subjected to prolonged hypothermic storage.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
All chemicals used in perfusate and storage solutions were supplied by BDH Ltd, Leicestershire, United Kingdom. Sodium pentobarbital was purchased from Rhone Merieux, Harlow, United Kingdom.

Lung preparation
Lungs were obtained from male Wistar rats weighing 250 to 330 g. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research, the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985) and the "Guidance on the Operation of the Animals (Scientific Procedures) Act 1986" published by Her Majesty’s Stationery Office, London, England.

Rats were anesthetized by intraperitoneal injection of pentobarbital (2 mL/kg of a 60 mg/mL solution). After tracheal intubation, animals were ventilated at 80 breaths/min by positive pressure with a Harvard small-animal ventilator. After laparotomy, the diaphragm was removed, and heparin sodium (500 IU) was injected into the vena cava. The animals were exsanguinated by way of the inferior vena cava, and the thorax was opened. A cannula was inserted into the pulmonary artery and held in place by tightening a ligature previously placed around the pulmonary artery and aorta. A second cannula was secured in the left atrium to receive the perfusate leaving the lungs.

The lungs were removed and suspended in a sealed, water-jacketed chamber maintained at 37°C. Perfusion was commenced with modified bicarbonate buffer (BB) (composition in millimoles per liter: NaCl, 118.5; KCl, 3.8; KH2O4, 1.2; NaHCO3, 25.0; CaCl2, 2.0; MgSO4, 1.2; glucose, 10.0) and whole rat blood (that drawn from the vena cava) mixed 4:1 to produce sanguineous BB (SBB). The perfusate flow rate was adjusted to 15 mL/min and was maintained at this value by a peristaltic pump (Watson Marlow 501). The SBB was held in a heated (37°C) reservoir and gassed with 100% carbon dioxide. In control lungs, this produced a pH of 7.2 to 7.3 entering the lungs and 7.4 to 7.5 leaving the lungs. Buffer leaving the lungs through the left atrial cannula was returned to the reservoir and recycled. Oxygenation of the perfusate was by the isolated lungs, which were ventilated with room air.

The peak tracheal pressure applied by the ventilator was set to give a tidal volume of 1.5 to 2.0 mL (0.6 mL/100 g of animal weight), and a positive end-expiratory pressure of 1 to 2 cm H2O was applied. A differential pressure transducer (Sensystem) attached to a sidearm of the tracheal cannula measured tracheal pressure. Another pressure transducer (Sensystem) connected to the inside of the sealed perfusion chamber measured changes in chamber pressure caused by the lung filling and emptying during ventilation. Injection of a known volume of air into the lung by syringe before commencement of each experiment allowed this transducer to be calibrated in terms of tidal volume. The ratio of tidal volume to tracheal pressure was taken as a measure of lung compliance. A third pressure transducer (Bell & Howell, Pasadena, CA) was connected by a sidearm to the tube flowing into the pulmonary artery cannula; this pressure divided by the perfusate flow rate measured vascular resistance. The output of each of the three pressure transducers was recorded using a Gould 4-channel chart recorder.

Ports on the perfusate inflow and outflow tubing allowed collection of samples of perfusate entering and leaving the lung for measurement of pH. As the lung exhales carbon dioxide, the perfusate pH increases as it passes through the lung, and this increase can be taken as an indicator of the gas-exchanging ability of the lung [10].

Experimental protocol
Lungs were perfused for an initial 20-minute period (control), during which time control lung function variables were measured (as described already). By switching a three-way tap to open a reservoir, the lungs were then flushed with BB or BB containing theophylline, 30, 100, 300, or 1,000 µmol/L, at a pressure of 30 cm H2O. They were initially flushed with 10 mL of solution at room temperature (20° to 25°C): this has been shown to reduce cold-induced vasoconstriction caused by sudden infusion of storage solution at 4°C in the heart [11]. After this initial 10-mL perfusion, flushing was continued with a further 20 mL of the same storage solution at 4°C.

The flushed lungs were immersed inflated, with the vasculature open, in the storage solution (4° to 6°C) for 6 hours. Lung inflation was achieved by attaching a syringe to the tracheal cannula after removal of the lungs from the perfusion chamber and injecting 2 mL of air; the trachea was then tied off to keep the lungs inflated.

After 6 hours of storage, the lungs were removed from the solution and reattached to the perfusion circuit, and reperfusion with SBB (at 37°C) was instituted for a 40-minute period. Reperfusion was at 15 mL/min, this rate being achieved within 1 minute of reattachment of vascular cannulas. During reperfusion, lung function variables were measured. A control, no-storage group of lungs was also studied, these were perfused in SBB for a total of 60 minutes, equivalent to total perfusion plus reperfusion time in stored lungs.

The lungs were perfused with a SBB during both the control perfusion and poststorage reperfusion periods. This provided stable preparations without the formation of edema during control perfusion, which has been a problem with other isolated lung models [12, 13].

Determination of wet to dry weight ratios
At the end of the 40-minute reperfusion period, the lungs were removed from the perfusion chamber, the surface fluid was blotted off, and they were weighed. The lungs were then placed in an 80°C oven for 24 hours, at which time the dry weight was obtained. No further decrease in weight occurred after this period. In a further group of 9 rats, wet to dry weight ratios were determined in lungs directly after removal from the animals. This provided a baseline wet to dry weight ratio and allowed the assessment of the effect of control 60-minute perfusion with SBB on edema formation.

Statistical analysis
Data are displayed as the mean ± the standard error of the mean. There were 5 to 6 animals per group. To compare the effects of the various treatments on lung function over the time course of reperfusion, trapezoid integration was used to calculate the area under the time–response curve for each variable for each animal. The individual values were then employed for comparisons between the various groups. Between-group comparisons were carried out by a one-way analysis of variance, and if this revealed significant differences, Dunnett’s test was used to compare multiple values with control. In all tests, a p value of less than 0.05 was taken as indicating significance.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Various baseline lung function variables were measured after 20 minutes of perfusion in all groups of lungs. No significant differences between groups for any of the measured variables were observed (Table 1).


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  		Table 1. Control (Prestorage) Values of Physiological Variablesa,b

 
Storage in BB alone for 6 hours resulted in a marked fall in pulmonary compliance from 0.073 ± 0.005 mL/cm H2O to 0.008 ± 0.004 mL/cm H2O after 40 minutes of reperfusion (Table 2; Fig 1A). In contrast, addition of theophylline to the storage BB prevented the fall in pulmonary compliance in a dose-dependent manner. This is reflected both in the area-under-the-curve values for this variable in the various treatment groups assessed over the 40 minutes’ reperfusion (see Table 2; Fig 1A) and the final values measured at the end of the reperfusion period (see Fig 1A). Lungs stored for 6 hours in BB containing 1,000 µmol/L theophylline showed no difference in pulmonary compliance after 40 minutes’ reperfusion compared with lungs that had not been stored (see Fig 1A). Similar findings were made with respect to vascular resistance (Fig 1B; see Table 2).


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  		Table 2. Effect of 6 Hours’ Storage in Various Solutions on Physiology of Isolated, Perfused Rat Lunga,b

 


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  		Fig 1. (A) Pulmonary compliance and (B) vascular resistance during 40 minutes’ reperfusion with sanguineous bicarbonate buffer in isolated rat lungs after no storage (•) or 6 hours’ storage in modified BB containing 0 ({blacksquare}), 30 ({square}), 100 ({circ}), 300 ({triangleup}), or 1,000 ({blacktriangleup}) µmol/L theophylline. Data are expressed as the mean ± the standard error of the mean; each group comprised lungs from 5 or 6 rats. Some error bars have been omitted for clarity. (*p < 0.05 by Dunnett’s test versus lungs stored for 6 hours in BB alone by area-under-curve analysis.)

 
The pH increase of perfusate across the lung (Fig 2A) showed a trend for theophylline to reverse the adverse effects of 6 hours’ storage, but this failed to reach significance (0.1 > p > 0.05 for 300 µmol/L, the most effective dose). As regards the use of perfusate pH increase across the lung as a measure of gas exchange, we used this for three reasons. First, no attempt was made to deoxygenate the recirculating perfusate before it entered the lung in this model, whereas gassing with carbon dioxide was performed at this stage, thus creating a perfusate–alveolar air gradient for this gas. Second, whereas transpulmonary pH gradients were available for all experimental groups, this was not the case for dissolved oxygen in the perfusate. Third, other authors [10] have shown that this pH gradient can be used as an indicator of gas exchange. It should also be noted that where perfusate oxygen pressure measurements were available in some unstored control tissues, an increase of 23.05 ± 2.29 mm Hg (n = 5) in this variable was seen in perfusate after transit through the lungs at the 60-minute point, despite the absence of perfusate deoxygenation. Furthermore, in three tissues undergoing 6 hours control storage in BB, the transpulmonary perfusate oxygen pressure gradient fell to 1.80 ± 1.80 mm Hg after 40 minutes’ reperfusion, thus demonstrating a pattern of decline similar to that seen in the transpulmonary pH gradient.



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  		Fig 2. Difference in perfusate pH leaving and entering isolated rat lungs (A) and wet to dry weight ratio of rat lungs (B) after no storage or 6 hours’ storage in modified bicarbonate buffer (BB) containing 0, 30, 100, 300, or 1,000 µmol/L theophylline followed by 40 minutes’ reperfusion with sanguineous BB. Data are expressed as the mean ± the standard error of the mean; each group comprised lungs from 5 or 6 rats. (*p < 0.05 by Dunnett’s test versus lungs stored for 6 hours in BB alone.)

 
Although theophylline was protective against poststorage deterioration for all the variables, some differences were apparent. Complete protection against the rise in vascular resistance was seen when theophylline was present at doses of 100 µmol/L or higher, whereas the highest dose used (1,000 µmol/L) was necessary to provide complete protection of pulmonary compliance. Further, the decline in gas exchange (transpulmonary pH gradient) was not completely reversed at any dose of theophylline studied.

The wet to dry weight ratios in no-storage control lungs perfused for 60 minutes with SBB (6.3 ± 0.5; n = 6) were not significantly different from those of lungs removed directly from the animals (5.5 ± 0.4; n = 9). Wet to dry weight ratios were increased by 6-hour storage in BB from 6.3 ± 0.53 to 9.9 ± 1.58 (Fig 2B). Although there was a trend toward reversal of this effect at all theophylline doses studied, this was significant only with 1,000 µmol/L (5.95 ± 0.59).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
There are both theoretical and experimental grounds for believing that raising cAMP levels will protect lungs from the adverse effects of prolonged hypothermic ischemia. Increased concentration of cAMP causes vascular smooth muscle relaxation [14], which would tend to counteract the vasoconstriction caused by hypothermia and raised potassium levels in preservation solutions. This vasoconstriction may be an important contributor to hydrostatic edema formation in the reperfused lung. During reperfusion, activated neutrophils may also play a role in damaging the tissue [4]; the inflammatory activity of these cells can be inhibited by raising their intracellular cAMP [15]. Finally, cAMP in the lung may activate an active transport mechanism that moves sodium from the airways back into the tissue [16]. As this will result in the passive movement of water with the ion, it will tend to counteract edema formation in the airways and provide a counterbalance to the forces driving fluid from the vasculature into the airways. These theoretical considerations are supported by the observation that the cAMP analogue dibutyryl-cAMP is protective in a lung transplant model [17].

A commonly applied pharmacologic approach to raising intracellular cAMP levels is to use an inhibitor of the catabolic phosphodiesterase enzymes. Such an approach has been applied in lung transplantation models using the xanthine derivative pentoxifylline [6, 7, 9]. These studies, however, used a single, relatively high dose of pentoxifylline, which, in common with other xanthine derivatives, also interacts with adenosine receptors [18]. Theophylline is a xanthine derivative, the pulmonary pharmacology of which has been extensively studied [19]. Our aims in this study were to establish the effect of theophylline in protecting isolated rat lung preparations from the adverse effects of 6 hours’ storage in BB at 4° to 6°C and to determine the dose–response relationship for this effect.

Because increased vascular resistance and permeability and consequent edema are important features of ischemia-reperfusion injury in the lung, an important feature of any model used to explore preservation techniques is a degree of hemodynamic stability. The absence of a significant difference between the wet to dry weight ratios of lungs perfused for 60 minutes in SBB (no-storage control) and lungs removed directly from the animals demonstrates the superiority of this sanguineous perfusate over asanguineous BB supplemented with bovine serum albumin used in an earlier study [12]. Despite the need of a second animal to provide blood for the reperfusion buffer, this model still retains the advantage of economy of animal usage over perfused lung systems requiring a support animal [20, 21], where, in addition to the lung donor and the support animal, a third animal is necessary to supply blood to prime the perfusion circuit. In addition, the need to maintain the support animal and the potential complication of humoral interactions between the isolated lung and the support animal are both avoided.

The graded nature of the effect of theophylline in improving poststorage lung function was most apparent in the attenuation of the storage-related fall in pulmonary compliance, with complete protection observed at 1,000 µmol/L. Similar trends to poststorage improvement resulting from theophylline were seen in the case of vascular resistance and gas exchange. The higher wet to dry weight ratio found in lungs stored for 6 hours in BB and then reperfused for 40 minutes was also attenuated by theophylline (1,000 µmol/L).

These findings confirm reports that xanthine derivatives can protect lungs from the effects of hypothermic storage in other models, particularly the dog [6, 7]. The dose of theophylline causing a 50% inhibition against a range of phosphodiesterase subtypes is between 100 and 300 µmol/L [22], and it is approximately 20-fold to 100-fold more potent as an adenosine receptor antagonist [23]. Thus the dose range with which we achieved protection in this model suggests that theophylline has to be administered in doses sufficient to inhibit phosphodiesterase activity to be effective. This may be particularly relevant in light of recent reports that the lung can exhibit ischemic preconditioning, which protects it from hypothermic storage [24, 25], and that ischemic preconditioning in the lung can be mimicked by adenosine receptor antagonism during the subsequent prolonged ischemic period [26].

Another noteworthy feature of the data presented here is the difference in potency of theophylline in protecting various features of lung function. Theophylline was most effective in attenuating the marked increase in vascular resistance, whereas gas exchange was improved the least. Although this might simply reflect pharmacokinetic consequences of the route of administration (by way of the vasculature), it might also be a genuine difference in the sensitivity of different lung components to the beneficial effects of theophylline. Some weight is lent to this latter explanation by the existence of several distinct families of phosphodiesterase isoenzyme subtypes that differ from one another in their cellular distributions [22]. Clearly, future studies with inhibitors showing greater selectivity for different phosphodiesterase isoenzyme subtypes will shed more light on the precise mechanisms of the beneficial effects of raising cAMP levels during long-term hypothermic storage of the lung. Such comparative studies will also be required for identification of optimally effective agents for lung protection.

In conclusion, theophylline in the dose range associated with phosphodiesterase inhibition provides a high degree of protection to the lung from the harmful effects of 6 hours of hypothermic storage.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Supported by British Heart Foundation grant PG97024.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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