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Ann Thorac Surg 2009;88:958-964. doi:10.1016/j.athoracsur.2009.05.075
© 2009 The Society of Thoracic Surgeons
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Right arrow Lung - transplantation

Original Articles: General Thoracic

Pharmacologic Modulation of Alveolar Liquid Clearance in Transplanted Lungs by Phentolamine and FK506

Makoto Sugita, MD, PhD, Yves Berthiaume, MD, MS*, Michael VanSpall, MD, André Dagenais, PhD, Pasquale Ferraro, MD

Centre de Recherche, CHUM, and Departments of Medicine and Surgery, University of Montreal, Montreal, Quebec, Canada

Accepted for publication May 20, 2009.

* Address correspondence to Dr Berthiaume, Centre de Recherche, CHUM-Hôtel-Dieu, 3850 St-Urbain, Montréal, Québec, H2W 1T7, Canada (Email: yves.berthiaume{at}umontreal.ca).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The lung's capacity to clear alveolar fluid can determine the severity of the edema seen after transplantation. We recently observed that alveolar liquid clearance was decreased in transplanted lungs. This study evaluates the ability of phentolamine and FK506 to modulate the severity of lung injury and the decline in alveolar liquid clearance after transplantation.

Methods: A canine orthotopic single-lung transplantation model was used. The lungs were preserved with a low-potassium-dextran solution (50 mL/kg) and transplanted after 3 hours of cold ischemia. The experimental protocol included a control group, a phentolamine group, in which donor lungs were infused with phentolamine (2 mg/kg), and a FK506 group, in which the animals received FK506 (25 mg/kg per hour) intravenously during reperfusion. After 4 hours of reperfusion, alveolar liquid clearance, wet-to-dry ratios, lung epithelial Na+ channel expression, and the response to β-adrenergic stimulation were measured.

Results: The increase in wet-to-dry ratios of transplanted lungs was less pronounced in the phentolamine and FK506 groups. The FK506 treatment led to improvement of alveolar liquid clearance. Neither phentolamine nor FK506 influenced lung epithelial Na+ channel expression in transplanted lungs or preserved alveolar cell ability to respond to β-adrenergic stimulation.

Conclusions: Phentolamine or FK506 treatment during reperfusion improves alveolar liquid clearance and decreases the severity of lung injury.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Primary graft failure after lung transplantation manifests itself by noncardiogenic pulmonary edema. This phenomenon represents a significant cause of morbidity and mortality [1, 2]. Clinical observations suggest that dysfunction of sodium (Na+) transport and alveolar liquid clearance might contribute to the development of pulmonary edema in the posttransplant period [3]. Recently, we reported that alveolar liquid clearance was significantly inhibited in a canine model of lung transplantation [4]. Alveolar liquid clearance is mediated by unidirectional Na+ transport from the apical to the basolateral side of the alveolar epithelium, which creates an osmotic gradient that leads to pulmonary edema resolution [5]. Sodium enters the cells by the epithelial sodium channel (ENaC) located at the apical surface and is extruded by sodium-potassium-adenoside triphosphatase (Na+-K+-ATPase) at the basolateral surface [5]. Modulation of Na+ transport and lung liquid clearance across the epithelium can be achieved by modulating the activity or the expression of ENaC or Na+-K+-ATPase [5–7].

Although the dysfunction in alveolar liquid clearance depends on the severity of the injury [8], the mechanism leading to this dysfunction is not completely understood. Studies using other lung injury models have shown that oxidative stress might be involved [9]. It has also been shown that the {alpha}-adrenergic blocker phentolamine can modulate the oxidative stress and alveolar liquid clearance in hemorrhagic shock–induced lung injury [10]. It has been also reported that FK506, an immunosuppressant utilized in solid organ transplantation, can decrease the severity of lung injury [11–13]. Based on these observations, we decided to test the hypothesis that alveolar liquid clearance and the severity of injury of transplanted lungs can be modulated by phentolamine or FK506.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Experimental Protocols and Surgical Procedures
Orthotopic left lung transplantations were performed in 34 dogs (18 to 26 kg). These experiments were conducted in accordance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health) as applied by the Animal Care Committee of our research center.

Three groups of animals were studied. In the control group (n = 6), the donor lungs were flushed with a low-potassium–dextran solution, 50 mL/kg (Perfadex; Vitrolife, Englewood, CO), but no pharmacologic treatment was given to the animals.

In the phentolamine group (n = 6), phentolamine (Paladin Labs, Montreal, Canada), 2 mg/kg, was infused over a 2-minute period into the lung vasculature of the donor animal through a pulmonary artery catheter before harvesting of the lungs. This phentolamine dose was used to inhibit increased vascular permeability of the lungs [14] and was greater than that administered to improve graft function after renal transplantation [15].

In the FK506 group (n = 5), FK506 (Tacrolimus; Fujisawa Canada, Markham, Canada) was infused intravenously (25 mg · kg–1 · h–1), starting 30 minutes before reperfusion in the recipient animals and running until the end of the 4-hour reperfusion period. This FK506 dose was shown to inhibit increased vascular permeability and decrease the severity of injury in an endotoxin lung injury model [11].

Detailed surgical procedures for both harvesting donor lungs and transplantation have been described elsewhere [4]. After flushing, the donor lungs were inflated with 100% oxygen, excised, and placed in crushed ice. The recipient animals were placed under general anesthesia for 30 minutes before the left lung transplantation. After anastomoses of the left mainstem bronchus, pulmonary artery, and left atrium, the lungs were reperfused, and ventilation was reestablished. Total ischemic time was 192 ± 4 minutes. Mean arterial pressure, mean pulmonary arterial pressure, heart rate, and arterial blood gas were recorded during anesthesia and monitored for 4 hours after transplantation.

Gravimetric Measurements and Pulmonary Myeloperoxidase Activity
To determine the severity of lung injury in our model, we measured the wet-to dry ratio of the native and transplanted lungs as well as the neutrophil sequestration as measured by the myeloperoxidase (MPO) activity assay [4]. After 4 hours of reperfusion, the transplanted left lung and native right lung were divided into three lobes on each side. The middle lobes were frozen in liquid nitrogen, and stored at –40°C for mRNA until wet-to-dry lung weight ratio, and lung MPO activity analyses were carried out.

Alveolar Liquid Clearance Measurement
Alveolar liquid clearance was the primary outcome of this protocol, and it was measured using an ex vivo fluid-filled lung preparation, as described previously [4]. Alveolar liquid clearance is determined by measuring the increase in protein concentration of a test solution instilled in the lungs [16]. This technique has recently been adapted for ex-vivo preparation [4, 17] and injured lungs [8]. Two lobes from each side were kept at 37°C and were instilled with a solution (130 mM Na+, 4 mM K+, 1.5 mM Ca++, 109 mM Cl-, 28 mM lactate, 11.1 mM glucose, 5.0 g/dL bovine serum albumin [Sigma Chemical, St. Louis, MO]). To examine the effect of β-adrenergic stimulation on alveolar liquid clearance we added 10-5 M terbutaline (Sigma Chemical) to the instillate solution of one lobe on each side (left transplanted and right native lungs) [4, 8]. After 4 hours, the instillate solution was aspirated and protein concentration of the aspirated liquid was measured by the Biuret method to calculate alveolar liquid clearance [4].

Northern Blot Hybridization
Since the Na+ channel (ENaC) is essential for Na+ transport and alveolar liquid clearance, we measured its level of expression in the native and transplanted lungs. Total RNA was prepared from frozen lung tissues by extraction with TRIZOL (Life Technologies, Grand Island, NY). For Northern blotting, 10 mg/lane of total RNA was fractionated by electrophoresis on 1% agarose-formaldehyde gel and transferred to nylon membranes. Hybridization was performed with dCTP 32P random-labeled full-length short cDNA probes for {alpha}ENaC. After normalization with 18S rRNA, the relative expression of the {alpha}ENaC was calculated by comparing specific densitometric signals of left lung mRNA with corresponding right lung mRNA.

Measurement of Whole Blood FK506 Concentration
Heparinized blood samples were obtained at 0, 120, and 240 minutes after reperfusion. Whole blood FK506 concentrations were measured by an enzyme multiplied immunoassay technique (EMIT-2000; Dade Behring Canada, Mississauga, ON).

Statistical Analyses
All results are expressed as means ± SD of the means. The data of Tables 2 and 3 and of Figure 3 were analyzed by a two-way analysis of variance and by post hoc test (Bonferroni) except for the comparison of the data clearance between control and terbutaline-treated lungs, which were compared by Student's paired t test as the experiments are done in different lobe obtained from the same lungs. The expression level of the right native lungs was considered to be 100%, and the left transplanted lungs were compared with the right native lungs by one-way analysis of variance. Differences with p values less than 0.05 were regarded as statistically significant.


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  		Table 2 Wet-to-Dry Ratio
 

Figure 3
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  		Fig 3. Time-course changes of whole blood FK506 concentrations. The FK506 perfusion was started 30 minutes before reperfusion so that, at time zero of reperfusion, the FK506 blood level was already between 50 and 60 ng/mL. The FK506 concentration before perfusion was either undetected or below 8 ng/mL (n = 3 in each group).

 

   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Physiological Variables
No clinically significant differences between groups were observed in heart rate, mean arterial blood pressure, mean pulmonary arterial pressure, and arterial pH (Table 1). Although there was an initial decrease in the PaO2/FIO2 ratio in the control and FK506 groups, the PaO2/FIO2ratio remained greater than 300 mm Hg during the course of the experimental protocol (data not shown).


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  		Table 1 Physiologic Variables
 
Wet-to-Dry Lung Weight Ratio and MPO Activity
The wet-to-dry lung ratio of the left transplanted lungs increased significantly after 4 hours of reperfusion in all groups (Table 2). However, the level of wet-to-dry ratio in the control group was significantly higher. The MPO activity in lung tissue, which is representative of neutrophil accumulation, was increased in transplanted lungs compared with right native lungs in the control and phentolamine groups (Table 3). In contrast, there was no significant difference in MPO activity between the right native lungs and the left transplanted lungs in the FK506 group.


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  		Table 3 Myeloperoxidase Activity in Lung Tissue
 
Alveolar Liquid Clearance
In right native lungs, no significant difference in basal alveolar liquid clearance was observed among the three groups (Fig 1A). Furthermore, terbutaline was able to significantly increase alveolar liquid clearance of the right native lungs in all groups. In transplanted lungs of the control group, basal alveolar liquid clearance was significantly decreased compared with the right native lungs (Fig 1B). Phentolamine pretreatment was unable to prevent the decline of basal alveolar liquid clearance. However, FK506 infusion resulted in the preservation of basal alveolar liquid clearance in transplanted lungs (Fig 1B). Terbutaline was unable to increase alveolar liquid clearance in transplanted lungs regardless of whether they had been treated or not with phentolamine or FK506.


Figure 1
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  		Fig 1. Alveolar liquid clearance of right native lungs (A) and left transplanted lungs (B). In the right native lungs (A), no significant difference of basal alveolar liquid clearance (open bars) was observed among the three groups, and alveolar liquid clearance was significantly increased by terbutaline stimulation (black bars). In the control group, alveolar liquid clearance was 16.1% ± 4.3% in the basal state and 28.8% ± 8.9% with terbutaline. In the left transplanted lungs (B), the control group (5.5% ± 6.9%) showed significantly decreased basal alveolar liquid clearance, which was preserved in the transplanted lungs of the phentolamine group (12.8% ± 6.0%) and the FK506 group (18.4% ± 12.5%). Terbutaline stimulation was unable to increase alveolar liquid clearance of the transplanted lungs in all groups. *p < 0.05 compared with baseline alveolar liquid clearance in each group; #p < 0.05 compared with the right native lungs of each group; &p < 0.05 compared with the transplanted lungs of the control group.

 
Expression of {alpha}ENaC After 4 Hours of Reperfusion
Expression of {alpha}ENaC decreased significantly in left transplanted lungs after 4 hours of reperfusion in the control, phentolamine, and FK506 groups (Fig 2).


Figure 2
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  		Fig 2. (A) Representive Northern blot: the expression of epithelial Na+ channel ({alpha}ENaC) mRNA as measured by Northern blotting. (B) Densitometric analysis (#p < 0.05): after 4 hours of reperfusion, the {alpha}ENaC mRNA expression level was significantly decreased in transplanted lungs compared with right native lungs in the control group (open bar), phentolamine group (down-hatched bar), and FK506 group (up-hatched bar).

 
FK506 Concentration
To confirm blood FK506 levels, we measured FK506 in whole blood samples (Fig 3). The FK506 concentrations quickly reached a plateau at 120 minutes after reperfusion (150 minutes after FK506 infusion, 86 ± 13 ng/mL), and remained unchanged after 240 minutes of reperfusion (270 minutes after FK506 infusion).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study demonstrates that FK506 infusion in recipient animals or pretreatment of the donor lungs with phentolamine prevents the decrease in alveolar liquid clearance and lessens the increase in wet-to-dry ratio in the posttransplant period. Neither treatment restores the ability of the β-adrenergic agonist terbutaline to stimulate alveolar liquid clearance in transplanted lungs.

Although ischemia-reperfusion–induced pulmonary edema is associated with increased microvascular permeability [18], alveolar epithelial cell dysfunction [19], especially its ion transport capacity [3, 4], may significantly contribute to the severity of ischemia-reperfusion injury. The present experiments explored the ability of phentolamine and FK506 to reduce the severity of lung injury and to modulate the capacity of the alveolar epithelium to clear alveolar edema in a canine lung transplantation model. Phentolamine treatment of allografts is associated with enhanced allograft function in kidney transplantation [15] and significantly improves the wet-to-dry lung weight ratio of transplanted lungs [20]. In addition, recent investigations have demonstrated that {alpha}-adrenergic blockade prevents the activation of gene expression of proinflammatory cytokines mediated by oxidative stress [10, 21] and is able to restore normal alveolar liquid transport capacity [10]. Therefore, donor lung treatment with systemic administration of phentolamine seems to be a rational choice for reducing lung injury. We found that pretreatment of the donors with phentolamine resulted in a significant decrease in the wet-to-dry lung ratio in transplanted lungs. This effect of the {alpha}-adrenergic blockade is similar to that observed by Kondo and coworkers [20] in a rat lung transplantation model. This decrease in the wet-to-dry ratio was associated with improvement of alveolar liquid clearance. We can speculate that the protective effect of phentolamine on alveolar liquid clearance is potentially related to the modulation of the oxidative stress as it was observed in the hemorrhagic shock lung injury model [10]. More importantly, these results demonstrate that by decreasing the severity of the injury, as measured by the wet-to-dry ratio, we can improve alveolar liquid clearance [8].

We also examined the effect of FK506, an immunomodulator used to prevent allograft rejection [22], because it has been shown to have a protective effect in ischemia-reperfusion [12, 23, 24] and endotoxin-induced lung injuries [11, 13]. Again, we observed that FK506 improved alveolar liquid clearance and the wet-to-dry lung ratio of transplanted lungs. The improvement in lung injury and alveolar liquid clearance is potentially due to a decrease in the inflammatory response of the lungs in the FK506 group. Although we could not demonstrate a reduction of neutrophil accumulation in the transplanted lungs, this response could be explained by the anti-inflammatory effect of FK506, which inhibited the production of molecules such as superoxide radicals [25] and tumor necrosis factor [26], mediators that can contribute to alteration of the alveolar barrier. The lack of decrease in neutrophil accumulation in the transplanted lung is related to neutrophil accumulation in the native lungs of FK506-treated animals. Although we do not have a clear explanation for this phenomenon, it is possible that FK506 might have increased blood flow in the right native lungs, allowing greater recruitment of neutrophils in them. Further experiments are needed to explain this result.

Is the modest effect observed with these pharmacologic treatments related to our experimental protocol? The difference can not be explained by the preservation solution employed, because we used a low-potassium–dextran solution that was associated with better graft function [27, 28] and was less cytotoxic to the alveolar epithelial cells [29, 30]. Furthermore, the lungs were preserved in an inflated state with oxygen as this is associated with better graft function [18], including better alveolar liquid clearance capacity [31]. However, there were two specificities with our protocol. First, our wet-to-dry ratios were somewhat more elevated than those observed in other experimental protocols [32]. The difference might be explained by the modification of pharmacologic treatment of the donor lungs and of the recipient animals in our protocol. We intentionally excluded prostaglandins and corticosteroids, drugs proven to improve graft function after transplantation [18], to avoid their potential confounding effect on ion transport and alveolar liquid clearance [8, 33]. The second specificity of our protocol was that the primary outcome measured was alveolar liquid clearance and not the wet-to-dry ratio or the PaO2/FiO2 ratio. We focused on this outcome because it could serve as a novel index of graft function in the posttransplantation period [3, 34]. Because alveolar liquid clearance is influenced by hypoxemia 17], we had to control the level of oxygenation. To achieve this goal, we did not exclude the pulmonary circulation of the right native lung, a technique often used to evaluate the impact of injury on gas exchange in transplanted lungs [35]. Furthermore, occlusion of the native lung could increase the wet-to-dry ratio in transplanted lungs [20], which would modify alveolar liquid clearance. Because of those potential negative effects, we did not use the occlusion technique to determine the level of injury in the transplanted lungs. Nevertheless, information obtained on alveolar liquid clearance might help to determine the potential role of alveolar epithelial dysfunction in posttransplant lung injury.

Could we have enhanced the response of phentolamine or FK506 with different doses or treatment times or even by combining both treatments? Although we cannot exclude the possibility that higher doses or longer treatment might have additional effects, it seems unlikely since these doses have been shown to exert beneficial effects in other models of transplantation or lung injury [11, 14, 20, 36]. Furthermore, we evaluated the effects of combined phentolamine and FK506 treatment in a group of 4 animals (data not shown). The wet-to-dry ratio was identical (5.3 ± 0.3) to that in the FK506 group (5.3 ± 0.3). Thus, it seems unlikely that manipulation of this treatment strategy would enhance its efficiency.

Although FK506 treatment only modestly modulated the severity of injury, it did restore basal alveolar liquid clearance to normal. The restoration of alveolar liquid clearance suggests that there could be a relationship between the severity of injury and alveolar liquid clearance [8]. However, such correction of liquid clearance occurs in the absence of correction of ENaC mRNA expression. That is unexpected when considering the importance of ENaC for alveolar liquid clearance [37]. Although it is possible that decreased ENaC mRNA expression does not reflect changes in protein expression or activity of the channel, it seems unlikely since we did observe a correlation between the reduction of ENaC mRNA and ENaC protein expression in our model [4]. Such a protective effect of FK506 or phentolamine could be secondary to the inhibition of synthesis of inflammatory molecules [25, 26] that increase the permeability of the alveolar barrier, one of the major determinants of alveolar liquid clearance [38]. Another possibility is that phentolamine and FK506 modulates the activity or expression of other transporters that are essential for alveolar liquid clearance, including Na+-K+-ATPase, as alteration of its activity has been observed after lung transplantation [39]. Interestingly, however, the absence of alveolar liquid clearance response to β-adrenergic agonists might be related to reduced ENaC expression because it has been reported recently that decreased ENaC expression leads to diminished stimulation of alveolar liquid clearance by β-adrenergic agonists [40].

In summary, our study suggests that pretreatment of the donor lungs with phentolamine or FK506 infusion in recipient animals improves alveolar liquid clearance and decreases lung injury immediately after reperfusion. These results suggest that a therapeutic approach that decreases the severity of injury after reperfusion should help maintain alveolar liquid clearance after reperfusion and accelerate patient recovery in the immediate postoperative period. Further studies are necessary, however, to determine if these therapies could be useful in modulating lung edema clearance during ischemia-reperfusion injury after clinical lung transplantation.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported in part by grants from the Canadian Institutes of Health Research (MT-10273) and by Astellas Pharma Canada, Inc. Makoto Sugita is the recipient of a Canadian Cystic Fibrosis Foundation/Canadian Institutes of Health Research fellowship. Pasquale Ferraro is supported by the Alfonso Minicozzi and Family Chair in Thoracic Surgery and Lung Transplantation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Christie JD, Bavaria JE, Palevsky HI, et al. Primary graft failure following lung transplantation Chest 1998;114:51-60.[Abstract/Free Full Text]
  2. Ferraro P, Martin J, Dery J, et al. Late retrograde perfusion of donor lungs does not decrease the severity of primary graft dysfunction Ann Thorac Surg 2008;86:1123-1129.[Abstract/Free Full Text]
  3. Ware LB, Golden JA, Finkbeiner WE, Matthay MA. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation Am J Respir Crit Care Med 1999;159:980-988.[Abstract/Free Full Text]
  4. Sugita M, Ferraro P, Dagenais A, et al. Alveolar liquid clearance and sodium channel expression are decreased in transplanted canine lungs Am J Respir Crit Care Med 2003;167:1440-1450.[Abstract/Free Full Text]
  5. Berthiaume Y, Lesur O, Dagenais A. Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium Thorax 1999;54:150-160.[Free Full Text]
  6. Eaton DC, Chen J, Ramosevac S, Matalon S, Jain L. Regulation of Na+ channels in lung alveolar type II epithelial cells Proc Am Thorac Soc 2004;1:10-16.[Abstract/Free Full Text]
  7. Sznajder JI, Factor P, Ingbar DH. Invited review. Lung edema clearance: role of Na(+)-K(+)-ATPase. J Appl Physiol 2002;93:1860-1866.[Abstract/Free Full Text]
  8. Berthiaume Y, Matthay MA. Alveolar edema fluid clearance and acute lung injury Respir Physiol Neurobiol 2007;159:350-359.[Medline]
  9. Modelska K, Matthay MA, Brown AS, Deutch E, Lu LN, Pittet JF. Inhibition of β-adrenergic-dependent alveolar epithelial clearance by oxidant mechanisms after hemorrhagic shock Am J Physiol 1999;276:L844-L857.[Medline]
  10. Laffon M, Lu LN, Modelska K, Matthay MA, Pittet JF. {alpha}-Adrenergic blockade restores normal fluid transport capacity of alveolar epithelium after hemorrhagic shock Am J Physiol 1999;277:L760-L768.[Medline]
  11. Koshika T, Ishizaka A, Nagatomi I, Sudo Y, Hasegawa N, Goto T. Pretreatment with FK506 improves survival rate and gas exchange in canine model of acute lung injury Am J Respir Crit Care Med 2001;163:79-84.[Abstract/Free Full Text]
  12. Krishnadasan B, Naidu B, Rosengart M, et al. Decreased lung ischemia-reperfusion injury in rats after preoperative administration of cyclosporine and tacrolimus J Thorac Cardiovasc Surg 2002;123:756-767.[Abstract/Free Full Text]
  13. Hanaoka M, Ge RL, Kaneki T, Koizumi T, Kobayashi T, Kubo K. Effect of tacrolimus on endotoxin-induced lung injury in sheep Respir Physiol Neurobiol 2002;130:89-97.[Medline]
  14. Poulat P, Couture R. Increased pulmonary vascular permeability and oedema induced by intrathecally injected endothelins in rat Eur J Pharmacol 1998;344:251-259.[Medline]
  15. Polyak MM, Arrington BO, Kapur S, Stubenbord WT, Kinkhabwala M. Donor treatment with phentolamine mesylate improves machine preservation dynamics and early renal allograft function Transplantation 2000;69:184-186.[Medline]
  16. Berthiaume Y, Staub NC, Matthay MA. Beta-adrenergic agonists increase lung liquid clearance in anaesthetized sheep J Clin Invest 1987;79:335-343.[Medline]
  17. Suzuki S, Noda M, Sugita M, Ono S, Koike K, Fujimura S. Impairment of transalveolar fluid transport and lung Na+-K+-ATPase function by hypoxia in rats J Appl Physiol 1999;87:962-968.[Abstract/Free Full Text]
  18. de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury Am J Respir Crit Care Med 2003;167:490-511.[Abstract/Free Full Text]
  19. Veldhuizen RA, Lee J, Sandler D, et al. Alterations in pulmonary surfactant composition and activity after experimental lung transplantation Am Rev Respir Dis 1993;148:208-215.[Medline]
  20. Kondo T, Horikoshi A, Fujimura S, Matsumura Y, Okada Y, Shimada K. Alpha-adrenergic blockade in preventing posttransplant edema of lung allograft Tohoku J Exp Med 1999;189:135-145.[Medline]
  21. Le Tulzo Y, Shenkar R, Kaneko D, et al. Hemorrhage increases cytokine expression in lung mononuclear cells in mice. Involvement of catecholamines in nuclear factor-kB regulation and cytokine expression. J Clin Invest 1997;99:1516-1524.[Medline]
  22. Reichenspurner H. Overview of tacrolimus-based immunosuppression after heart or lung transplantation J Heart Lung Transplant 2005;24:119-130.[Medline]
  23. Garcia-Criado FJ, Palma-Vargas JM, Valdunciel-Garcia JJ, et al. Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia Transplantation 1997;64:594-598.[Medline]
  24. Squadrito F, Altavilla D, Squadrito G, et al. Tacrolimus limits polymorphonuclear leucocyte accumulation and protects against myocardial ischaemia-reperfusion injury J Mol Cell Cardiol 2000;32:429-440.[Medline]
  25. Burnett D, Adams DH, Martin TJ, et al. Inhibition by FK506 of formyl peptide-induced neutrophil activation and associated protein synthesis Biochem Pharmacol 1994;48:1081-1088.[Medline]
  26. Kawano K, Kim YI, Kai T, et al. Evidence that FK506 alleviates ischemia/reperfusion injury to the rat liver: in vivo demonstration for suppression of TNF-a production in response to endotoxemia Eur Surg Res 1994;26:108-115.[Medline]
  27. Struber M, Wilhelmi M, Harringer W, et al. Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation Eur J Cardiothorac Surg 2001;19:190-194.[Abstract/Free Full Text]
  28. Keshavjee SH, Yamazaki F, Yokomise H, et al. The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation J Thorac Cardiovasc Surg 1992;103:314-325.[Abstract]
  29. Maccherini M, Keshavjee SH, Slutsky AS, Patterson GA, Edelson JD. The effect of low-potassium-dextran versus Euro-Collins solutions for preservation of isolated type II pneumocytes Transplantation 1991;52:621-626.[Medline]
  30. Suzuki S, Inoue K, Sugita M, Tsubochi H, Kondo T, Fujimura S. Effects of EP4 solution and LPD solution vs Euro-Collins solution on Na(+)/K(+)-ATPase activity in rat alveolar type II cells and human alveolar epithelial cell line A549 cells [in process citation] J Heart Lung Transplant 2000;19:887-893.[Medline]
  31. Sakuma T, Tsukano C, Ishigaki M, et al. Lung deflation impairs alveolar epithelial fluid transport in ischemic rabbit and rat lungs Transplantation 2000;69:1785-1793.[Medline]
  32. de Perrot M, Fischer S, Liu M, et al. Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines Transplantation 2001;72:1505-1512.[Medline]
  33. Sakuma T, Zhao Y, Sugita M, Sagawa M, Hida M, Toga H. A prostacyclin analogue, OP-41483alpha-CD, restores the ability of a beta2-adrenergic agonist to stimulate alveolar fluid clearance in rats Surg Today 2004;34:429-436.[Medline]
  34. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome Am J Respir Crit Care Med 2001;163:1376-1383.[Abstract/Free Full Text]
  35. Sakamaki F, Hoffmann H, Muller C, Dienemann H, Messmer K, Schildberg FW. Reduced lipid peroxidation and ischemia-reperfusion injury after lung transplantation using low-potassium dextran solution for lung preservation Am J Respir Crit Care Med 1997;156:1073-1081.[Abstract/Free Full Text]
  36. Koshika T, Hirayama Y, Ohkubo Y, Mutoh S, Ishizaka A. Tacrolimus (FK506) has protective actions against murine bleomycin-induced acute lung injuries Eur J Pharmacol 2005;515:169-178.[Medline]
  37. Egli M, Duplain H, Lepori M, et al. Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice J Physiol 2004;560:857-865.[Abstract/Free Full Text]
  38. Frank JA, Pittet JF, Lee H, Godzich M, Matthay MA. High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance Am J Physiol Lung Cell Mol Physiol 2003;284:L791-L798.[Abstract/Free Full Text]
  39. Kim JD, Baker CJ, Danto SI, Starnes VA, Barr ML. Modulation of pulmonary NA+ pump gene expression during cold storage and reperfusion Transplantation 2000;70:1016-1020.[Medline]
  40. Li T, Folkesson HG. RNA interference for alpha-ENaC inhibits rat lung fluid absorption in vivo Am J Physiol Lung Cell Mol Physiol 2006;290:L649-L660.[Abstract/Free Full Text]



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Right arrow Lung - transplantation

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