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Ann Thorac Surg 2000;70:423-428
© 2000 The Society of Thoracic Surgeons

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Original articles: general thoracic

Platelet activating factor acetylhydrolase decreases lung reperfusion injury

^a Department of Cardiothoracic Surgery, University of Southern California and Childrens Hospital Los Angeles, Los Angeles, California, USA

Address reprint requests to Dr Barr, Department of Cardiothoracic Surgery, University of Southern California, 1510 San Pablo St, Suite 415, Los Angeles, CA 90033
e-mail: mbarr{at}surgery.usc.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Ischemia-reperfusion injury involves free radical production, polymorphonuclear neutrophil chemotaxis/degranulation, and production of proteolytic enzymes, complement components, coagulation factors, and cytokines. Activated polymorphonuclear neutrophils, endothelial cells, and macrophages produce platelet activating factor, which further promotes these inflammatory reactions. The recently cloned plasma form of platelet activating factor-acetylhydrolase (PAF-AH) demonstrates antiinflammatory effects by degrading platelet activating factor. We evaluated the effects of PAF-AH in an isolated perfused rat lung model by adding it to the flush solutions or to the reperfusion blood.

Methods. Rat lungs were isolated, flushed with Euro-Collins (EC) or University of Wisconsin (UW) solution, stored at 4°C for 6 or 12 hours, and reperfused using a cross-circulating syngeneic support rat. During reperfusion, oxygenation, compliance, and capillary filtration coefficient were calculated. There were four groups in the study; group I (control) had no PAF-AH added, group II had PAF-AH added to the flush solution, group III had PAF-AH added to reperfusion blood, and group IV had PAF-AH added to both flush solution and reperfusion blood.

Results. After 6 hours of storage, oxygenation, compliance, and capillary filtration coefficient significantly improved for EC in group IV. For UW, oxygenation improved in group IV whereas compliance improved in groups II, III, and IV. After 12 hours of storage, compliance improved for EC in group IV and capillary filtration coefficient improved in groups III and IV. For UW, oxygenation and compliance improved in groups II and IV, whereas capillary filtration coefficient improved in group IV.

Conclusions. Addition of PAF-AH to intracellular organ preservation solutions and to the blood reperfusate significantly improves postreperfusion oxygenation and compliance, and reduces lung capillary permeability.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Successful lung transplantation is still limited by suboptimal preservation techniques. Prolonged ischemic storage complicated by reperfusion injury increases cellular damage resulting in diminished functional capacity. Platelet activating factor (PAF) amplifies the inflammatory response during reperfusion injury and has been shown to promote cell activation and cytokine release in hypoxic human lung cell cultures [1].

Platelet activating factor is a glycerophospholipid originally identified to cause activation of platelets. Subsequently, PAF has been implicated in numerous other proinflammatory actions. Platelet activating factor promotes neutrophil activity including aggregation, adherence, degranulation, and chemotaxis [2, 3]. Given systemically, PAF decreases cardiac output, increases vascular permeability, and promotes bronchoconstriction. Platelet activating factor also acts as a potent cytokine and activates other cytokines such as interleukin-1 and tumor necrosis factor-alpha to recruit and activate leukocytes [1, 4].

Platelet activating factor is synthesized by numerous cell types including basophils, polymorphonuclear neutrophils, monocytes, macrophages, alveolar macrophages, and vascular endothelial cells [4, 5]. It has a very short plasma half-life, due to degradation by platelet activating factor-acetylhydrolase (PAF-AH) [6]. Recently, a recombinant PAF-AH (rPAF-AH) has been developed. Studies have shown that rPAF-AH may be effective in protecting against oxidative stress-induced cell death [7]. In the present study, we investigated whether rPAF-AH is effective in protecting against ischemia-reperfusion injury in an isolated perfused rat lung model.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
There were four groups in the study. Rat lungs in each group were flushed with either Euro-Collins (EC) or University of Wisconsin (UW) solutions and cold stored for 6 or 12 hours. After storage, the lungs were reperfused using a cross-circulating syngeneic support rat. Group I was the control group with no PAF-AH added. Group II had PAF-AH (Icos, Bothell, WA) added to the flush solution only. Group III had PAF-AH added to the reperfusion blood only. Group IV had PAF-AH added to both flush solution and reperfusion blood. The concentration of PAF-AH added to the flush solutions and the support rat was 60 µg/mL. The support rat blood volume was estimated based on weight.

Isolated perfused lung model
Donor procedure
Male Lewis rats (250 to 350 g) were anesthetized with sodium pentobarbital (50 mg/kg) intraperitoneally. A tracheostomy was performed using a 14-gauge angiocatheter and the lungs were ventilated (Harvard Apparatus, South Natick, MA) with 100% O₂ at a respiratory rate of 55 breaths/min, tidal volume of 10 mL/kg, and positive end-expiratory pressure of 2 cm H₂O. The heart-lung block was exposed via median sternotomy and the rat was heparinized (1,000 U/kg) through the inferior vena cava. Once heparinized, blood was harvested using a 19-gauge needle through the inferior vena cava. The apex of the heart was then amputated and the lungs were flushed through the main pulmonary artery with 50 mL/kg of cold preservation solution (4°C) from a height of 30 cm. The heart-lung block was excised and a support rod was threaded through the esophagus. The lungs were submerged inflated in the same cold solution and stored at 4°C for either 6 or 12 hours.

Support rat
Male Lewis rats (250 to 350 g) were anesthetized as before. Bilateral inguinal incisions were made and the femoral arteries and veins were isolated. A 19-gauge femoral line catheter was placed in the inferior vena cava by catheterizing one of the femoral veins. Both of the femoral arteries were catheterized with 21-gauge arterial catheters. A heparinized (10 U/mL) normal saline solution was used to flush the catheters. The rats also underwent a tracheostomy using a 14-gauge angiocatheter as before. All incisions were closed using absorbable sutures. The support rat was kept warm throughout the experiment by using a heat lamp, and the blood pressures were monitored using of the arterial catheters. The support rat maintained spontaneous respiration of room air through the tracheostomy.

Reperfusion
The pulmonary artery and the left atrium of the stored lung block were cannulated with 14-gauge angiocatheters and subsequently suspended by the esophagus from a force transducer in a 37°C humidified chamber at atmospheric pressure. The lungs were ventilated with 50% O₂ at a rate of 50 breaths/min, tidal volume of 10 mL/kg body weight, and a positive end-expiratory pressure of 2 cm H₂O (Harvard Apparatus). The support rat was placed 25 cm above the suspended lung block. To initiate reperfusion, the inflow of blood from the femoral vein catheter of the support rat was connected to the pulmonary artery catheter of the lung block. The output flow from the left atrium of the lung block was collected in a reservoir and pumped back to the support rat through a femoral artery catheter to maintain a mean pressure between 80 and 120 mm Hg. The lung block was reperfused for 15 minutes. Then, the outflow and inflow were clamped to equalize pressures and determine the isogravimetric capillary pressure. Reperfusion was then resumed by unclamping both inflow and outflow for an additional 10 minutes. At the end of reperfusion, the outflow was closed and the inflow was switched from the support rat to a reservoir containing syngeneic blood. The height of the reservoir was adjusted to achieve a capillary pressure 4 mm Hg above the isogravimetric capillary pressure and the weight of the lung block was monitored for the next 15 minutes.

Monitoring
Throughout reperfusion and the capillary filtration coefficient measurement period, the weight (FT 03 force-displacement transducer; Grass Instruments, Quincy, MA), inflow pressure, outflow pressure (DTX model T4812 AD-R pressure transducer; Viggo-Spectramed, Oxnard, CA), tracheal pressure (DP 45-24 differential pressure transducer; Validyne, Northridge, CA), and tidal volume (Fleisch No. 2 pneumotachograph, Berne, Switzerland: Validyne DP 45-14 pressure transducer) were monitored. All data were transmitted to an AST Bravo (Fort Worth, TX) IBM-compatible computer through a Validyne CD 280 and MC 1-3 carrier demodulator and a Dash 16 analog-to-digital converter, and processed and displayed by a customized version of Microsoft Visual Basic Pro software. Data were collected and recorded every 10 seconds. During the reperfusion period, blood was collected from the left atrium every 5 minutes and the oxygen tension was measured (Ciba-Corning 288, Medfield, MA).

All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).

Data analysis
Capillary filtration coefficient
As described in previous work, capillary filtration coefficient (K_f) is a sensitive measure of capillary permeability [8]. Increases in capillary pressure are accompanied by an increase in extravasation of fluid into the interstitium. K_f represents the permeability of the capillary. The isogravimetric capillary pressure was measured according to the method of Gaar and colleagues [9]. During the isogravimetric state, both the inflow and the outflow were clamped. The subsequent steady state pressure reached by the inflow and the outflow was the isogravimetric capillary pressure. During K_f measurement, the inflow pressure was increased 4 mm Hg above the isogravimetric capillary pressure and the outflow was clamped. An initial sudden rise in weight, corresponding to vascular filling, was followed by a gradual increase in weight, corresponding to extravasation. The initial rate of fluid filtration was estimated by extrapolating the slow weight gain, under logarithmic transformation, to the initial time of change in capillary pressure. This rate of fluid filtration was divided by the change in capillary pressure and normalized by weight to give K_f, the permeability constant [10–12].

Blood gas analysis
Blood samples from the left atrium were measured for oxygen tension (PO₂).

Compliance
Lung compliance was calculated by dividing tidal volume with the change in tracheal pressure from end expiration to end inspiration.

Statistical analysis
All data are reported as the mean ± SEM. The data were analyzed by 1-way analysis of variance and all comparisons tested by Dunnett multiple comparisons test.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Oxygen tension
The results of oxygen tension are shown in Figures 1 and 2. For EC, oxygenation significantly improved at 6 hours of storage compared with control when PAF-AH was added to both the flush solution and the reperfusion blood, group IV (141 ± 8 versus 113 ± 9 mm Hg, p = 0.04). There was no improvement in oxygenation after 12 hours of storage for EC. Oxygenation improved for UW when PAF-AH was added to both the flush solution and the reperfusion blood (group IV) after both 6 and 12 hours of storage when compared with control (6 hours: 328 ± 8 versus 285 ± 12 mm Hg, p = 0.01; 12 hours: 302 ± 9 versus 260 ± 14 mm Hg, p = 0.03). There was also a significant improvement when PAF-AH was added to the flush solution only (group II) when compared with control (300 ± 9 versus 260 ± 14 mm Hg, p = 0.04) at 12 hours.

View larger version (36K): [in this window] [in a new window]   Fig 1. Oxygen tension (PO2 in mm Hg) after 6 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. Oxygenation improved for both EC and UW when platelet activating factor-acetylhydrolase was added to the flush solution and the reperfusate blood (EC: 141 ± 8 versus 113 ± 9 mm Hg, p = 0.04; UW: 328 ± 8 versus 285 ± 12 mm Hg, p = 0.01).

View larger version (36K): [in this window] [in a new window]   Fig 2. Oxygen tension (PO2 in mm Hg) after 12 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. Oxygenation improved for UW when platelet activating factor-acetylhydrolase (PAF-AH) was added to the flush solution and the reperfusate blood (302 ± 9 versus 260 ± 14 mm Hg, p = 0.03). There was also a significant improvement with PAF-AH added to the flush solution only (group II) when compared with control (300 ± 9 versus 260 ± 14 mm Hg, p = 0.04).

View larger version (44K): [in this window] [in a new window]   Fig 3. Compliance measured after 6 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. Compliance increased for EC when platelet activating factor-acetylhydrolase was added to the flush solution and the reperfusate blood (0.164 ± 0.006 versus 0.145 ± 0.003 mL/cm H2O, p = 0.04). For UW, all three groups showed improvements in compliance when compared with control (group II: 0.250 ± 0.009 versus 0.219 ± 0.008 mL/cm H2O, p = 0.03; group III: 0.253 ± 0.011 versus 0.219 ± 0.008 mL/cm H2O, p = 0.01; group IV: 0.245 ± 0.004 versus 0.219 ± 0.008 mL/cm H2O, p = 0.01).

View larger version (39K): [in this window] [in a new window]   Fig 4. Compliance measured after 12 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. For EC, only group IV showed improvement in compliance when compared with control (0.1377 ± .003 versus 0.1258 ± .003 mL/cm H2O, p = 0.031). For UW, groups II and IV both showed improvements in compliance compared with control (group II: 0.244 ± 0.014 versus 0.194 ± 0.008, p = 0.003; group IV: 0.240 ± .008 versus 0.194 ± .008 mL/cm H2O, p = 0.004).

View larger version (27K): [in this window] [in a new window]   Fig 5. Capillary filtration coefficient (Kf, mL/min/mm Hg/100 g) after 6 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. Kf decreased when platelet activating factor-acetylhydrolase was added to EC flush and reperfusate blood (1.58 ± 0.26 versus 2.42 ± 0.27 mL/min/mm Hg/100 g, p = 0.02).

View larger version (35K): [in this window] [in a new window]   Fig 6. Capillary filtration coefficient (Kf, mL/min/mm Hg/100 g) after 12 hours of cold ischemic storage for Euro-Collins (EC) and University of Wisconsin (UW) solutions. Kf decreased for both EC and UW when platelet activating factor-acetylhydrolase was added to the flush solution and the reperfusate blood (EC: 2.45 ± 0.36 versus 4.16 ± 0.60 mL/min/mm Hg/100 g, p = 0.01; UW: control (0.65 ± 0.10 versus 1.35 ± 0.19 mL/min/mm Hg/100 g, p = 0.02). EC also showed lower Kf at 12 hours of storage for group III compared with control (2.78 ± 0.22 versus 4.16 ± 0.60 mL/min/mm Hg/100 g, p = 0.05).

	Comment

Top Abstract Introduction Material and methods Results Comment References

Although previous studies used PAF receptor antagonists [16–21], this study examined the potential of rPAF-AH, a naturally occurring biological enzyme, in preventing ischemia-reperfusion injury. Platelet activating factor-acetylhydrolase is a lipase found in vivo to mediate the enzymatic degradation of PAF [22–24]. Both the free plasma form and the bound intracellular form are found in vivo. A recombinant free form of PAF-AH has been cloned recently. Early studies have shown that with low doses of rPAF-AH, a prolonged degradation of PAF was seen with reduction in inflammatory reactions [25]. Other studies have shown that with multiorgan failure or sepsis, low levels of PAF-AH correlated with a worse outcome [26].

This model extended the potential use of PAF inhibition by treating the reperfusion blood in addition to the preservation solution, thereby mimicking treatment of the recipient in the clinical setting. Euro-Collins and UW solutions were used in this study because they are they most widely used preservation solutions in clinical lung transplantation in the United States. Although some of the groups demonstrated statistical improvements when PAF-AH was added to either the flush solution or the reperfusate, most of the statistical improvements occurred when PAF-AH was added to both the flush solution and the reperfusate. When considering oxygenation, compliance, and K_f for both EC and UW, 10 of the 12 parameters measured in group IV demonstrated statistical improvements. Only oxygenation for EC at 12 hours and K_f for UW at 6 hours were not significantly improved. These results demonstrate that when rPAF-AH was used in both the flush solution and the support rat, better preservation of the lung was seen. Oxygenation, compliance, and capillary filtration coefficient all improved. When rPAF-AH in only the flush solution or the support rat was used, inconsistent results were noted. This observation may be important in the design of future experimental reperfusion injury models as well as in the clinical setting as there was an additive benefit of treating both the preservation solution and the reperfusion blood.

In this study, we did not give rPAF-AH to the donor rats prior to harvest. Perhaps premedicating the donor should also be considered. Other possible extensions of this study would be to combine the use of rPAF-AH with other antiinflammatory agents. Future work should include adding inhibitors of PAF to extracellular lung preservation solutions, such as low potassium dextran glucose (Perfadex; Biophausia, Uppsala, Sweden) or Celsior (SangStat Medical, Fremont, CA), which are being utilized increasingly in clinical lung transplantation in Europe. Another limitation of the study is that no direct measurement of platelet activating factor activity or levels was performed.

Although extrapolation from an ex vivo rodent model to clinical human lung transplantation is always problematic, early clinical evidence suggests that the concept of PAF inhibition can be beneficial in the context of clinical lung transplantation. In a recently reported prospectively randomized clinical trial from Wittwer and colleagues [27] in Germany, addition of the PAF antagonist BN-52021 (Ginkolide B) to modified EC flush solution and to the recipient prior to reperfusion was evaluated in double lung transplant patients with a resulting improvement in alveolar - arterial oxygen difference. This promising clinical study supports the concept of PAF inhibition as a potentially useful strategy.

	Acknowledgments

 
This work was supported by the Hastings Foundation and a grant to Dr Barr from the Heart and Lung Surgery Foundation, Los Angeles, CA.

	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): Jong D. Kim Vaughn A. Starnes Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, J. D. Articles by Barr, M. L. Search for Related Content PubMed PubMed Citation Articles by Kim, J. D. Articles by Barr, M. L.