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Ann Thorac Surg 1995;59:7-13
© 1995 The Society of Thoracic Surgeons

Neutrophil Modulation Results in Improved Pulmonary Function After 12 and 24 Hours of Preservation

Kay Uthoff, MD, Kenton J. Zehr, MD, Paul C. Lee, BA, Rick A. Low, MD, William A. Baumgartner, MD, Duke E. Cameron, MD, R. Scott Stuart, MD

Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Neutrophils are important mediators of reperfusion injury, and suppression of neutrophil function or numbers can reduce reperfusion injury and improve long-term organ preservation in transplantation. NPC 15669, a leumedin, is a novel compound that prevents recruitment of neutrophils at inflammatory foci by inhibiting CD11b/CD18 adhesion molecule expression. NPC 15669 was used to inhibit neutrophil adhesion during reperfusion of isolated rabbit lungs after 12 and 24 hours of cold storage. Lungs (New Zealand White male rabbits, 2 to 3 kg) were flushed with 4°C Euro-Collins (EC) solution, harvested en bloc, stored under various study conditions, and reperfused for 3 hours with fresh whole blood at 37°C in an isolated perfusion system at constant flow and an inspired oxygen fraction of 1. Four groups (n = 6 each) were studied. Group I underwent immediate whole blood reperfusion. Group II were stored for 12 hours in 4°C EC solution before reperfusion. Group III were stored for 12 hours in 4°C EC solution and reperfused with whole blood containing NPC 15669 (10 mg/kg whole body weight). Group IV were stored for 24 hours in 4°C EC solution and reperfused with whole blood containing NPC 15669 (10 mg/kg). Pulmonary artery and peak airway pressures were significantly lower and compliance higher in groups III and IV lungs after 3 hours of reperfusion (p < 0.05) compared with group I. Group I and III lungs had significantly less edema than group II (p < 0.05). The arterial partial pressure of oxygen was similar in all stored groups (II to IV). Inhibition of neutrophil adhesion with NPC 15669 during reperfusion of the isolated lung after long-term cold storage significantly improves pulmonary function. This study suggests a clinical means by which pulmonary injury during reperfusion can be ameliorated.


   Introduction
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 Abstract
 Introduction
Material and Methods
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 Comment
 References
 
See also page 12.

R eperfusion injury after organ preservation is a devastating phenomenon resulting in severe transient or prolonged impairment in pulmonary physiology [1]. It is widely accepted that organ injury can occur during the time of reperfusion after a relative ischemic period [2–7]. Tissue damage is in part caused by cytotoxic metabolites released by activated neutrophils [7]. Before being activated, neutrophils express MAC-1 (CD11b/CD18) surface receptors allowing adherence to the vascular endothelium [6, 8–10]. After adhesion, diapedesis through endothelium takes place. In vivo and ex vivo studies using various preservation methods have shown that neutrophil depletion before reperfusion ameliorates pulmonary injury []2, 3, 11–13]. Other studies have shown improved pulmonary function after inhibition of neutrophil adhesion using monoclonal antibodies against MAC-1 components [9, 10, 14–16].

NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy) carbonyl]-L-leucine) is a potent inhibitor of neutrophil adhesion to vascular endothelium [17]. This compound is a member of a new class of antiinflammatory agents termed leumedins [17, 18]. They specifically prevent recruitment of neutrophils at inflammatory foci by inhibiting surface expression of the CD11b/CD18 (MAC-1) adhesion molecule [17]. The study was designed to determine whether inhibition of neutrophil adhesion during reperfusion (after long-term hypothermic lung storage) using NPC 15669 can reduce pulmonary injury during whole blood reperfusion. A model of extracorporeal rabbit lung perfusion was used as described by Stuart and colleagues [19].


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Experimental Groups
Sixty New Zealand male rabbits (2 to 3 kg) were used. Thirty animals served as organ donors and 30 as blood donors. Five perfusion experiment groups (n = 6 in each) were set up. Group I lungs were immediately perfused with whole blood after organ harvest. Group II lungs were flushed with Euro-Collins (EC) solution (Fresonius USA, Inc, New Brunswick, NJ) and stored for 12 hours in 4°C EC solution before reperfusion. Group III lungs were flushed and stored in 4°C EC solution for 12 hours, then reperfused with whole blood containing NPC 15669 (10 mg/kg of whole body weight) (provided as a gift from Scios-Nova Inc, Baltimore Operations, Baltimore, MD). Group IV lungs were stored for 24 hours in 4°C EC solution after EC solution perfusion before whole blood reperfusion containing NPC 15669 (10 mg/kg). Group V lungs were perfused as with group III and IV lungs and stored in 4°C EC solution for 48 hours and then reperfused with whole blood containing NPC 15669 (10 mg/kg). NPC 15669 was added to the reperfusate as a bolus at reperfusion initiation in groups III to V.

Experimental Procedure
The rabbit lungs were harvested according the methods of Breda and colleagues Au: Breda first author in ref 2[2]. Rabbits were anesthetized with intravenous pentobarbital using an ear vein. A tracheostomy was performed and the rabbits were placed on a Harvard ventilator (model 665Au: location of manufacturer?). The carotid artery was cannulated. Heparin (300 U/kg) was given and the blood collected in blood donor animals. A median sternotomy was done on organ donor animals and the heart-lung block removed. The pulmonary artery and left atrium were cannulated and the lungs flushed with 50 mL of room temperature EC solution at 60 mm Hg, followed by 50 mL of 4°C EC solution containing Electrolyte Solution for Kidney Preservation (Travenol Laboratories, Inc, Deerfield, IL), 3.0% dextrose, and 10 IU/mL of heparin sodium. The vascular outflow and inflow were closed sequentially. With the trachea clamped and the lungs inflated partially, the preparation was submerged in 4°C modified EC and stored at 4°C. Total ischemic time before submersion ranged from 10 to 20 minutes.

After storage, lungs were set up in the reperfusion apparatus and reperfusion with fresh whole blood was initiated slowly using a Sarns nonpulsatile roller pump and Harvard ventilator as described previously [2]. The apparatus was enclosed in a Plexiglas box to preserve heat and moisture. The left atrial, pulmonary artery, and tracheal cannulae were associated with pressure transducers to monitor pressure constantly (Hewlett-Packard 7754B monitoring system; Hewlett-Packard, Andover, MA). Reperfusion was maintained for 3 hours in all animals. The respiratory rate was 11. Tidal volumes used were 10 mL/kg body weight. The inspired oxygen fraction was set at 1. Flow rates of 27.4 mL/min were maintained.

Physiologic Measurements
Pulmonary artery pressure, left atrial pressure, and peak airway pressures were recorded continuously. Blood reservoir losses were recorded. Arterial blood gases were analyzed on a Radiometer ABL-30 analyzer (Radiometer, Copenhagen, Denmark). Static lung compliance was calculated as tidal volume (mL) divided by peak airway pressure (mm Hg). Pulmonary vascular resistance (PVR) was determined according to the equation PVR = 79.92 x (Mean pulmonary artery pressure - Mean left atrial pressure)/Cardiac output (L/min).

Lung Tissue Myeloperoxidase
A biopsy specimen was taken from a small portion of the right upper lobe of the lung from 15 blood donor rabbits before exsanguination and from all lungs of study animals 3 hours after extracorporeal fresh blood reperfusion. The biopsy specimens were flash frozen in liquid nitrogen and myeloperoxidase assay was performed in the following manner. Tissue was disrupted by homogenizing at 4°C and placed into 0.5% hexyldecyltrimethylammonium bromide in 50 mmol/L potassium phosphate solution (pH 6.0; 1 mL/100 mg lung tissue). Tissue was disrupted further by sonication and then underwent three freeze-thaw cycles (liquid nitrogen bath/37°C water bath). The solution was centrifuged at 18,000 g for 20 minutes at 4°C. Aliquots (0.04 mL) of supernatant were added to 0.96 mL of assay buffer (0.17 mg/mL O-dianiside, 0.05% H2O2, 50 µmol/L sodium phosphate, pH 6.0). Absorbance at 460 nm was measured after 5 minutes of incubation by spectrophotometry (Beckman, Silver Springs, MD). Lung tissue myeloperoxidase activity was expressed as µmol • 10 mg-1 • min-1.

Percent Lung Water
The 5- to 10-g sample of right lung was weighed and incubated at 100°C for 24 hours, then reweighed. Percent lung wet weight was calculated as (Wet weight - Dry weight)/Wet weight x 100.

Histology
After reperfusion the lungs were perfused-fixed with a 4% formaldehyde solution and representative sections of the three lobes were processed for hematoxylin and eosin staining. Pulmonary edema was quantified morphometrically.

Statistical Analysis
All values are expressed as mean ± standard error of the mean. Statistical significance was accorded to p values of less than 0.05. Intergroup comparisons were made using the Neuman-Keuls analysis of variance and Student's t test where appropriate.

Animal Care
All animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Physiologic Parameters
The arterial partial pressure of oxygen after 3 hours of reperfusion was comparable in groups I to IV: 191 ± 3.1, 174 ± 2.8, 178 ± 6.8 Hg, and 166 ± 6.4 mm Hg, respectively (p = not significant). All group V lungs failed immediately after initiation of reperfusion. Pulmonary artery pressures were significantly lower in group I (19 ± 2.8 mm Hg), group III (14.4 ± 2.6 mm Hg), and group IV (15 ± 3.2 mm Hg) compared with group II (34.8 ± 6.9 mm Hg) (p < 0.01). Peak airway pressures were also different (group I, 10 ± 0.8 mm Hg; group III, 9.4 ± 1.6 mm Hg; and group IV, 9.2 ± 0.96 mm Hg compared with group II, 28.5 ± 11.8 mm Hg) (p < 0.01). Pulmonary vascular resistance differed significantly between group II (28,000 ± 5,500 dyne • s • cm-5) and group I (15,000 ± 2,200 dyne • s • cm-5), group III (9,600 ± 2,600 dyne • s • cm-5), and group IV (12,000 ± 2,600 dyne • s • cm-5) (p < 0.01). Static lung compliance differed significantly between group II (1.87 ± 0.15 mL/mm Hg) and group I (0.80 ± 0.13 mL/mm Hg), group III (2.12 ± 0.34 mL/mm Hg), and group IV (2.36 ± 0.34 mL/mm Hg) (p < 0.001) (Figs 1Go-4).



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  		Fig 1. . Pulmonary artery pressure.

 
Reservoir Fluid Loss and Lung Water Content
Fluid loss from the reservoir was significantly higher for group II (313 ± 19 mL) compared with group I (15 ± 19 mL), group III (9 ± 1 mL), and group IV (50 ± 4 mL) (p < 0.001). Lung water expressed as the dry/wet ratio after 3 hours of reperfusion was 83.3% ± 0.02% in group I, 86.9% ± 0.02% in group III, 88.5% ± 0.01% in group IV, and 91.6% ± 0.01% in group II (p < 0.001 for group II versus groups I, III, and IV) (Figs 5 and 6GoGo).



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  		Fig 5. . Cumulative reservoir fluid loss.

 


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  		Fig 6. . Lung water content.

 
Tissue Myeloperoxidase Activity
Tissue myeloperoxidase activity was significantly higher in group II (0.017 ± 0.004 µg • mg-1 • min-1) compared with group I (0.01 ± 0.002 µg • mg-1 • min-1), group III (0.004 ± 0.0004 µg • mg-1 • min-1), and group IV (0.009 ± 0.0002 µg • mg-1 • min-1) (p < 0.05 for group II versus groups I, III, and IV). Normal rabbit lungs (n = 15) had a range of 0.007 ± 0.0006 µg • mg-1 • min-1 lung tissue myeloperoxidaseAu: OK? activity (Fig 7Go).



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  		Fig 7. . Lung tissue myeloperoxidase (MPO) activity.

 
Histology
Using a 10 x 10 grid reticle under x400 magnification, the entire lung specimen was examined for percentage area with intraalveolar edema and hemorrhage. The mean percent edema was 39% ± 13% for group III, 6.5% ± 4.1% for group I, and 8.2% ± 2.7% for group II (p = 0.06) (Fig 8Go).



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  		Fig 8. . (A) Representative photomicrograph of a lung specimen treated with Euro-Collins solution. Demonstrates extensive intraalveolar hemorrhage and edema. (B) Representative photomicrograph of an NPC 15669-treated lung (12 hours of preservation). Demonstrates focal intraalveolar eosinophilic granular material consistent with edema fluid. The normal alveolar architecture is preserved. (C) An acutely reperfused lung preparation demonstrating focal intraalveolar edema with preserved alveolar architecture. (D) Normal rabbit lung photomicrograph. (All x250 before 28% reduction.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Reperfusion injury after ischemic lung preservation remains a problem in lung transplantation [1]. Attempts have been made to solve this problem using various preservation additives [20–24]. There is evidence to suggest that injury occurs during warm blood reperfusion as well as during the ischemic preservation time [2–7]. Many cytotoxic metabolites have been purported as mediators of tissue damage such as oxygen free radicals, activated neutrophils, platelet activating factor, and complement [4, 5, 7, 8, 21, 25, 26]. The experimental use of neutrophil-depleted blood during reperfusion to improve pulmonary function emphasizes the importance of neutrophils as mediators of reperfusion injury [11, 27]. Neutrophil adhesion to vascular endothelium is a key event in initiating cytotoxic activity [11, 27–29]. Adhesion molecule blockade has reduced pulmonary reperfusion injury successfully in animal models [14–16].

NPC 15669, a leumedin, belongs to a new class of antiinflammatory agents. This drug appears to modulate neutrophil function. The potential to decrease pulmonary injury pharmacologically during reperfusion is extremely attractive. Neutrophil depletion has been clinically difficult to perform secondary to cumbersome mechanical devices. The problem of adequate depletion, flow rates through filters, and potential infection risk remain [2]. A significant inhibitory effect on CD11b/CD18 expression has been observed in flow cytometry studies [17]. It does not compete as an antagonist for the adhesion molecules on the neutrophil such as monoclonal antibodies. It not only inhibits adherence in activated neutrophils but can reverse adherence in vitro. Expected shape changes associated with stimulation with activating factors did not occur. Thus studies suggest that the compound works by an intracellular mechanism. Currently, no pharmaceutical agents are available that work by this mechanism. NPC 15669 does not inhibit the respiratory burst or release of cytoplasmic granules per se. However, in vivo, adhesion appears to be a requirement for these processes to take place. Indeed, NPC 15669 has shown an ability to diminish recruitment of activated neutrophils at inflammatory foci in vivo [18]. NPC 15669 has been effective as a parenteral agent to reduce pulmonary injury after cardiopulmonary bypass [30]. In this study we observed similar pulmonary parameters in our NPC 15669-treated reperfused lungs compared with those in previous studies reperfused with neutrophil-depleted blood [11]. Compared to the dramatic failure of the 12-hour EC-stored lungs, the 12- and 24-hour EC lungs reperfused with a leumedin showed significantly less pulmonary injury. The experimental model is limited in relation to physiologic models, particularly with regard to altered drug pharmacokinetics. As in previous studies lung histology and lung wet/dry ratio were a sensitive measurement of pulmonary injury [2, 11, 19, 27]. Addition of NPC 15669 during reperfusion led to diminished lung edema as compared with the other perfused groups. There was also a significant decrease in the tissue myeloperoxidase content in the groups perfused with NPC 15669-treated blood.

Thus, NPC 15669 had a potent effect on neutrophil adhesion or migration during reperfusion after hypothermic long-term storage of lungs. It reduced pulmonary injury as evidenced by decreased pulmonary edema, decreased pulmonary vascular resistance, decreased loss of compliance, and reduced airway pressures. This study provides corroborative evidence that neutrophils contribute significantly to pulmonary reperfusion injury after transplantation. Clinical use of the drug could enhance pulmonary function after long-term hypothermic storage allowing for prolonged procurement times.



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  		Fig 2. . Pulmonary vascular resistance.

 


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  		Fig 3. . Peak airway pressures.

 


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  		Fig 4. . Pulmonary compliance.

 

   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Presented at the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 31-Feb 2, 1994.

Address reprint requests to Dr Stuart, Division of Cardiac Surgery, The Johns Hopkins Hospital, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287-4618.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Stevens JH, Raffin TA, Baldwin JC. The status of transplantation of the human lung. Surg Gynecol Obstet 1989;169: 179–85.[Medline]
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  3. Schueler S, De Valeria PA, Hatanaka M, et al. Successful twenty-four-hour lung preservation with donor core cooling and leukocyte depletion in an orthotopic double lung transplantation model. J Thorac Cardiovasc Surg 1992;104:73–82.[Abstract]
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  9. Doerschuk CM, Winn RK, Coxson HO, Harlan JM. CD18-dependent and independent mechanisms of neutrophil emigration in the pulmonary and systemic microcirculation. J Immunol 1990;144:2327–33.[Abstract]
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  13. Shimizu N, Miyai Y, Aoe M, Nakata M, Date H, Teramoto S. The effects of radical scavengers and leukocyte-depleted blood on reperfusion injury of extirpated rabbit lung. Tohoku J Exp Med 1992;1663:321–9.
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  15. Vedder NB, Winn RK, Rice CL, Chi EY, Arfors KE, Harlan JM. Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear. Proc Natl Acad Sci USA 1990;87:2643–6.[Abstract/Free Full Text]
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  17. Bator JM, Weitzberg M, Burch RM. N-[9H-(2,7-Dimethylfluorenyl-9-methoxy)-L-leucine, NPC 15669, prevents neutrophil adherence to endothelium and inhibits CD11b/CD18 upregulation. Immunopharmacology 1992;23:139–49.[Medline]
  18. Burch RM, Weitzberg M, Blob N, et al. N-(fluorenyl-9-methoxycarbonyl) amino acids, a class of antiinflammatory agents with a different mechanism of action. Proc Natl Acad Sci USA 1991;88:355–9.[Abstract/Free Full Text]
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