HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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): Stefanos Demertzis Anton Moritz Hans-Joachim Schäfers Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scherer, M. Articles by Schäfers, H.-J. Search for Related Content PubMed PubMed Citation Articles by Scherer, M. Articles by Schäfers, H.-J. Related Collections Lung - transplantation Related Article

Ann Thorac Surg 2002;73:233-238
© 2002 The Society of Thoracic Surgeons

---

Original article: general thoracic

C1-esterase inhibitor reduces reperfusion injury after lung transplantation

^a Department of Thoracic and Cardiovascular Surgery, J.W. Goethe University, Frankfurt/Main, Germany
^b Cardiocentro Ticino, Lugano, Switzerland
^c Department of Thoracic and Cardiovascular Surgery, University Hospitals, Homburg/Saar, Germany

Accepted for publication August 14, 2001.

* Address reprint requests to Dr Scherer, Department of Thoracic and Cardiovascular Surgery, J. W. Goethe University, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany
e-mail: m.scherer{at}em.uni-frankfurt.de

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Activation of the complement system and polymorphonuclear neutrophilic leukocytes plays a major role in mediating reperfusion injury after lung transplantation. We hypothesized that early interference with complement activation would reduce lung reperfusion injury after transplantation.

Methods. Unilateral left lung autotransplantation was performed in 6 sheep. After hilar stripping the left lung was flushed with Euro-Collins solution and preserved for 2 hours in situ at 15°C. After reperfusion the right main bronchus and pulmonary artery were occluded, leaving the animal dependent on the reperfused lung (reperfused group). C1-esterase inhibitor group animals (n = 6) received 200 U/kg body weight of C1-esterase inhibitor as a short infusion, half 10 minutes before, the other half 10 minutes after reperfusion. Controls (n = 6) underwent hilar preparation only. Pulmonary function was assessed by alveolar-arterial oxygen difference and pulmonary vascular resistance. The release of ß-N-acetylglucosaminidase served as indicator of polymorphonuclear neutrophilic leukocyte activation. Extravascular lung water was an indicator for pulmonary edema formation. Biopsy specimens were taken from all groups 3 hours after reperfusion for light and electron microscopy.

Results. In the reperfused group, alveolar-arterial oxygen difference and pulmonary vascular resistance were significantly elevated after reperfusion. All animals developed frank alveolar edema. The biochemical marker ß-N-acetylglucosaminidase showed significant leukocyte activation. In the C1-esterase inhibitor group, alveolar-arterial oxygen difference, pulmonary vascular resistance, and the level of polymorphonuclear neutrophilic leukocyte activation were significantly lower.

Conclusions. Treatment with C1-esterase inhibitor reduces reperfusion injury and improves pulmonary function in this experimental model.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Lung transplantation has been established as therapy for end-stage lung disease. However, early pulmonary allograft dysfunction remains an unpredictable clinical complication occurring in 10% to 15% of the recipients. After reperfusion of preserved lung grafts, various mechanisms are activated that may impair graft function and viability beyond ischemic damage. Pulmonary reperfusion injury is clinically similar to that seen in adult respiratory distress syndrome, resulting in increased pulmonary vascular permeability, increased pulmonary vascular resistance (PVR), and inflammatory infiltrates [1]. Mediators of reperfusion injury include polymorphonuclear neutrophilic granulocytes (PMNL), oxygen-derived free radical species, the blood coagulation contact system, and the complement system [2, 3]. The complement system is one of the major pathways and is thought to be involved directly by activation of complement cleavage products and indirectly by complement-mediated PMNL activation [4, 5]. A common inhibitor, C1-esterase inhibitor (C1-INH), regulates activation of the blood contact, as well as the complement, system. Evidence has accumulated that C1-INH appears to have a causative role in the regulation of the body’s inflammatory response. The mechanisms of the protective effect of C1-INH involves preservation of vascular endothelial function and diminished PMNL accumulation leading to reduced neutrophil-mediated tissue injury [6]. Therapeutic intervention with C1-INH in patients with volume-refractory septic shock, systemic inflammatory response syndrome and capillary leak syndrome after administration of high doses of the cytokine interleukin 2 for end-stage cancer led to a substantial decrease in the amount of vasopressor medication needed [7]. C1-esterase inhibitor reduces also postischemic reperfusion injury in the myocardium, liver, and orthotopic lung transplantation in experimental studies [3, 4, 8].

We studied the potential of C1-INH in the amelioration of lung reperfusion injury in an experimental model of left-lung autotransplantation in sheep.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Animals
Eighteen female Merino sheep weighing 25 to 35 kg were used. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" formulated by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-32, revised 1985). The experimental protocol was approved by the local regulatory authorities.

Anesthesia and surgical technique
A model of left lung in situ autotransplantation was designed for these experiments and described previously [9, 10]. Animals were premedicated with azaperone (Stresnil, Jansen, Neuss, Germany, 200 mg) and atropine sulfate (atropine sulfate, B. Braun, Melsungen, Germany, 0.5 mg) both given by intramuscular injection. A venous line was established by puncturing an auricular vein. Induction of anesthesia was performed with sodium thiopental (Trapanal, Byk Gulden, Konstanz, Germany, 250 mg intravenously). Animals were intubated with an orotracheal tube (8.5-mm internal diameter, Rüsch, Belp, Switzerland). Volume-controlled mechanical ventilation was instituted (Siemens Servo 900C respirator, Siemens, Erlangen, Germany). Initially tidal volume was set to 10 mL/kg body weight, respiratory rate to 14 breaths/min with an inspired fraction of oxygen of 0.5. The respirator settings were subsequently adjusted to achieve a PaCO₂ of 40 to 45 mm Hg and arterial oxygen saturation of more than 90%.

Anesthesia was maintained with sodium thiopental and fentanyl (300 mg Trapanal and 0.2 mg fentanyl) both given as intravenous bolus injection every 15 to 30 minutes; for muscular relaxation pancuronium bromide (4 mg intravenously, Pancuroniumbromid, Organon Teknika, Eppelheim, Germany) was added as appropriate. The experiment was terminated by intravenous injection of T61 (10 mL, Hoechst, Frankfurt/Main, Germany).

After the sheep was placed in right lateral position, a central venous catheter was inserted in the left external jugular vein percutaneously using the Seldinger technique. An additional central venous port for subsequent placement of a Swan-Ganz catheter was introduced in the same fashion. An arterial catheter for invasive blood pressure monitoring was placed in the left carotid artery using the Seldinger technique.

A lateral thoracotomy was performed in the left fourth intercostal space. The left main pulmonary artery and bronchus were isolated. The pericardium was opened, and the space between the right pulmonary artery and tracheal bifurcation was dissected. A tape was passed around the right main bronchus. The pulmonary veins were dissected at their entrance into the left atrium. During these steps particular care was taken to minimize manipulation of the ventilated left lung.

A Swan-Ganz catheter was inserted through the central venous port; monitoring and palpation verified the correct position. Also a catheter was inserted into the left atrial appendage for continuous monitoring of left atrial pressure.

After heparin was given intravenously (300 IU/kg), a cannula was placed in the pulmonary artery and the artery was cross-clamped proximally. A side-biting clamp was placed on the left atrium central to the left pulmonary veins, and an incision was made for fluid drainage. The left lung was then flushed with cold modified Euro-Collins solution (60 mL/kg). Pulmonary pressure was monitored during flushing and was kept between 12 and 15 mm Hg. During perfusion ventilation was continued.

After perfusion, the main left bronchus was transected between two vascular clamps with the lung kept semiinflated. The lung was left in situ and covered with cold towels. The temperature was measured in the left interlobar space. When the temperature exceeded 15°C additional cold saline was applied to the towels.

Total ischemic time of the left lung was set at 2 hours. The transected left bronchus was reconstructed at the end of the ischemia with a continuous 4-0 Prolene (Ethicon, Hamburg, Germany) suture with the left lung deflated. The incision of the left atrium was closed, and reperfusion was begun after removing the clamp from the pulmonary artery. Right pulmonary artery and right main bronchus were then occluded by vascular clamps, thus making the animal dependent on the left lung only.

Experimental groups
Three experimental groups were studied. In group C (control), animals underwent thoracotomy and preparation of both hili without ischemia and subsequent manipulation. In the EC (Euro-Collins) group the left lung was flush-perfused with Euro-Collins solution and kept preserved for 2 hours as described above. The animals in the C1-INH group received C1-esterase inhibitor (200U/kg body weight) 10 minutes before and during the first 10 minutes of reperfusion. Each group comprised six successful experiments. The dose of C1-INH was chosen after reviewing published reports on the use of this agent in capillary leak syndrome [7] and reperfusion injury after ischemia of solid organs, such as myocardium [4], liver [8], and lung [3, 6].

Experimental protocol
Cardiopulmonary assessment
Cardiopulmonary function was assessed as follows:

• measurement of cardiac output by thermodilution (Cardiac Output Computer, Hoyer, Bremen, Germany)
  
• registration of pulmonary artery, left atrial, central venous, and arterial pressure
  
• measurement of arterial blood gases (Blood Gas Analyser Model 178; CIBA Corning, Oberlin, OH)
  

Subsequently alveolar-arterial oxygen difference (AaDO₂), systemic vascular resistance (SVR), and PVR were calculated according to the following formulas:

where Pbar is the barometric pressure, FiO₂ is the inspiratory oxygen fraction, and PaO₂ and PaCO₂ are the arterial partial pressures for O₂ and CO₂, respectively.

where MAP is the mean arterial pressure, CVP is the central venous pressure, and CO is cardiac output.

where PAP is the pulmonary artery mean pressure and PCWP is the pulmonary capillary wedge pressure.

The variables above were measured at the start of the experiment, after hilar preparation, and 60, 120, and 180 minutes after reperfusion.

Biochemical assessment of leukocyte activation
ß-N-acetylglucosaminidase (ß-NAG) enzyme activity was measured in whole blood fluorometrically according to Dwenger and Schweitzer [11] with 4-methylumbelliferyl-N-acetyl-ß-D-glucosaminidase as a substrate and 4-methylumbelliferone as a standard. One unit of ß-NAG was defined as the activity that catalyzed the reaction of 1 µmol of substrate per minute under the test conditions used. Fluorescence was measured with a model RF-510 spectrofluorophotometer (Shimadzu, Kyoto, Japan).

The variables were measured at baseline, after hilar preparation, and 60, 120, and 180 minutes after reperfusion.

Extravascular lung water
Two biopsy specimens were taken, one from the right lung after hilar preparation, one from the left lung at the end of the experiment. Both specimens were obtained from the upper lobe. Extravascular lung water (in grams per gram blood-free dry lung weight) was measured according to the method published by Drake and colleagues [12].

Light and electron microscopy
After hilar preparation five representative samples were taken from the right upper lobe and were stained with hematoxylin-eosin for histologic analysis, which was performed by light microscopy. At the end of the experiment another five representative samples were taken from the left upper lobe. Ultrathin sections were then cut with a diamond knife, stained with uranyl acetate and lead citrate, and examined with an electron microscope [13].

Statistical analysis
The results are expressed as the mean ± standard deviation of the mean of the absolute values. Comparison among means was made by analysis of variance followed by post hoc tests (Bonferroni or Dunn). Nonparametric values were compared either with the Wilcoxon or the ² test. Analyses were performed with the SPSS/Mac statistical software (SPSS Inc, Chicago, IL). Statistical significance level was defined as p less than 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Cardiopulmonary assessment
Alveolar-arterial oxygen difference
The AaDO₂ in the controls remained stable throughout the experiment. A similar course could be observed for the AaDO₂ values in C1-INH group (range, 218 ± 61 to 280 ± 101 mm Hg; Fig 1). The AaDO₂ values in the EC group increased significantly during reperfusion (range, 209 ± 48 to 510 ± 148 mm Hg). There were statistically significant differences between groups C and EC, as well as between groups C1-INH and EC (p < 0.05). The differences between groups C and C1-INH were not statistically significant.

View larger version (56K): [in this window] [in a new window]   Fig 1. Values for alveolar-arterial oxygen difference as a function of time (means ± standard deviation).*p < 0.05 controls (C) versus Euro-Collins reperfused (EC) group, **p < 0.05 EC group versus C1-esterase inhibitor (C1-INH) group.

View larger version (60K): [in this window] [in a new window]   Fig 2. Values for pulmonary vascular resistance as a function of time (means ± standard deviation). *p < 0.05 controls (C) versus Euro-Collins reperfused (EC) group, **p < 0.05 EC group versus C1-esterase inhibitor (C1-INH) group.

Biochemical assessment of leukocyte function
No substantial ß-NAG release took place in groups C and C1-INH. In the EC group, values increased significantly after reperfusion, ranging from 0.43 ± 0.19 to 0.85 ± 0.43 U/L (Fig 3). There were statistically significant differences between groups C and EC, as well as between groups C1-INH and EC (p < 0.05). The differences between groups C and C1-INH were not statistically significant.

View larger version (49K): [in this window] [in a new window]   Fig 3. Values for ß-N-acetylglucosaminidase as a function of time (means ± standard deviation). *p < 0.05 controls (C) versus Euro-Collins reperfused (EC) group, **p < 0.05 EC group versus C1-esterase inhibitor (C1-INH) group.

View larger version (54K): [in this window] [in a new window]   Fig 4. Extravascular lung water 180 minutes after reperfusion. *p < 0.05 Euro-Collins reperfused (EC) group versus controls (C) and C1-esterase inhibitor (C1-INH) group.

View larger version (170K): [in this window] [in a new window]   Fig 5. Histology of lung graft from the controls and C1-esterase inhibitor group. Only a minimal alveolar-interstitial leukocyte infiltrate was observed.

View larger version (172K): [in this window] [in a new window]   Fig 6. Histology of lung from a representative animal in the Euro-Collins reperfused group. A marked alveolar-interstitial leukocyte infiltrate was present.

View larger version (55K): [in this window] [in a new window]   Fig 7. Electronmicrograph of lung graft from a representative animal in the Euro-Collins reperfused group. (* = interstitial edema; N = nucleus; PMN = polymorphonuclear neutrophilic leukocyte; SM = smooth muscle.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

After reperfusion of preserved organ grafts, various mechanisms are activated that may impair graft function and viability beyond ischemic damage. Alterations in microvascular perfusion caused by the production of an alveolar exudate rich in leukocytes and platelets and containing a high content of clotting factors are of central importance, and are characterized by capillary perfusion breakdown (no-reflow), accumulation and adhesion of leukocytes to the microvascular endothelium (reflow-paradox), and impairment of endothelial barrier function [16]. The mechanisms involved in the development of the alveolar-capillary exudate have not been fully established; several cytotoxic metabolites such as oxygen radicals, activated neutrophils, platelet-activating factor, leukotrienes, and complement factors have been proposed as mediators of tissue damage.

The exact mechanism of complement activation during lung allograft reperfusion remains unknown. Metabolically active cells maintain defense mechanisms that protect them against complement attack. Ischemia and reperfusion could impair their defense by damaging membrane proteins. Activation of the complement cascade by either the classic or alternative pathways leads to the cleaving of C3 and then of C5 into their biologically active cleavage products. The smaller cleavage products (C3a and C5a) are extremely potent proinflammatory mediators. Both C3a and C5a cause histamine release from mast cells and basophils and contraction of smooth muscle, and increase permeability of vessels [2]. C5a also activates endothelial cells, and is a powerful chemoattractant for neutrophils and monocytes. The consequence of endothelial cell activation includes adhesion and extravascular migration of neutrophils and monocytes. Activation of these inflammatory cells causes enzyme release with subsequent damage of the vascular endothelium. The end product of the complement system is the membrane attack complex (C5–C9), which is able to form a channel through the plasma membrane and cause target cell lysis [6].

The activation of the classic pathway of complement and of bradykinin contact systems is regulated by C1-INH. There are close interrelations between both systems. Activation of the contact system results in the formation of bradykinin cleaved from kininogen by kallikrein. Bradykinin has strong vasodilating properties, causes contraction of smooth muscle, and increases permeability of vessels [7]. C1-esterase inhibitor is the only known inhibitor in plasma of the first component of complement (C1). Furthermore, it is able to inactivate kallikrein, plasmin, and factors XIIa and XIIf.

The clinical picture of reperfusion injury includes increased PVR, interstitial and alveolar pulmonary edema, and impaired gas exchange. In addition, a systemic vasodilation and intravascular hypovolemia in the face of third-space loss was observed. In our study we were able to reproduce the reperfusion injury after unilateral lung autotransplantation. During reperfusion the function of the autotransplanted lung declined continuously.

The activity of ß-NAG in plasma suggests significant respiratory burst–induced degranulation of PMNL throughout reperfusion. This enzyme is located in the PMNL azurophilic granula. After 30 minutes of reperfusion the activity of ß-NAG increased maximally. Probably after a short time of reperfusion, highly activated PMNL released their phagocytic granula after contact with the activated or damaged cellular surface ("frustrane" phagocytosis).

The increase in PVR can be caused by vascular microthromboses, vasoconstriction, and swelling of endothelial cells. One of the reasons for microvessel thrombosis is leukocyte sequestration in the lung [17]. Pulmonary ischemia and reperfusion appeared to injure the pulmonary capillary bed. Partial detachment of the cells from the basement membrane of the blood gas barrier could be explained by inhibition of basement membrane glycoprotein synthesis in a hypoxic environment [18]. The increase in permeability was probably caused by changes in the endothelial cell itself. The mechanism of such endothelial cell dysfunction is unclear, but ischemia–reperfusion disturbs many metabolic processes with impairment of membrane integrity. Neutrophil–endothelial cell interaction increases lung permeability in many types of experimental lung injury [19]. Our observations are in accord with this study.

The inhibition of the complement system during reperfusion of lung autografts reduced reperfusion edema in our study, and improved gas exchange and PVR. The precise mechanism by which C1-INH prevents PMNL activation and pulmonary dysfunction is not known; inhibition of both the contact system and complement system may prevent leukocyte cell activation [3]. This may explain the absence of pulmonary exudates and lack of intraalveolar or interstitial PMNL migration in sheep receiving C1-INH. In other experimental studies C1-INH was found to reduce reperfusion edema but not to improve hemodynamic variables and PVR [6].

The accuracy of our conclusions might be limited by the fact that we did not measure the complement cascade products at all, such as C3a, C5a, and total complement activity. However, inhibition of the complement system is only one of the effects of C1-INH. It is our understanding that the efficiency of this substance in the amelioration of reperfusion injury is, at least in part, the result of an early cross-inhibition of the kallikrein-bradykinin cascade, which also can contribute to the capillary leakage and generalized vasodilation seen in reperfusion injury after lung transplantation. Comparing our results with results obtained by others who interfered with complement activation at a lower level [6], it is our impression that C1-INH seemed indeed to inhibit the initial spread of activation throughout the subsystems of the nonspecific immune reaction.

In conclusion, we were able to demonstrate that C1-INH reduces reperfusion injury after experimental lung autotransplantation in sheep. In combination with inhibition of other arms of the inflammatory response the administration of C1-INH before reperfusion may play a role in prevention or treatment of early graft failure.

	References

Top Abstract Introduction Material and methods Results Comment References

 

1. Post S., Messmer K. Die Rolle des Reperfusionsschadens. Chirurg 1996;67:318-323.[Medline]
2. Baldwin W.M., Pruitt S.K., Brauer R.B., Daha M.R., Sanfilipo F. Complement in organ transplantation. Transplantation 1995;59:797-808.[Medline]
3. Salvatiera A., Velasco F., Rodriguez M., et al. C1-esterase inhibitor prevents early pulmonary dysfunction after lung transplantation in the dog. Am J Respir Crit Care Med 1997;155:1147-1154.[Abstract]
4. Buerke M., Prufer D., Dahm M., Oelert H., Meyer J., Darius H. Blocking of classical complement pathways inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury. J Pharmacol Exp Ther 1998;286:429-438.[Abstract/Free Full Text]
5. Hofmeister J.W., Lucchesi B.R. Complement activation and inhibition in myocardial ischemia and reperfusion injury. Annu Rev Pharmacol Toxicol 1994;34:17-40.[Medline]
6. Schmidt R.A., Zollinger A., Singer T., et al. Effect of soluble complement receptor type 1 on reperfusion edema and neutrophil migration after lung allotransplantation in swine. J Thorac Cardiovasc Surg 1998;116:90-97.[Abstract/Free Full Text]
7. Eisele B., Delvos U. From localized angioedema to generalized capillary leak syndrome: evidence for a pivotal role of C1-inhibitor in septic shock-like syndromes. Update Intensive Care Emerg Med 1994;18:501-527.
8. Lehmann T.G., Heger M., Munch S., Kirschfink M., Klar E. In vivo microscopy reveals that complement inhibition by C1-esterase inhibitor reduces ischemia/reperfusion injury in the liver. Transpl Int 2000;13(Suppl 1):547-550.
9. Demertzis S., Langer F., Graeter T., Dwenger A., Georg T., Schäfers H.-J. Amelioration of lung reperfusion injury by L- and E-selectin blockade. Eur J Cardiothorac Surg 1999;16:174-180.[Abstract/Free Full Text]
10. Demertzis S., Scherer M., Langer F., Dwenger A., Hausen B., Schäfers H.-J. Ascorbic acid for amelioration of reperfusion injury in a lung autotransplantation model in sheep. Ann Thorac Surg 2000;70:1684-1689.[Abstract/Free Full Text]
11. Dwenger A., Schweitzer G. Bronchoalveolar lavage fluid and plasma proteins, chemiluminescence response and protein contents of polymorphonuclear leukocytes from blood and lavage fluid in traumatized patients. J Clin Chem Clin Biochem 1986;24:73-88.[Medline]
12. Drake R.E., Smith J.H., Gabel J.C. Estimation of the filtration coefficient in intact dog lungs. Am J Physiol 1980;238:430-438.
13. Mills A.N., Hooper T.L., Hall S.M., McGregor C.G., Haworth S.G. Unilateral lung transplantation: ultrastructural studies of ischemia-reperfusion injury and repair in the canine pulmonary vasculature. J Heart Lung Transplant 1992;11:58-67.[Medline]
14. Haydock D.A., Trulock E.P., Kaise L.R., et al. Lung transplantation: analysis of thirty-six consecutive procedures performed over a twelve-month period. J Thorac Cardiovasc Surg 1992;103:329-340.[Abstract]
15. Zenati M., Yousem S.A., Dowling R.D., Stein K.L., Griffith B.P. Primary graft failure following pulmonary transplantation. Transplantation 1990;50:165-167.[Medline]
16. Nolte D., Messmer K. Tissue protection by anti-ischemic drugs. Minerva Cardioangiol 1995;43:485-491.[Medline]
17. Kuhnle G.E., Reichenspurner H., Lange T., et al. Microhemodynamics and leukocyte sequestration after pulmonary ischemia and reperfusion in rabbits. J Thorac Cardiovasc Surg 1998;115:937-944.[Abstract/Free Full Text]
18. Humphries D.E., Lee S.-L., Fanburg B.L., Silbert J.E. Effects of hypoxia and hyperoxia on proteoglycan production by bovine pulmonary artery endothelial cells. J Cell Physiol 1986;126:249-253.[Medline]
19. Meyrick B., Brigham K.L. Acute effect of Escherichia coli endotoxin on the pulmonary microcirculation of anesthetized sheep. Lab Invest 1983;4:458-470.

This article has been cited by other articles:

				K. Baig, R. Nassar, D. M. Craig, G. Quick Jr, H. X. Jiang, M. M. Frank, A. J. Lodge, P. A.W. Anderson, and J. Jaggers Complement Factor 1 Inhibitor Improves Cardiopulmonary Function in Neonatal Cardiopulmonary Bypass Ann. Thorac. Surg., April 1, 2007; 83(4): 1477 - 1483. [Abstract] [Full Text] [PDF]

				C. R. Weiler and R. G. Van Dellen Genetic Test Indications and Interpretations in Patients With Hereditary Angioedema Mayo Clin. Proc., July 1, 2006; 81(7): 958 - 972. [Abstract] [Full Text] [PDF]

				N. C. Riedemann and P. A. Ward Complement in Ischemia Reperfusion Injury Am. J. Pathol., February 1, 2003; 162(2): 363 - 367. [Full Text] [PDF]

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): Stefanos Demertzis Anton Moritz Hans-Joachim Schäfers Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scherer, M. Articles by Schäfers, H.-J. Search for Related Content PubMed PubMed Citation Articles by Scherer, M. Articles by Schäfers, H.-J. Related Collections Lung - transplantation Related Article