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

This Article Abstract 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): Hani Shennib Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Serrick, C. Articles by Shennib, H. Search for Related Content PubMed PubMed Citation Articles by Serrick, C. Articles by Shennib, H.

Ann Thorac Surg 1997;63:202-208
© 1997 The Society of Thoracic Surgeons

---

Original Articles: General Thoracic

Prolonged Ischemia Is Associated With More Pronounced Rejection in the Lung Allograft

The Montreal Lung Transplant Program, Montreal, Quebec, Canada

Accepted for publication August 6, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Background. Previously it was found that ischemia-reperfusion injury in a left lung autotransplantation model could be a minor inducer of major histocompatibility complex (MHC) class II antigen expression. Thus, we hypothesized that prolonged ischemic times may result in increased expression of MHC class II antigens and predispose the lungs to the development of acute rejection early after transplantation.

Methods. Twenty conditioned dogs underwent single left lung allotransplantation. Donor lungs were subjected to 4 or 24 hours (n = 10 each) of cold ischemia. Open lung biopsies, bronchoalveolar lavage fluid, and blood samples were taken preoperatively and at various intervals up to 1 week after transplantation. Lung biopsy specimens were examined histologically for MHC class II expression and graded for acute rejection. Bronchoalveolar lavage fluid and plasma were analyzed for cytokines interleukin-2 and interferon-.

Results. In the 4-hour ischemia group, there was mild diffuse staining of the bronchial epithelium and cellular infiltrate for MHC class II antigens after 1 week with subsequent grade 1-2 rejection. In the 24-hour ischemia group, MHC expression after 1 week revealed strong diffuse staining of bronchial epithelium, vascular endothelium, and cellular infiltrates with a significantly higher grade of rejection. Interleukin-2 and interferon- significantly increased in BAL fluid early after transplantation in both groups.

Conclusions. Ischemic injury may predispose the lung allograft to the development of acute rejection, in part, through the upregulation of MHC class II antigen expression and the local release of cytokines.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Because of its delicate alveolar capillary network, the lungs are markedly sensitive to ischemia and have a higher incidence of early rejection than other solid-organ transplants [1]. However, with the growing experience in lung transplantation and the storage of donor lungs, ischemic times longer than 6 hours are considered acceptable by most centers despite this potential risk for early graft dysfunction [2].

In a left lung autograft model, we [3] have shown that 4 hours of cold ischemia results in mild expression of major histocompatibility complex (MHC) class II antigens on lung epithelium 1 week after transplantation. These findings provided evidence that 4 hours of ischemia combined with reperfusion injury may be a potential inducer of MHC class II antigen expression through either the stimulated release of various cytokines or some other mechanism. Alterations in tissue density of MHC class II antigens are likely to influence the alloimmune response against that tissue [4]. Indeed, many investigators have shown a direct correlation between MHC class II hyperexpression in an allograft and its rejection [5, 6]. However, it is not known whether there is an association between ischemia and increasing MHC class II antigen expression and, through this mechanism, episodes of more intense acute rejection.

We hypothesized that subjecting lung allografts to different lengths of ischemic injury may increase the immunogenicity of the allograft through the upregulation of MHC class II antigen expression and thus lead to the development of more severe acute rejection. In this study, lung allografts were subjected to either 4 or 24 hours of ischemia and then examined for MHC class II antigen expression and severity of acute rejection.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Twenty conditioned mongrel dogs weighing 20 to 25 kg underwent single left lung allotransplantation. Lungs were harvested from size-matched donor dogs and flushed with 2 L of cold modified Euro-Collins solution (3 mEq/L of sodium bicarbonate + 12.8 mEq/L of magnesium sulfate) at a perfusion pressure of approximately 70 mm Hg while ventilation was continued. Both lungs were then stored at 4°C for 4 or 24 hours in an inflated state. Immediately prior to implantation, the left lung was separated from the block, and the hilar structures were prepared for anastomosis. Left lungs were transplanted using a technique previously described [7]. Time for implantation of the allograft was approximately 1 hour.

Open lung biopsy specimens, bronchoalveolar lavage fluid (BAL), and plasma specimens were obtained at various intervals from the two groups of recipients, ie, those receiving allografts after 4 hours of storage (n = 10) and those receiving allografts after 24 hours of storage (n = 10). To avoid the effects of repetitive procedures on the allograft, samples were taken preoperatively, and 1 hour and 4 hours postoperatively in 10 animals and preoperatively and 24 hours and 1 week after transplantation in another 10 animals (5 animals per group).

For immunosuppression, animals received cyclosporine (30 mg/kg orally) preoperatively and 17 mg • kg^-1 • d^-1 in divided doses postoperatively. Azathioprine (2 mg/kg) was started preoperatively and continued daily postoperatively. Intravenous methylprednisolone (10 mg/kg) was given prior to reperfusion followed by 5 mg/kg intravenously every 8 hours for three doses; thereafter, prednisone (20 mg orally) was given once a day. All dogs were killed with a lethal injection of potassium chloride at the end of the study.

All animals received humane care in compliance with the Animal Care Committee regulations of The Montreal General Hospital and McGill University as well as 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' published by the National Institutes of Health (NIH publication 85-23, revised 1985).

	Histology

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Open lung biopsies were performed before BAL in all animals by wedging out a small fragment of the lung and stapling the lung with a linear stapler (Proximate Linear cutter 75; Ethicon, Cincinatti, OH). Specimens were fixed in Bouin's solution at room temperature. Tissues were then washed several times with 30% ethanol and processed in paraffin. Sections 4 µm thick were cut from several levels of each block and mounted on glass slides. Conventional staining was done using hematoxylin and eosin. Rejection was diagnosed according to the method of Berry and colleagues [8].

Immunohistochemistry was performed using the avidin-biotin complex method. In brief, sections were dewaxed in xylene, dehydrated in decreasing concentrations of ethanol, washed in 0.1 mol/L phosphate buffer and 0.15 mol/L saline solution (phosphate-buffered saline solution or PBS), and incubated in PBS containing 2% hydrogen peroxide to block endogenous peroxidase activity. The sections were then washed in PBS, incubated in 10% normal horse serum, and incubated with B1F6, a monoclonal antibody capable of recognizing canine MHC class II antigen [9], for 16 hours at 4°C. After three 5-minute washes in PBS, sections were incubated with biotinylated horse anti-mouse immunoglobulin G (Vector Laboratories Inc, Burlingame, CA), diluted 1:200, for 45 minutes at room temperature. This was followed by three more 5-minute washes in PBS and further incubation in avidin-biotin-peroxidase complex (Vectastain Elite Kit; Vector Laboratories, Inc), diluted 1:200, for 45 minutes at room temperature. The immunoreaction was visualized by developing sections in 0.025% diaminobenzidine and 0.03% hydrogen peroxide for 5 minutes at room temperature. Sections were then counterstained with hematoxylin, washed in distilled water, dehydrated in ethanol, cleared in xylene, and mounted. Negative control sections were immunostained in the absence of the first- or second-layer antiserum. Positive control sections were immunostained with antiserum to von Willebrand factor (factor VIII–related antigen). The immunostaining was graded as described by Giaid and co-workers [10]: 0 = no staining, similar to negative control samples; 1 = focal staining (few scattered cells); 2 = mild diffuse staining; 3 = moderate diffuse staining; and 4 = strong diffuse staining.

	Bronchoalveolar Lavage

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Bronchoalveolar lavage was performed as previously described [11]. In brief, aliquots of 10 mL of sterile saline solution were injected into selected lung segments through a bronchoscope wedged into the segmental bronchus and gently aspirated. Of a total of 140 mL of saline solution injected into the segment, approximately 75% was retrieved. Lavage fluid from a given lung was taken from different pulmonary segments to avoid cellular changes in the BAL fluid secondary to repeated lavage of the same region as previously described in dogs [12]. Lavage fluid was filtered through two layers of sterile surgical gauze to remove clumps of mucus. The supernatant was separated from the cells by centrifugation at 1,800 rpm for 10 minutes, concentrated 5-fold or 10-fold (depending on the amount of the sample) using a positive-pressure filtration technique with an Amicon YM10 membrane filter (Amicon Inc, Beverly, MA), and then divided into aliquots and stored at -80°C until cytokine levels could be measured.

Blood samples were taken in heparinized vacuum tubes at the time of lavage in all animals. The plasma was separated from the red blood cells by centrifugation at 1,800 rpm for 10 minutes, and samples were stored at -80°C until cytokine levels could be measured.

	Cytokine Measurement

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Interleukin-2 (IL-2) and interferon- (IFN) were measured using an enzyme-linked immunosorbent assay in kit form as described previously [11]. The kits used were InterTest 2 (Genzyme, Cambridge, MA) and Hbt Human gamma-IFN kit (Holland Biotechnology BV, Netherlands), respectively, which have been known to cross-react with canine cytokines [11, 13]. Each kit is a sandwich type of immunoassay. Only active cytokines are detected. There is no cross-reactivity with denatured or other cytokines. The variable concentrations of the cytokine samples were corrected for data analysis by dividing the concentration determined in the assay by the concentrating factor.

	Statistical Analysis

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Comparison of immunostaining grades was assessed using a one-factor analysis of variance and the Tukey-Kramer multiple comparison test. For cytokines, a Wilcoxon signed-rank nonparametric test was used to compare the different time intervals within each group with each animal's preoperative levels. The Mann-Whitney U test was used to compare the 4-hour ischemia group with the 24-hour ischemia group at the various time intervals. A p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
MHC Class II Staining
FOUR-HOUR ISCHEMIA GROUP.
Immunohistochemical staining of preoperative specimens showed no evidence of MHC class II expression on either bronchial or vascular tissue. By 24 hours, focal staining in the peribronchial tissue of lung allografts was seen. At 1 week, there was evidence of a more diffuse, mild staining in the peribronchial tissue (Fig 1a), which was significant (p < 0.001) (Fig 2). Similarly, increased focal staining of the perivascular and peribronchial mononuclear cellular infiltrate was detected at 1 week, but this was not significant (Fig 3). The vascular endothelium remained negative (Fig 4).

View larger version (145K): [in this window] [in a new window]   Fig 1. . (a–c) Photomicrographs showing major histocompatibility complex (MHC) class II immunostaining. (a) Lung biopsy specimen from 4-hour ischemia group 1 week postoperatively with peribronchial tissue staining (arrow). (b) Biopsy specimen from 24-hour ischemia group 24 hours after reperfusion showing diffuse expression of MHC class II reactivity in airway epithelium. (c) Interstitial inflammatory cells in lung biopsy specimen 1 week after transplantation in 24-hour ischemia group. (d–f) Hematoxylin and eosin staining of lung biopsy specimens. (d). Grade 1-2 rejection with a perivascular mononuclear cell infiltrate in a lung allograft biopsy specimen from 4-hour ischemia group 1 week after transplantation. (e) Lung tissue biopsy specimen showing diffuse aveolar edema, hemorrhage, and inflammatory cells in interstitum from 24-hour ischemia group 24 hours after transplantation. (f) Lung biopsy specimen showing perivascular infiltration representing grade 3 rejection 1 week after transplantation in 24-hour ischemia group. (a–d, f x400; e x200; all before 9% reduction.)

View larger version (27K): [in this window] [in a new window]   Fig 2. . Major histocompatibility complex class II staining of bronchial epithelium. Data are shown as the mean ± the standard error of the mean. (* = p < 0.05 compared with preoperative value; = p < 0.05 compared with 4-hour ischemia group; = p < 0.01 compared with 24; ** = p < 0.001 compared with preoperative, 1 hour and 4 hours.)

View larger version (27K): [in this window] [in a new window]   Fig 3. . Major histocompatibility complex class II staining of cellular infiltrate. Data are shown as the mean ± the standard error of the mean. (* = p < 0.05 compared with preoperative and 1 hour values; = p < 0.01 compared with 4-hour ischemia group.)

View larger version (23K): [in this window] [in a new window]   Fig 4. . Major histocompatibility complex class II staining of vascular endothelium. Data are shown as the mean ± the standard error of the mean. ( = p < 0.01 compared with 4-hour ischemia group; * = p &lt; 0.05 compared with preoperative and 1 hour values; = p < 0.001 compared with 4-hour ischemia group.)

FOUR-HOUR VERSUS 24-HOUR ISCHEMIA GROUPS.
There was a significantly greater expression of MHC II antigens on the bronchial epithelium after 24 hours of reperfusion in the 24-hour ischemia group compared with the 4-hour ischemia group (p < 0.05) (see Fig 2). There was also a significantly greater antigen expression on the vascular endothelium at 4 hours (p < 0.01), 24 hours (p < 0.001), and 1 week (p < 0.001) after transplantation in the 24-hour ischemia group than in the 4-hour group (see Fig 4). The same trend was also seen on the cellular infiltrate at 24 hours and 1 week (p < 0.01) (see Fig 3).

Histology
FOUR-HOUR ISCHEMIA GROUP.
Hematoxylin and eosin staining of lung biopsy specimens showed evidence of an inflammatory response by 1 hour after reperfusion with neutrophil margination and areas of alveolar wall edema. These changes were more pronounced at 4 hours, with areas of neutrophil infiltration into the parenchyma and alveolar spaces persisting at 24 hours. In 4 of the 5 animals studied at 1 week, there was evidence of grade 1-2 rejection with perivascular lymphocyte cuffing (Fig 1d).

TWENTY-FOUR-HOUR ISCHEMIA GROUP.
Hematoxylin and eosin staining of lung biopsy specimens revealed slight ischemic changes and edema 1 hour after reperfusion. The vessels were clear with few inflammatory cells. After 4 hours of reperfusion, lung tissues showed more pronounced ischemic reperfusion damage consisting of alveolar hemorrhagic exudate, reactive type II cells, and inflammatory cells in the interstitium and airways. At 24 hours, these changes were more predominant with diffuse alveolar edema and hemorrhage. There was an increase in the number of inflammatory and type II cells in the interstitium and thickened alveolar septa (Fig 1e). Again at 48 hours, there were signs of diffuse alveolar damage with edema and hemorrhage with grade 1 rejection in 3 dogs. One week after transplantation, 2 dogs had grade 1-2 rejection, and 3 dogs had grade 3 diffuse rejection (Fig 1f). This was a significantly higher grade of rejection compared with that in the 4-hour ischemia group at 1 week (p < 0.05). Again rejection was evident despite maintenance of triple-drug immunosuppression.

Cytokines
Cytokine levels in BAL fluid and plasma after transplantation are expressed as a percentage of preoperative values and are summarized in Tables 1 and 2, respectively.

	FOUR-HOUR ISCHEMIA GROUP.

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
After 4 hours of cold ischemia, IL-2 levels increased significantly in BAL fluid 1 hour and 4 hours after reperfusion (p < 0.05) and returned to baseline after 24 hours. Levels of IFN followed the same pattern with a significant increase 1 hour and 4 hours after operation (p < 0.05) and a decrease after 24 hours (Fig 5). Plasma cytokine levels did not change significantly over the various intervals for either IL-2 or IFN.

View larger version (15K): [in this window] [in a new window]   Fig 5. . Cytokine levels in bronchoalveolar lavage fluid from 4-hour ischemia group lung allografts. Values are shown as a percentage of preoperative values (mean ± standard error of the mean). (IL-2 = interleukin-2; IFN = interferon-gamma; * = p < 0.05 compared with preoperative value.)

	TWENTY-FOUR-HOUR ISCHEMIA GROUP.

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

View larger version (16K): [in this window] [in a new window]   Fig 6. . Cytokine levels in bronchoalveolar lavage fluid from 24-hour ischemia group lung allografts. Values are shown as a percentage of preoperative values (mean ± standard error of the mean). (IL-2 = interleukin-2; IFN = interferon-gamma; * = p < 0.05 compared with preoperative value.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

Acute graft rejection almost never occurs without MHC class II hyperexpression, a finding suggesting that MHC induction plays a permissive role in graft dysfunction and allograft rejection by making the lung allograft more immunogenic [4]. With an increased expression of MHC class II antigens on the cellular infiltrate of the lung allograft, the host's antigen-presenting cells become more effective at the uptake and presentation of foreign antigen, and the cells of the graft are better recognized as targets [15]. The amount of MHC class II product on the bronchial epithelium and the vascular endothelium will also determine the donor or target cell susceptibility to lysis. For example, Flyer and associates [16] found that various viruses can alter MHC product expression on target cells either up or down with the susceptibility of the target cell to lysis by cytotoxic T cells varying in the same direction.

These two effects of MHC class II upregulation, ie, more effective antigen-presenting cells and increased susceptibility of donor cells to lysis, are a critical step in the development of acute rejection. Thus, despite the maintenance of triple-drug immunosuppression as in our study, 24 hours of ischemia resulted in an intense MHC class II expression on the lung allograft. It is this increased antigen expression that may have caused the significant increase in rejection 1 week after transplantation in the 24-hour-ischemia group. This was confirmed in the lung allografts after 4 hours of cold ischemia where MHC antigen expression and rejection was much less severe.

This MHC class II hyperexpression may be triggered by the early release of mediators of injury such as cytokines during the ischemia/reperfusion period after transplantation. We observed in this study that cytokines IL-2 and IFN increased significantly in the bronchoalveolar compartment of the lung allograft shortly after transplantation in both the 4-hour and 24-hour cold ischemia group. Besides its immunostimulatory effects, for example, as a T lymphocyte growth factor, IL-2 has been known to induce lung injury mediated by oxygen free radicals [17]. Interleukin-2 is also the major regulator of IFN production. Interferon-, in turn, is a potent inducer of MHC gene and gene product expression [15]. This early intragraft release can be correlated with the increased presence of MHC class II staining on the bronchial epithelium, the vascular endothelium, and the cellular infiltrate of the lung allograft. The differences in cytokine intensity between the two groups at 24 hours may be the reason for the more-intense diffuse MHC antigen expression seen in the 24-hour ischemia group. In the 4-hour ischemia group, levels of IFN and IL-2 increased significantly up to 4 hours after transplantation and decreased after 24 hours. However, both are significantly increased for 24 hours after transplantation in the 24-hour ischemia group. Thus, cytokines may be released over a much longer time after a prolonged ischemic period and result in a more intense inflammatory reaction. The MHC class II expression continues long after IFN levels subside, which indicates that although cytokine levels diminish, their effects can be long lasting.

Interestingly, after 4 hours of ischemia, MHC class II expression was observed on bronchial epithelium and cellular infiltrate only. After 24 hours of cold ischemia, not only was there a stronger MHC class II antigen expression but it was found on the vascular endothelium as well. These seemingly contradictory results are, in fact, supported by a number of studies. For example, as in our 4-hour ischemia group, Romaniuk and associates [18] demonstrated that in the presence of rejection, MHC class II antigens were induced only on bronchial tissue in immunosuppressed rat lung allografts. However, work by Chang and colleagues [13] using a canine model of lung transplantation supports the findings in our 24-hour ischemia group. These authors suggested that MHC class II antigens are equally expressed over bronchial epithelium and vascular endothelium when rejection is induced by withholding immunosuppression.

These results might represent a difference in the severity of rejection. Twenty-four-hour ischemia causes a much greater insult and more damage to the lung and therefore more severe rejection than 4 hours of cold ischemia, which is a milder ischemic insult. Greater changes such as higher cytoplasmic calcium concentrations [19], increased loss of intracellular adenosine triphosphate levels [20], production of oxygen free radicals [21], and lipid peroxidation [22] occur in intracellular homeostasis and lead to structural changes in membranes and membrane components. Phagocytes become more activated and degranulate, releasing cytotoxic metabolites that can cause endothelial or epithelial cell surface damage and destruction [23]. The combined effect of all these mechanisms results in increased cellular edema and cell death.

The finding of differing antigen expression on various cell types could also reflect the higher vulnerability of the bronchial epithelium to ischemic insults, particularly because our method of preservation involves administering Euro-Collins solution through the pulmonary artery and because until recently, we focused our evaluation of methods of preservation on lung parenchymal function and not airway integrity. Euro-Collins solution preserves the vascular endothelium for 4 hours of ischemia, but this preservation technique fails for both the bronchial epithelium and the vascular endothelium during 24 hours of ischemia.

In conclusion, this study has shown that a longer ischemic period is associated with the development of more pronounced acute rejection after transplantation. The more prominent MHC class II antigen expression and the local release of cytokines in grafts subjected to longer ischemia suggest that intense ischemic injury may prime the lung for the development of rejection. Therefore, if longer periods of ischemia are to be achieved in a clinical setting, better methods of lung preservation must be developed.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
We thank Dr Rudolfo Alejandro for generously supplying the B1F6.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 
Address reprint requests to Dr Shennib, The Montreal General Hospital, Suite L9 121, 1650 Cedar Ave, Montreal, PQ, Canada H3G 1A4.

	References

Top Footnotes Abstract Introduction Material and Methods Histology Bronchoalveolar Lavage Cytokine Measurement Statistical Analysis Results FOUR-HOUR ISCHEMIA GROUP. TWENTY-FOUR-HOUR ISCHEMIA GROUP. Comment Acknowledgments References

 

1. Novick RJ, Menkis A, McKenzie FN. New trends in lung preservation: a collective review. J Heart Lung Transplant 1992;11:377–92.[Medline]
2. Burdine J, Hertz MI, Snover DC, Bolman RM. Heart-lung and lung transplantation: perioperative pulmonary dysfunction. Transplant Proc 1991;23:1176–7.[Medline]
3. Serrick C, La Franchesca S, Giaid A, Shennib H. Cytokine IL-2, TNF and IFN release after ischemia reperfusion injury in a novel lung autograft animal model. Am J Respir Crit Care Med 1995;152:277–82.[Abstract]
4. Halloran PF, Wadgymar A, Autenried P. The regulation of expression of major histocompatibility complex products. Transplantation 1986;41:413–20.[Medline]
5. Carlquist JF, Hammond ME, Yowell RL, O'Connell JB, Anderson JL. Correlation between class II antigen (DR) expression and interleukin-2-induced lymphocyte proliferation during acute cardiac allograft rejection. Transplantation 1990;50:582–8.[Medline]
6. DiSesa VJ, Kuo PC, Horvath KA, Mudge GH, Collins JJ Jr, Cohn LH. HLA histocompatibility affects cardiac transplant rejection and may provide one basis for organ allocation. Ann Thorac Surg 1990;49:220–4.[Abstract]
7. Nguyen D, Mulder D, Shennib H. Warm ischemia induces alteration in lung immune cell function. J Thorac Cardiovasc Surg 1991;101:1030–6.[Abstract]
8. Berry GJ, Brunt EM, Chamberlain D, et al. A working formulation of the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. J Heart Transplant 1990;9:593–601.[Medline]
9. Alejandro R, Shienvold FL, Latif Z, Esqenazi V, Miller J, Mintz DH. Monoclonal antibodies recognizing canine and human Ia-like antigens. Transplantation 1984;38:542–4.[Medline]
10. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–9.[Abstract/Free Full Text]
11. Serrick C, Adoumie R, Giaid A, Shennib H. The early release of interleukin 2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. Transplantation 1994;58:1158–62.[Medline]
12. Cohen A, Batra G. Bronchoscopy and lung lavage induced bilateral pulmonary neutrophil influx and blood leukocytosis in dogs and monkeys. Am Rev Respir Dis 1980;122:239–47.[Medline]
13. Chang S, Hsu H, Perng R, Shiao G, Lin C. Increased expression of MHC class II antigens in rejecting canine lung allografts. Transplantation 1990;49:1158–63.[Medline]
14. Miller L, Naftel D, Bourge R, Kirklin J, Brozena S. Infection after heart transplantation: a multi-institutional analysis. J Heart Lung Transplant 1994;13:381–92.[Medline]
15. Trinchieri G, Perussia B. Immune interferon: a pleiotropic lymphokine with multiple effects. Immunol Today 1985;6:131–6.
16. Flyer D, Burakoff S, Faller D. Retrovirus-induced changes in major histocompatibility complex antigen expression influence susceptibility to lysis by cytotoxic T lymphocytes. J Immunol 1985;135:2287–92.[Abstract]
17. Klausner JM, Paterson IS, Goldman G, et al. Interleukin-2-induced lung injury is mediated by oxygen free radicals. Surgery 1991;109:169–75.[Medline]
18. Romaniuk A, Prop J, Petersen A, Wildevuur C, Nieuwenhuis P. Expression of class II major histocompatibility complex antigens by bronchial epithelium in rat lung allografts. Transplantation 1987;44:209–14.[Medline]
19. Nayler WG, Poole-Wilson PA, Williams A. Hypoxia and calcium. J Mol Cell Cardiol 1979;11:683–706.[Medline]
20. Cooper JD, Vreim CE. NHLBI workshop summary. Biology of lung preservation for transplantation. Am Rev Respir Dis 1992;146:803–7.[Medline]
21. Paull DE, Keagy BA, Kron EJ, Wilcox BR. Reperfusion injury in the lung preserved for 24 hours. Ann Thorac Surg 1989;47:187–92.[Abstract]
22. Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Med 1982;47:412–26.
23. Repine JE, Cheronis JC, Rodell TC, Linas SL, Patt A. Pulmonary oxygen toxicity and ischemia-reperfusion injury: a mechanism in common involving xanthine oxidase and neutrophils. Am Rev Respir Dis 1987:136:483–5.[Medline]

This article has been cited by other articles:

				A. S. McCourtie, A. S. Farivar, S. M. Woolley, H. E. Merry, P. S. Wolf, B. Mackinnon-Patterson, J. C. Keech, E. FitzSullivan, and M. S. Mulligan Alveolar Macrophage Secretory Products Effect Type 2 Pneumocytes Undergoing Hypoxia-Reoxygenation. Ann. Thorac. Surg., December 1, 2008; 86(6): 1774 - 1779. [Abstract] [Full Text] [PDF]

				M. L. Molitor-Dart, J. Andrassy, J. Kwun, H. A. Kayaoglu, D. A. Roenneburg, L. D. Haynes, J. R. Torrealba, J. L. Bobadilla, H. W. Sollinger, S. J. Knechtle, et al. Developmental Exposure to Noninherited Maternal Antigens Induces CD4+ T Regulatory Cells: Relevance to Mechanism of Heart Allograft Tolerance J. Immunol., November 15, 2007; 179(10): 6749 - 6761. [Abstract] [Full Text] [PDF]

				R. Stovold, I. A. Forrest, P. A. Corris, D. M. Murphy, J. A. Smith, S. Decalmer, G. E. Johnson, J. H. Dark, J. P. Pearson, and C. Ward Pepsin, a Biomarker of Gastric Aspiration in Lung Allografts: A Putative Association with Rejection Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1298 - 1303. [Abstract] [Full Text] [PDF]

				T. Goto, A. Ishizaka, F. Kobayashi, M. Kohno, M. Sawafuji, S. Tasaka, E. Ikeda, Y. Okada, I. Maruyama, and K. Kobayashi Importance of Tumor Necrosis Factor-{alpha} Cleavage Process in Post-Transplantation Lung Injury in Rats Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1239 - 1246. [Abstract] [Full Text] [PDF]

				A. Pereszlenyi, G. Lang, H. Steltzer, H. Hetz, A. Kocher, P. Neuhauser, W. Wisser, and W. Klepetko Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 858 - 863. [Abstract] [Full Text] [PDF]

				S. M. Fiser, C. G. Tribble, S. M. Long, A. K. Kaza, J. A. Kern, D. R. Jones, M. K. Robbins, and I. L. Kron Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome Ann. Thorac. Surg., April 1, 2002; 73(4): 1041 - 1048. [Abstract] [Full Text] [PDF]

				K. C. Mange, W. S. Cherikh, J. Maghirang, and R. D. Bloom A Comparison of the Survival of Shipped and Locally Transplanted Cadaveric Renal Allografts N. Engl. J. Med., October 25, 2001; 345(17): 1237 - 1242. [Abstract] [Full Text] [PDF]

				J.-M. CHARPIN, M. STERN, D. GRENET, and D. ISRAËL-BIET Insulinlike Growth Factor-1 in Lung Transplants with Obliterative Bronchiolitis Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 1991 - 1998. [Abstract] [Full Text]

This Article Abstract 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): Hani Shennib Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Serrick, C. Articles by Shennib, H. Search for Related Content PubMed PubMed Citation Articles by Serrick, C. Articles by Shennib, H.