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Ann Thorac Surg 1996;62:866-872
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Major Histocompatibility Complex Expression and Lung Ischemia-Reperfusion in Rats

Divisions of Thoracic Surgery and Respirology, and Department of Immunology, University of Toronto and The Toronto Hospital, Toronto, Ontario, Canada

Accepted for publication May 1, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Clinical studies in kidney and liver transplantation have suggested that poor early function is associated with increased graft loss due to rejection. Ischemia-reperfusion injury may contribute to rejection by enhancing graft immunogenicity.

Methods. A rat model of unilateral in situ pulmonary ischemia-reperfusion was used to examine class II major histocompatibility complex (MHC) antigen expression. The effects of deflation during ischemia (which augments subsequent injury) as well as concurrent allostimulation were also examined. Major histocompatibility complex expression was examined 9 days after ischemia using the binding of radiolabeled anti-class II antibody and immunohistochemistry.

Results. Four hours of ischemia in full inflation or 2 hours of atelectatic ischemia both led to severe lung injury. Ischemia-reperfusion injury led to greater MHC expression in the ischemic lung compared with the nonischemic side. Allostimulation with mononuclear cells did not increase MHC expression in the nonischemic lung but did enhance the increase found in the ischemic lung. This was not due to a graft-versus-host response because allostimulation with F₁ cells also led to a significant increase.

Conclusions. Severe ischemic lung injury leads to significant increases in MHC expression, detectable after 9 days of reperfusion. Deflation during ischemia, which augments lung injury, also augments increased MHC expression. Concurrent allostimulation with foreign mononuclear cells appears to potentiate increased MHC expression after ischemia. Increases in graft MHC expression may enhance immunogenicity and increase the rejection response.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Lung transplantation has become an accepted and increasingly popular option for end-stage lung disease. However, infection and rejection remain significant problems. Current lung preservation technique includes pulmonary vasodilation with prostaglandin and pulmonary vascular flush with cold crystalloid solutions, usually Euro-Collins. The importance of keeping the lungs well inflated during ischemia has also recently been appreciated [1]. During lung preservation for transplantation and in other forms of ischemia-reperfusion injury, there are increases in both pulmonary vascular resistance and capillary permeability that lead to alveolar edema, hemorrhage, and poor gas exchange [2]. There is also a significant cellular influx and the production of cytokines [3], some of which are capable of regulating major histocompatibility complex (MHC) expression.

The MHC is a set of genes that are critical for self-nonself discrimination. Class II MHC antigens present target peptides to CD4+ (helper) T cells, and increased MHC expression can enhance T cell responses. Increased class II expression is found in rejecting allografts, including lungs [4], and usually precedes rejection. Class II expression is regulated by cytokines that might be present in rejection, such as interferon- (IFN) [5], or might be found after ischemic or other injury, such as tumor necrosis factor- [6]. However, the role of ischemia-reperfusion injury in pulmonary MHC expression is unknown.

A number of studies have suggested that poor initial organ function, presumably due to ischemia-reperfusion injury, is correlated with higher rates of graft loss due to rejection [7, 8]. One possible explanation is that ischemia-reperfusion enhances the immunogenicity of the graft. Indeed, increased class I and II MHC expression on renal tubular epithelium has previously been noted in a mouse model of unilateral ischemia-reperfusion injury [9, 10]. The current study was undertaken to examine the effect of unilateral ischemia-reperfusion on pulmonary class II MHC expression. We found that ischemia-reperfusion injury increased MHC expression and that this increased expression was more in keeping with the severity of injury rather than simply the duration of ischemia. We also found that allostimulation concurrent with ischemia-reperfusion significantly enhanced the increase in MHC expression.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Surgical Models
Male Brown Norway (BN) rats (Harlan Sprague Dawley Inc, Indianapolis, IN) were used in pulmonary ischemia experiments. Both Lewis (LEW) (Charles River Canada Inc, St. Constant, Que, Canada) and LEWxBN F₁ (Harlan Sprague Dawley) rats were used as a source of allogeneic mononuclear cells. Animals were anesthetized with halothane (Halocarbon Laboratories Inc, North Augusta, SC), intubated, and ventilated with 50% oxygen and 1% to 1.5% halothane. A left thoracotomy was performed through the fifth intercostal space. For in situ ischemia, a medium Ligaclip (Ethicon, Peterborough, Ont, Canada) was applied to the hilum, occluding bronchus, artery, and vein. The chest was closed and the animal was extubated and allowed to recover in 50% oxygen. For experiments involving deflation, the hilum was clamped at end-expiration instead of end-inspiration and the animal recovered in room air, to encourage the transpleural absorption of oxygen from the lung to promote complete atelectasis. After the ischemic period, the animal was reanesthetized, the thoracotomy reopened, and the Ligaclip removed. The lung was gently reinflated, if necessary, and the airway suctioned before closing the chest for the second time. After long ischemic periods, copious edema was found in the airway and repeated suctioning was required to ensure survival of the animal. Sham animals underwent identical surgical manipulation without hilar clamping. The animals were sacrificed and the lungs removed 9 days after the operation because preliminary data suggested that increases in MHC expression would be detectable at that time.

Allostimulation
To mimic the cytokine milieu of allograft implantation, we injected animals with irradiated foreign mononuclear cells at the time of ischemia-reperfusion injury. Lewis or LEWxBN F₁ rats were killed with sodium pentobarbital (MTC Pharmaceuticals, Cambridge, Ont, Canada) and their spleens were removed. A suspension of mononuclear cells was prepared by gently passing spleen tissue through a wire mesh followed by density gradient centrifugation on Ficoll-Paque (Pharmacia LKB, Uppsala, Sweden). Cells from the interface were resuspended in Hanks' balanced salt solution (H2387; Sigma Chemical Co, St. Louis MO) at 10⁷ cells/mL and irradiated with 15 Gy. Cell viability was greater than 90% by trypan blue exclusion. Cells were resuspended at 10⁸ cells/mL and 10⁸ cells injected were into the azygos vein after release of the hilar clamp.

A second series of operations (series B) was performed to eliminate several potential artefacts. These experiments were performed under sterile conditions, as opposed to the initial set of experiments (series A), which were performed under clean but not sterile conditions. To rule out spillage of injected allogeneic cells into the left pleural space, in the second group of experiments (series B) the cells were injected into the dorsal vein of the penis before occlusion of the pulmonary artery. In addition, LEWxBN F₁ rather than LEW rats were used as cell donors to eliminate the possibility of a graft-versus-host response.

Antibodies
MRC-OX6 (Cedarlane Labs, Hornsby, Ont, Canada) is a monoclonal immunoglobulin G₁ mouse anti-rat MHC class II antibody directed against RT1^b [11]. Isotype-matched affinity-purified monoclonal controls and peroxidase-conjugated goat–anti-mouse immunoglobulin G were also obtained from Cedarlane.

Radiolabeled Antibody Binding Assay
Quantification of MHC antigens was performed using a modified radiolabeled antibody binding technique [9]. OX6 was purified on a protein A column and labeled with iodine 125 (Amersham Canada Ltd, Oakville, Ont, Canada) using chloramine T [11]. The control antibody was purchased already purified and therefore was directly labeled. Both were diluted to an activity of between 1 and 1.25 x 10⁶ counts per minute (cpm)/mL. The entire lung (to avoid regional sampling variation) was homogenized with a Polytron (Brinkman Instruments (Canada) Ltd, Rexdale, Ont, Canada) for 30 seconds, and centrifuged at 27,000 g, and the pellet was stored frozen until assayed. A small quantity of thawed homogenate was weighed and a sufficient amount of phosphate-buffered saline solution added to result in a concentration of 10 mg/mL. This was then homogenized for 15 seconds. Triplicate samples of 300 µL of this suspension were added to microcentrifuge tubes and centrifuged at 4,000 g for 6 minutes, and the supernatant was aspirated. The pellet was resuspended in 100 µL of radiolabeled antibody for 1 hour at 0°C with shaking. One milliliter of cold PBS was added and the tubes were again centrifuged (4,000 g for 6 minutes) and the supernatants aspirated. The pellets and tubes were then counted in a gamma counter (Gamma 5500; Beckman Instruments (Canada), Mississauga, Ont, Canada). Because OX6 reacts with all rat strains, nonspecific binding was calculated using 3 mg of homogenized rabbit lung. These counts were subtracted from all results before analysis.

Immunohistochemistry
At sacrifice, some lungs were gently filled with cryostat mounting compound (OCT compound 4538; Miles, Elkhart, IN) and frozen sections, 6 to 7 µm thick, were cut. Sections were fixed in acetone (Anachemia, Toronto, Ont, Canada) at -20°C for 10 minutes, washed in phosphate-buffered saline solution, blocked in 10% normal goat serum for 30 minutes, and incubated with OX6 for 60 minutes at room temperature. After washing in phosphate-buffered saline solution, the sections were incubated with a second goat–anti–mouse peroxidase-conjugated antibody for 30 minutes and washed in Tris-buffered saline solution. The color was developed with 3-3-diaminobenzidine (D5673; Sigma) and H₂O₂ before light counterstaining with hematoxylin (BDH, Toronto, Ont, Canada). Negative control slides were prepared with omission of the primary antibody. Positive control slides were prepared from 3 animals that had undergone left lung allotransplantation from LEW donors into BN recipients. For these studies, an operative microscope was used to perform orthotopic left lung transplantation using a cuff technique [12]. No immunosuppression was used, and the animals were sacrificed on the fourth postoperative day.

Statistics
Each figure represents a single assay only. As the specific activity of each batch of labeled antibody decreased over time, the cpm bound to normal lung decreased. Results from independent assays were analyzed using the SAS software program (SAS Institute, Cary, NC). Analysis of variance was used to compare the right or left lung in each group with the right or left lung in normal, unoperated rats. Whenever the overall F value was significant, Fisher's least significant difference test was used to compare multiple groups. Paired t tests were used to compare right and left lungs in the same animals. All data are expressed in the text as percentage of the treated (left) lung MHC class II antigen expression over the untreated (right) lung. Graphs were prepared using mean ± standard error of the mean.

Animal Care
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research, the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23, revised 1985), and the "Guide to the Care and Use of Experimental Animals" formulated by the Canadian Council of Animal Care. All protocols were approved by the Animal Care Committee of the Toronto Hospital, General Division.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Table 1 summarizes the series and groups in this study. In the first series (series A), 65 rats underwent thoracotomy and hilar dissection and there were nine technical problems (pneumothorax and lacerated pulmonary artery or vein). Only animals that survived for at least 30 minutes and had normal chest wall motion by visual inspection were included in the survival rate calculations. All animals that died within 30 minutes had evidence of pneumothorax at autopsy. In series B (ie, sterile operating conditions and allostimulation before ischemia, via the dorsal vein of the penis), 28 rats were used with two technical problems.

View larger version (14K): [in this window] [in a new window]   Fig 1. . Survival after ischemia-reperfusion lung injury and the effect of deflation. Survival is decreased due to increased lung injury in animals treated with 4 hours of ischemia and, to a greater degree, in animals treated with 2 hours of ischemia while the lung was atelectatic.

View larger version (17K): [in this window] [in a new window]   Fig 2. . Ischemia-reperfusion injury increases pulmonary major histocompatibility complex expression. At 9 days after injury there is a significant increase in binding of radiolabeled anti-class II antibody to the injured left lung compared with the nonischemic right lung (n = 5 in all groups). (*p < 0.01 by analysis of variance compared with normal left lung and also by paired t test compared with matched nonischemic right lungs.) (CPM = counts per minute.)

View larger version (18K): [in this window] [in a new window]   Fig 3. . Duration of ischemia increases the degree of major histocompatibility complex expression. Significant increases in binding of radiolabeled anti-class II antibody are seen after 4 hours of ischemia(*p < 0.05), whereas lesser increases are seen after 2 hours of ischemia in the inflated state (n = 5 in all groups). (CPM = counts per minute.)

Deflation During Ischemia Decreases Survival and Increases MHC Expression
In a separate assay shown as Figure 4, 2 hours of ischemia produced a 60.5% increase in OX6 binding (p = 0.085 versus normal left lung), whereas a 117% increase was found after 2 hours of ischemia in the deflated state (p = 0.015). This large increase was almost as great as that seen after allostimulation (see below).

View larger version (17K): [in this window] [in a new window]   Fig 4. . Deflation during ischemia augments increased class II expression. There is significant binding of anti-class II antibody to the left lung after atelectatic injury, which is larger and more significant than after 2 hours of inflated ischemia (n = 5 in all groups). (CPM = counts per minute; *p = 0.085 by analysis of variance compared with normal left lung; **p = 0.015.)

View larger version (21K): [in this window] [in a new window]   Fig 5. . Allostimulation acts in combination with ischemia to increase class II major histocompatibility complex expression. Binding of radiolabeled anti-class II antibody is much greater after ischemia with concurrent allostimulation with Lewis mononuclear cells than after either ischemia alone or sham ischemia and allostimulation (n = 5 in all groups). (*p = 0.085 by analysis of variance compared with normal left lung;**p = 0.002 by paired t test compared with matched right lung and p = 0.0001 by analysis of variance compared with normal left lung.)

View larger version (23K): [in this window] [in a new window]   Fig 6. . Effect of allostimulation is not due to graft-versus-host disease. Similar large increases are seen in class II expression after allostimulation with either Lewis or Lewis x Brown Norway F1 mononuclear cells and 2 hours of ischemia followed by 9 days of reperfusion (n = 5 in all groups except where indicated). (*p = 0.0003 by analysis of variance compared with normal left lung; **p = 0.005 by paired t test over matched right lung and p < 0.0001 by analysis of variance compared with normal left lung.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Under normal circumstances, the majority of class II expression is constitutive; however, in a variety of disease states, inducible expression appears to be important. Increased class I and II MHC antigen expression has been described in a variety of other pulmonary injury models, such as chronic bronchiectasis [14], asbestosis [15], silicosis [16], and bleomycin-induced lung injury [17]. Increased class II was found on both alveolar type II cells and bronchial epithelium, but the exact mechanism for increased expression in these models has not yet been determined. The most potent regulator of MHC expression is IFN, a product of activated T cells. In vitro studies have shown that MHC gene transcription is upregulated by IFN [5]. In vivo injection of IFN in mice also leads to increased MHC expression, including a twofold to threefold increase in the level of class II in lung tissue [18]. Tumor necrosis factor- [6] and interleukin-4 [19] also increase class II expression. Catecholamines, which are probably released after this degree of acute lung injury, have a synergistic effect on class II expression, at least on brain capillary endothelial cells [20]. After implantation of a lung allograft, recipient T cells will become activated and probably produce IFN both systemically and within the lung. Injection of allogenic cells was used to simulate the cytokine milieu of transplantation. We speculate that, in our studies, catecholamines, tumor necrosis factor, and other cytokines released by cells within the lung as a consequence of ischemia-reperfusion injury acted together with IFN released after the injection of allogenic cells to enhance the expression of MHC. In our model of injected foreign cells, pulmonary levels of IFN are probably lower than after lung transplantation and increases in MHC expression after ischemic injury in the context of lung allografting might be even larger.

We were not able to localize increases in class II expression to any specific cell type in lung tissue. Bronchial epithelium and capillary endothelium remained negative. This was not due to technical limitations, because we were able to demonstrate that rejection of rat lung allografts was associated with massive increases in MHC class II expression on the bronchial epithelium, as has been previously reported [13]. Previous studies have documented that alveolar macrophages [21] and alveolar type II cells [22] have both constitutive and IFN-inducible class II expression, whereas bronchial epithelial cells are capable of MHC expression only after IFN exposure, such as during allograft rejection [13]. In contrast to other species, MHC expression has not been reported on rat pulmonary capillary endothelium. In the absence of definitive immunohistochemical localization, we cannot distinguish between recruitment of class II-positive cells into the lung, quantitative increases in expression by previously class II-positive cells, or induction of class II on previously negative cells. Indeed, it is likely that several such mechanisms operate simultaneously.

Although class I and class II expression on endothelial and a variety of epithelial cell types frequently accompanies allograft rejection, its significance remains controversial. Biopsy material has demonstrated class II expression in human renal, cardiac, liver, and lung allografts [23]. However, in some animal models of prolonged allograft survival, there can be increased MHC expression without allograft rejection [24]. In vitro evidence suggests that quantitative differences in MHC expression might influence rejection. The cytotoxicity of CD8⁺ T cells is proportional to the quantity of MHC class I expressed on the target cell surface. Similarly, the effectiveness of cells presenting antigen to CD4⁺ T cells increases with increased levels of MHC class II expression. There is also in vivo evidence that MHC expression is relevant to the strength or timing of rejection. Rat heart vascular endothelial cells, after MHC induction with IFN, are able to provoke the rejection of heart allografts, in contrast to untreated endothelial cells [25].

In summary, we have shown that severe pulmonary injury due to warm ischemia and reperfusion is associated with significant increases in class II MHC expression. Atelectasis during ischemia enhances the degree of lung injury and also the increase in MHC expression. Increased class II MHC expression is not associated with class II induction on the bronchial epithelium. Injection of foreign mononuclear cells, to mimic the cytokine milieu associated with allograft implantation, was strongly synergistic with ischemia-reperfusion injury in increasing MHC expression. This may enhance the immunogenicity of the graft and may be one factor explaining the clinical relationship between ischemia-reperfusion injury and long-term graft outcome.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported by the Medical Research Council of Canada and the Canadian Cystic Fibrosis Foundation.

We are grateful for the helpful comments of Professor Judy Wade and the excellent technical assistance of John Mates, Yan-Chun Wang, and Stephanie Diamant.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Slutsky, Mount Sinai Hospital, 600 University Ave, #656A, Toronto, Ont M5G 1X5, Canada.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Waddell, T. K. Articles by Slutsky, A. S. Search for Related Content PubMed PubMed Citation Articles by Waddell, T. K. Articles by Slutsky, A. S.