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Ischemia-reperfusion injury
Ischemia-Reperfusion Injury N.L. Tilney, D. Paz, J. Ames, M. Gasser, I. Laskowski, and W.W. Hancock
T
HE OBSERVATION that the success of kidneys transplanted from living-unrelated sources is virtually identical to that of one haplotype-matched living-related donors and consistently better than those from cadavers must be based on nonspecific, antigen-independent variables. Allografted organs that experience early injury may not be biologically inert at the time of transplantation but are already inflamed and programmed to initiate or amplify subsequent host alloresponsiveness. Among several donorassociated factors, ischemia/reperfusion injury (I/R) may be the most important.1 An obvious manifestation of this initial result, at least in kidney transplantation, is initial delayed graft function (DGF), resulting from acute tubular necrosis. DGF affects about 20% to 30% of cadaver-donor kidneys and that number may be considerably higher in some units. The incidence of primary nonfunction is about 1 to 2%. The rate of these conditions may rise as more organs are removed from “marginal” or “extended” donors. I/R may also be an important component of the state of brain death, while the increasing use of non-heart-beating donors may also contribute. Long-term graft behavior may be affected by initial I/R injury. In one study, only 69% of renal allografts that had sustained early DGF functioned at 5 years compared to 79% of those that functioned immediately.2 In another series, 61% of those with initial ischemic injury functioned well at 1 year versus 84% of those with satisfactory early behavior. Well-controlled experimental studies have also shown that late functional and morphologic changes, indistinguishable from those associated with chronic rejection, are directly related to the primary nonspecific insult.3 The early insult upregulates a series of inflammatory events including the expression of major histocompatibility antigens. The increased immunogenicity of the injured organ amplifies the continuum between antigen-independent and antigen-dependent events and may explain the apparent synergy between ATN and acute rejection of renal allografts, which together produce worse results over both the short- and long-term than with either injury alone. In one series, for example, the 5-year survival rate of cadaver kidneys without either insult was 85%; that of grafts experiencing both was 60%; grafts undergoing one such injury, regardless of type, had intermediate results.4 © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
MOLECULAR AND CELLULAR EVENTS ASSOCIATED WITH I/R
I/R injury produces rapid changes in the affected tissues.5,6 Active ion transmembrane transport is inhibited, energyrich ATP stores are depleted, and calcium overload, disturbances in arachidonic acid metabolism, elevated production of vasoconstrictive agents, and increased leukocyte-endothelial cell and neutrophil-neutrophil interactions occur. Endothelial cell swelling secondary to influx of ions and water from the intravascular space impinge on the vascular lumina. Because of transmigration of water, circulating leukocytes, initially polymorphonuclear leukocytes (PMN) and subsequently T lymphocytes and macrophages, become stiffer and obstruct the microvasculature on resumption of the blood supply. Passive trapping and tangling of erythrocytes accentuate the process. These factors in combination obstruct flow after the circulation is restored, leading to additional ischemia and further damage to the already injured cells, the “no reflow” phenomenon. Although reperfusion with oxygenated blood is necessary for the viability of ischemic tissue, it may also produce cell injury and death, activating both the vascular endothelium and circulating leukocytes and triggering the adhesion molecule/cytokine cascade via production of oxygen free radicals. These, in turn, may arise from several sources, including injured leukocytes and endothelial cells via mitochondria and microsomal transport systems, intracellular generation by autooxidation of endogenous substrates, and by activity of cytoplasmic enzymes. Inflammatory mediators include the endothelins, which are potent vasoconstrictors; platelet activating factor, which enhances vascular permeability; leukocyte adhesion; and the leukotrienes and thromboxanes, which are chemoattractants for granulocytes. A series of cytokines are also released within minutes of reperfusion, presumably both by activated endothelium and leukocytes. Cellular dynamics contribute to subsequent graft
From the Surgical Research Laboratory, Harvard Medical School and the Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts. Supported by USPHS grants 5 RO1 DK 46190-26 and PO1 AI 40152-05. Address reprint requests to Dr N.L. Tilney, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02115. 0041-1345/01/$–see front matter PII S0041-1345(00)02341-1 843
Transplantation Proceedings, 33, 843–844 (2001)
844
changes. P-selectin molecules are rapidly translocated to endothelial surfaces within 5 minutes of revascularization of the organ, initiating steps leading to tethering of PMNs to the vascular intima. These in turn, activate other leukocyte populations and promote expression of their products. The inflammatory effects of infiltrating PMNs in injured tissues is closely connected with their ability to produce and excrete free oxygen radicals, proteolytic enzymes, and various cytokines. PMNs peak in injured tissues within 6 hours and may remain active for several days. T lymphocytes and macrophages, presumably recruited by ongoing inflammatory activity, enter the tissue after about 3 days. Activated T cells also orchestrate host alloresponsiveness. Infiltrating macrophages may activate T cells via their role as antigen presenting cells and by upregulating the expression of
TILNEY, PAZ, AMES ET AL
various surface accessory molecules. This population may also influence long-term graft changes by elaboration of fibrosis inducing cytokines.
REFERENCES 1. Chertow GM, Milford EL, Mackenzie HS, et al: JAMA 276:1732, 1997 2. Troppmann C, Gillingham KJ, Benedetti E, et al: Transplant 59:962, 1995 3. Azuma H, Nadeau KC, Takada M, et al: Transplant 64:190, 1997 4. Naimark DMJ, Cole E: Transplant Rev 3:93, 1994 5. Jassem W, Roake JA: Transplant Rev 12:14, 1998 6. Land W, Messmer K: Transplant Rev 10:108, 1996
T
HE OBSERVATION that the success of kidneys transplanted from living-unrelated sources is virtually identical to that of one haplotype-matched living-related donors and consistently better than those from cadavers must be based on nonspecific, antigen-independent variables. Allografted organs that experience early injury may not be biologically inert at the time of transplantation but are already inflamed and programmed to initiate or amplify subsequent host alloresponsiveness. Among several donorassociated factors, ischemia/reperfusion injury (I/R) may be the most important.1 An obvious manifestation of this initial result, at least in kidney transplantation, is initial delayed graft function (DGF), resulting from acute tubular necrosis. DGF affects about 20% to 30% of cadaver-donor kidneys and that number may be considerably higher in some units. The incidence of primary nonfunction is about 1 to 2%. The rate of these conditions may rise as more organs are removed from “marginal” or “extended” donors. I/R may also be an important component of the state of brain death, while the increasing use of non-heart-beating donors may also contribute. Long-term graft behavior may be affected by initial I/R injury. In one study, only 69% of renal allografts that had sustained early DGF functioned at 5 years compared to 79% of those that functioned immediately.2 In another series, 61% of those with initial ischemic injury functioned well at 1 year versus 84% of those with satisfactory early behavior. Well-controlled experimental studies have also shown that late functional and morphologic changes, indistinguishable from those associated with chronic rejection, are directly related to the primary nonspecific insult.3 The early insult upregulates a series of inflammatory events including the expression of major histocompatibility antigens. The increased immunogenicity of the injured organ amplifies the continuum between antigen-independent and antigen-dependent events and may explain the apparent synergy between ATN and acute rejection of renal allografts, which together produce worse results over both the short- and long-term than with either injury alone. In one series, for example, the 5-year survival rate of cadaver kidneys without either insult was 85%; that of grafts experiencing both was 60%; grafts undergoing one such injury, regardless of type, had intermediate results.4 © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
MOLECULAR AND CELLULAR EVENTS ASSOCIATED WITH I/R
I/R injury produces rapid changes in the affected tissues.5,6 Active ion transmembrane transport is inhibited, energyrich ATP stores are depleted, and calcium overload, disturbances in arachidonic acid metabolism, elevated production of vasoconstrictive agents, and increased leukocyte-endothelial cell and neutrophil-neutrophil interactions occur. Endothelial cell swelling secondary to influx of ions and water from the intravascular space impinge on the vascular lumina. Because of transmigration of water, circulating leukocytes, initially polymorphonuclear leukocytes (PMN) and subsequently T lymphocytes and macrophages, become stiffer and obstruct the microvasculature on resumption of the blood supply. Passive trapping and tangling of erythrocytes accentuate the process. These factors in combination obstruct flow after the circulation is restored, leading to additional ischemia and further damage to the already injured cells, the “no reflow” phenomenon. Although reperfusion with oxygenated blood is necessary for the viability of ischemic tissue, it may also produce cell injury and death, activating both the vascular endothelium and circulating leukocytes and triggering the adhesion molecule/cytokine cascade via production of oxygen free radicals. These, in turn, may arise from several sources, including injured leukocytes and endothelial cells via mitochondria and microsomal transport systems, intracellular generation by autooxidation of endogenous substrates, and by activity of cytoplasmic enzymes. Inflammatory mediators include the endothelins, which are potent vasoconstrictors; platelet activating factor, which enhances vascular permeability; leukocyte adhesion; and the leukotrienes and thromboxanes, which are chemoattractants for granulocytes. A series of cytokines are also released within minutes of reperfusion, presumably both by activated endothelium and leukocytes. Cellular dynamics contribute to subsequent graft
From the Surgical Research Laboratory, Harvard Medical School and the Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts. Supported by USPHS grants 5 RO1 DK 46190-26 and PO1 AI 40152-05. Address reprint requests to Dr N.L. Tilney, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02115. 0041-1345/01/$–see front matter PII S0041-1345(00)02341-1 843
Transplantation Proceedings, 33, 843–844 (2001)
844
changes. P-selectin molecules are rapidly translocated to endothelial surfaces within 5 minutes of revascularization of the organ, initiating steps leading to tethering of PMNs to the vascular intima. These in turn, activate other leukocyte populations and promote expression of their products. The inflammatory effects of infiltrating PMNs in injured tissues is closely connected with their ability to produce and excrete free oxygen radicals, proteolytic enzymes, and various cytokines. PMNs peak in injured tissues within 6 hours and may remain active for several days. T lymphocytes and macrophages, presumably recruited by ongoing inflammatory activity, enter the tissue after about 3 days. Activated T cells also orchestrate host alloresponsiveness. Infiltrating macrophages may activate T cells via their role as antigen presenting cells and by upregulating the expression of
TILNEY, PAZ, AMES ET AL
various surface accessory molecules. This population may also influence long-term graft changes by elaboration of fibrosis inducing cytokines.
REFERENCES 1. Chertow GM, Milford EL, Mackenzie HS, et al: JAMA 276:1732, 1997 2. Troppmann C, Gillingham KJ, Benedetti E, et al: Transplant 59:962, 1995 3. Azuma H, Nadeau KC, Takada M, et al: Transplant 64:190, 1997 4. Naimark DMJ, Cole E: Transplant Rev 3:93, 1994 5. Jassem W, Roake JA: Transplant Rev 12:14, 1998 6. Land W, Messmer K: Transplant Rev 10:108, 1996