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Ann Thorac Surg 1996;62:302-314
© 1996 The Society of Thoracic Surgeons

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Current Review

Lung Preservation: The Importance of Endothelial and Alveolar Type II Cell Integrity

Transplantation-Immunobiology Group, Robarts Research Institute, and Division of Cardiovascular-Thoracic Surgery, London Health Sciences Centre, London, Ontario, Canada

	Abstract

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
The practice of lung transplantation is constrained by a shortage of suitable donor organs. Furthermore, even "optimal" donor lung grafts are at risk of significant dysfunction perioperatively. Significant insights into the cellular and molecular mechanisms of pulmonary ischemia-reperfusion injury have occurred since the publication of previous reviews on lung preservation 3 to 4 years ago. Recent evidence indicates that the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction and is a major target during lung injury. In addition, the composition, function, and metabolism of pulmonary surfactant produced by alveolar type II cells are increasingly being recognized as important factors in pulmonary ischemia-reperfusion injury. We hypothesize that reperfusion after a period of pulmonary ischemia results in significant endothelial and alveolar type II cell dysfunction and that an important strategy in lung preservation is to preserve the integrity of these cells in the face of this injury. Given the persistent shortage of lungs available for transplantation, laboratory studies need to focus also on the "rescue" of compromised donor lungs that would have been previously regarded as unsuitable. Importantly, innovative work from the laboratory needs to be translated into clinical practice via prospective, randomized trials to ensure that the prevalence of postoperative lung graft dysfunction is reduced and the shortage of lung grafts for transplantation is alleviated.

	Introduction

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
Since the publication of recent review articles on lung graft preservation [1, 2], significant progress has been made in understanding the complex molecular events that modulate ischemia-reperfusion lung injury. Despite this increased knowledge, transplanted lungs remain vulnerable to perioperative injury, and severe graft dysfunction occurs in 10% to 20% of lung transplant recipients. Primary lung graft dysfunction results clinically in progressive hypoxemia, decreased pulmonary compliance, high permeability pulmonary edema, and widespread alveolar densities on chest radiographs; transbronchial biopsies characteristically show histologic features of diffuse alveolar damage [3]. Although severe graft dysfunction can be reversible, it is often associated with the need for prolonged intensive care and increased mortality. Recent evidence indicates that prolonged mechanical ventilation due to lung graft dysfunction may result in adverse long-term consequences such as a higher prevalence of airway healing complications after lung transplantation [4]. Ischemia-reperfusion injury may also predispose grafts to early rejection via upregulation of class II major histocompatibility complex antigens [5] or increased local production of cytokines [6], although this issue remains controversial [7]. Nonetheless, clinical studies have revealed that significant upregulation of inflammatory mediators during the immediate postoperative period is predictive of worse graft and patient survival after lung transplantation [8].

Although lung graft ischemic times of more than 6 hours are now commonplace in clinical practice, recent registry reports have confirmed that the number of lung transplant procedures performed worldwide has plateaued since 1993 [9]. Studies have revealed that only 10% to 25% [10, 11] of multiorgan donors have lungs that are potentially suitable for transplantation. Although the successful outcome of lung transplantation is not compromised if donor lungs with mild hypoxemia, chronic tobacco exposure, or a minor contusion or infiltrate are used [11], this practice has not yet significantly affected the donor organ shortage. New strategies to improve the preservation of more severely injured lung grafts are essential to expand the donor pool.

This review highlights the advances in lung preservation research that have occurred during the past 4 years, with emphasis on an increased understanding of the mechanisms of lung injury before, during, and after transplantation.

	Donor Lung Injury Before Harvest

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
Many donor lungs exhibit severe hypoxemia and diffuse infiltrates on chest roentgenograms due to edema, infection, aspiration, contusion, or ventilator-induced injury. The high-permeability pulmonary edema that is prevalent in many lung donors often results from neurogenic edema, with or without concomitant iatrogenic overhydration. Neurogenic pulmonary edema occurs after a sudden, massive sympathetic neural discharge, which engenders a "blast injury" to the pulmonary circulation and may disrupt the anatomic integrity of the pulmonary capillaries [12]. Recent studies using Fourier analysis have confirmed that in the hours after brain death pulmonary vascular impedance and resistance decreased significantly, in concert with significant increases in right ventricular hydraulic power and pulmonary artery blood flow [13]. These changes, along with increases in systemic and pulmonary vascular pressures, may lead to pulmonary endothelial cell injury, impaired lymphatic drainage, and an increase in pulmonary extravascular lung water [13]. Even in donors who do not have overt lung injury by standard criteria, measurements of intrapulmonary shunt may be highly abnormal and fiberoptic bronchoscopy may reveal aspiration of a significant volume of gastric contents or blood [14]. A significant number of cases of "severe ischemia-reperfusion injury" probably result from evolving donor lung dysfunction that was not readily apparent during the preharvest assessment.

Brainstem death develops in most multiorgan donors as a result of spontaneous intracerebral bleeding or severe head injury. Prospective studies of patients with multiple trauma (without lung contusion) have revealed significant alterations in pulmonary surfactant, including decreased concentrations of phosphatidylcholine and phosphatidylglycerol and increased concentrations of cell membrane lipids in bronchoalveolar lavages [15]. In addition, animal studies have shown that hypovolemic shock results in microvascular pulmonary occlusion by platelet and leukocyte aggregates, pulmonary endothelial injury and pulmonary parenchymal neutrophil sequestration [16, 17]. A recent clinical report has documented significant increases in serum tumor necrosis factor-alpha (TNF) and interleukin (IL)-1 beta levels early after severe blunt trauma, followed by an increase in the concentration of IL-6 [18], all of which can subsequently cause pulmonary endothelial dysfunction. The fact that vascular adhesion molecules and major histocompatibility complex class I and class II antigens are easily detectable in stored, but not reperfused, donor lungs may indicate that these proteins had been upregulated in organ donors before procurement [19]. Further research on pulmonary endothelial cell physiology and on the function, composition, and metabolism of surfactant in organ donors is required, to devise strategies to minimize preharvest dysfunction in lung grafts.

	Mechanisms of Pulmonary Ischemia-Reperfusion Injury

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
During the past few years many of the cellular and molecular events modulating the inflammatory response to ischemia-reperfusion injury have been elucidated [20–22]. One of the critical steps mediating this injury is the interaction between white cells and the endothelium at the onset of reperfusion. Pulmonary endothelial cells interact with a complex system of adhesion molecules, including heterodimeric proteins such as integrins [20, 23] and membrane glycoproteins such as selectins [24]. A clear understanding of the lung injury literature has been hampered by the diverse nomenclature of selectins, which has interfered with the dissemination of information concerning their properties. Fortunately, the nomenclature of selectins has recently been standardized [25] and these proteins have been classified into three groups: E-selectin (previously known as ELAM-1), P-selectin (previously GMP-140 or PADGEM), and L-selectin (previously LEC.CAM-1, LECAM-1, LAM-1, or the MEL-14, Leu-8, TQ1 and DREG.56 antigens originally described on lymphocytes).

One of the events contributing to reperfusion injury is the migration of leukocytes out of pulmonary capillaries to induce an inflammatory response. Leukocyte extravasation is thought to occur in four steps [26] (Fig 1). The first of these is mediated by P-selectin, which is induced on endothelial cells within minutes of reperfusion, and E-selectin, which appears after a few hours. Both of these molecules recognize the sialyl-Lewis^x moiety on specific glycoproteins of leukocytes. The interaction of P-selectin and E-selectin with these surface glycoproteins permits weak adhesion of leukocytes to the vessel wall, so that the leukocytes "roll" along the endothelial surface. This weak adhesive interaction allows the stronger interactions of subsequent steps.

View larger version (62K): [in this window] [in a new window]   Fig 1. . During reperfusion injury leukocytes interact with pulmonary endothelial cells via a complex system of adhesion molecules such as integrins and selectins. The first step in this interaction (top panel) involves weak binding of leukocytes to the endothelium through interactions between selectins and their carbohydrate ligands on the leukocyte, shown here for E-selectin and its ligand the sialyl-Lewisx moiety (s-Lex). This weak binding does not anchor the cells against the shearing force of blood flow, and the leukocytes therefore roll along the endothelium. The weak binding does, however, permit stronger adhesive interactions, which occur as a result of the induction of ICAM-1 on the endothelium and the activation of its ligands LFA-1 and Mac-1 (not shown) on the leukocyte. Tight binding between these molecules allows the leukocyte to extravasate between the endothelial cells forming the wall of the blood vessel. The leukocyte integrins LFA-1 and Mac-1 are acquired for extravasation and for migration toward chemoattractants. Finally, the leukocyte migrates along a concentration gradient of chemokines (here shown as interleukin-8 [IL-8]) secreted by endothelial and other cells. (Reproduced from Janeway CA, Travers P. Immunobiology: the immune system in health and disease. New York/London: Garland/Current Biology, 1994:9–14, with permission.)

Studies during the past decade have revealed that many of the cellular and molecular processes in the lung are controlled by a vast network of cytokines, which function as extracellular signalling proteins [27, 28]. Cytokines such as IL-1 and TNF play critical roles in the inflammatory response to ischemia-reperfusion injury. Both of these cytokines cause endothelial cells to become markedly adhesive for neutrophils, eosinophils, basophils, and monocytes [26, 28]. Tumor necrosis factor- and IL-1 induce E-selectin expression, augment ICAM-1 expression, and cause the synthesis of platelet-activating factor [28]. Tumor necrosis factor-induced neutrophil stimulation results in increased neutrophil phagocytosis, respiratory burst activity, and degranulation, causing pulmonary vascular endothelial cell injury in vivo as well as in vitro [29]. Studies in animal lung transplant models have demonstrated the significant early release of TNF [6, 30], IL-2 [6], interferon- [6], and IL-6 [31] from bronchoalveolar lavages. Additional work has shown that IL-8, one of the major neutrophil chemotactic factors in the lung, is produced locally in high concentrations during reperfusion lung injury in rabbits; administration of a neutralizing monoclonal antibody against IL-8 prevented pulmonary neutrophil infiltration as well as histologic evidence of lung injury [32]. Other cytokines such as IL-10 have been found to decrease pulmonary ischemia-reperfusion injury in the rat [33], which is consistent with previous work showing that IL-10 inhibited the production of TNF, IL-1, IL-6, and IL-8 by cultured human monocytes [34]. It is thus evident that pulmonary ischemia-reperfusion injury has multifaceted effects on the complex cytokine network within the lungs and that the infusion of IL-10 or monoclonal antibodies directed against selected cytokines involved in the early stages of this injury may ultimately prove useful clinically, especially if administered before the onset of reperfusion.

Although the peak serum IL-6 level has been correlated with the severity of preservation injury in lung transplant patients [8], documentation of the levels of other cytokines in bronchoalveolar lavage and serum during the first few days after clinical lung transplantation has yet to be reported. However, an analysis of cytokine gene transcripts in transbronchial biopsies from human pulmonary allograft recipients has been recently published [35]. Serial analysis of these transcripts may yield valuable insights concerning the pathogenesis of acute graft dysfunction after lung transplantation.

	Pulmonary Ischemia-Reperfusion Injury: The "Neutrophil Controversy"

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
Pro: Neutrophils Are Important in Ischemia-Reperfusion Lung Injury
Recent studies have confirmed that lung dysfunction after storage and reperfusion is associated with significant direct cellular oxidant injury to lipids, protein, and DNA [36]. The extent to which neutrophils are essential participants in this process is a source of controversy. The number of neutrophils in the normal lung is approximately three times the circulating pool of neutrophils [37]. Previous work has shown that depletion of circulating neutrophils before the onset of reperfusion decreases lung injury [38]. However, this and other studies did not document the degree to which neutrophil depletion reduced the much larger pool of marginated neutrophils within the lung [37].

Evidence that neutrophils play an important role in the evolution of lung injury has been demonstrated by recent studies using monoclonal antibodies directed against the leukocyte integrins LFA-1 and Mac-1, the endothelial cell surface ligand ICAM-1, and L- and E-selectin. Laboratory experiments have revealed that monoclonal antibodies directed against Mac-1 mitigated the acute lung injury induced by TNF [39] and that antibodies against leukocyte CD18 and ICAM-1 prevented the increase in lung permeability and pulmonary neutrophil sequestration after prolonged pulmonary artery occlusion in rabbits [21, 22]. In a canine left lung transplant model, anti-CD18 monoclonal antibody administered just before reperfusion partially decreased lung injury during reperfusion after 4 hours of preservation [40]. Similar findings were noted in an ex vivo model of rabbit lung preservation after 18 hours of hypothermic storage [41]. In this model, high-dose anti–ICAM-1 antibody resulted in improved oxygenation during reperfusion, but in no significant differences in pulmonary vascular resistance, airway compliance, or lung weight as compared with untreated animals [41]. In a model of in situ lung ischemia in sheep, a monoclonal antibody that inhibited L- and E-selectin was shown to prolong survival, although oxygen tension, pulmonary vascular resistance, and intrapulmonary shunt were not significantly different from control animals during reperfusion [42]. Recently, a study in isolated rabbit lungs documented the ability of a new class of antiinflammatory agents called leumedins to inhibit neutrophil adhesion and to improve pulmonary function after long-term cold storage [43].

During reperfusion after pulmonary ischemia, neutrophils may contribute to lung injury in several ways [44, 45]. First, neutrophils can produce reactive oxygen metabolites such as the superoxide anion, hydroxyl radical, and hydrogen peroxide, which can damage pulmonary endothelium directly or indirectly [45]. Second, activated neutrophils are stiffer than quiescent cells, making them less prone to deformation as they circulate through the pulmonary capillaries and thus more likely to induce capillary plugging [37, 44]. Third, activated neutrophils can produce significant quantities of TNF, IL-1, IL-6, and IL-8 [46–48]. Fourth, neutrophils can generate leukotriene B₄, a potent chemotactic agent that activates neutrophils and promotes their adherence to the endothelium [49]. Finally, upon degranulation neutrophils release elastase and other proteases, which directly injure pulmonary endothelial and parenchymal cells [20, 44, 50]. Neutrophil protease inhibitors have been shown to attenuate lung injury after 2 hours of warm ischemia in dogs [51] and to improve compliance and lessen edema in isolated, perfused rabbit lungs subjected to 18 hours of cold ischemia [52].

Con: Ischemia-Reperfusion Lung Injury Can Occur by Neutrophil-Independent Mechanisms
Despite the fact that neutrophils play a multifaceted role in lung injury, studies in a rat lung model have demonstrated that neutrophils are not necessary for the induction of ischemia-reperfusion injury. Treatment of rats with an antineutrophil antibody that caused severe neutropenia did not decrease lung injury in vivo after 90 or 180 minutes of warm ischemia [53]. Additional experiments in which the reperfusion time was prolonged from 30 minutes to 4 hours confirmed that antineutrophil antibody had no protective effect against microvascular permeability at 30 minutes of reperfusion [44]. After the first hour of reperfusion, however, there was a gradual increase in microvascular permeability in control (nonneutropenic) animals, associated with a progressive increase in myeloperoxidase activity in the lung. Induced neutropenia significantly decreased lung injury at 4 hours of reperfusion in this model. The results of these studies indicated that ischemia-reperfusion lung injury in rats occurs in a bimodal pattern via early neutrophil-independent mechanisms and later neutrophil-mediated effects [44]. These studies would have been strengthened if the density of neutrophils in pulmonary parenchyma, in addition to the number of circulating neutrophils, were measured. Indeed, even after the depletion of circulating leukocytes, 100 to 200 neutrophils/mm² may remain in pulmonary tissue [37], thus contributing to endothelial injury early during reperfusion.

The observation that pulmonary ischemia-reperfusion injury can occur despite a marked reduction in circulating neutrophils is not surprising in view of the fact that isolated cultures of pulmonary artery endothelial cells can generate oxygen free radicals, which attack the endothelium directly [54]. Oxygen free radical-mediated injury has been shown to occur when rabbit lungs are stored at 10°C while inflated with 100% oxygen, before reperfusion with blood elements [55]. Moreover, other cells aside from neutrophils are known to release inflammatory mediators and participate in ischemia-reperfusion injury. For instance, mast cells increase significantly in number and degranulate after pulmonary ischemia and reperfusion, resulting in an increased release of thromboxane B₂ and leukotriene B₄ in bronchial lavages [56]. Alveolar macrophages are known to produce significant quantities of TNF and other cytokines in vitro, but the contribution of macrophage-produced cytokines to ischemia-reperfusion injury is not yet known. Importantly, pulmonary alveolar type II cells can secrete IL-6 [57] and IL-8 [58], both of which are important neutrophil chemotactic factors during lung injury. Pulmonary ischemia-reperfusion injury is sufficiently complex that no one cell type is essential for its induction, although neutrophils play a major role in amplifying the injury later during reperfusion.

	Endothelial Dysfunction During Pulmonary Ischemia-Reperfusion Injury

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
During the hypothermic storage of lung grafts, the first site of contact with preservation solutions is the pulmonary endothelium, which is markedly susceptible to preservation injury. Endothelial dysfunction is a critical early event during reperfusion and can be triggered within 2 to 3 minutes of the generation of a large burst of superoxide radicals [20, 59]. Endothelial injury during reperfusion is compounded by the activation of adhesion molecules on neutrophils, which bind to their corresponding ligands on activated endothelial cells. Once activated, neutrophils secrete second-generation oxygen free radicals such as hydrogen peroxide and the hydroxyl radical, cytokines and proteases that induce further endothelial dysfunction [20]. Recent studies in isolated rabbit [60] and porcine [61] pulmonary arteries have confirmed significant reductions in endothelial-mediated relaxation after lung ischemia and reperfusion.

Endothelial Protective Agents
Under basal conditions as well as during evolving lung injury, the function of the pulmonary endothelium depends on a dynamic balance between endothelial protective and proinflammatory substances (Fig 2). Three important protective agents produced by endothelial cells are prostacyclin, nitric oxide, and adenosine [20]. Prostacyclin is a potent eicosanoid that causes vasodilation, prevents neutrophil adherence, inhibits platelet aggregation, and stabilizes lysosomal membranes [62]. Prostacyclin has a half-life of 1 to 2 minutes and exerts its effects by activating adenylate cyclase, with a resultant increased production of cyclic adenosine monophosphate (AMP) [62, 63]. Nitric oxide is produced in endothelial cells by nitric oxide synthase, a calcium- and calmodulin-dependent enzyme [20]. The effects of nitric oxide are mediated by activation of guanylate cyclase, resulting in the formation of cyclic guanosine monophosphate (GMP) [64]. Nitric oxide has a shorter biological half-life than prostacyclin (10 to 20 seconds), is able to quench superoxide radicals produced by endothelial cells, and causes vasodilatation, decreased neutrophil adherence, and inhibition of platelet aggregation [20, 64, 65].

View larger version (18K): [in this window] [in a new window]   Fig 2. . The balance of endothelial cytoprotective agents and proinflammatory agents determines endothelial cell integrity or dysfunction during reperfusion after pulmonary ischemia. (cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate.)

ProInflammatory Agents Released by the Endothelium
In addition to cytoprotective agents, the endothelium generates substances that have a marked vasoconstrictor and thrombogenic effect, thus promoting cell injury. One of the most powerful vasoconstrictors produced by the pulmonary endothelium is endothelin-1, a 21-amino acid peptide that constricts vascular tissue by moderating dihydropyridine-sensitive calcium channels [20, 67]. In the presence of hypoxia, endothelin gene expression and endothelin secretion were markedly increased in cultured human endothelial cells [68, 69]. In rat lungs subjected to 60 minutes of warm ischemia and reperfusion, plasma endothelin-1 concentrations rose significantly and endothelin-1 messenger RNA expression increased in both the ischemic-reperfused left lung and the nonischemic native right lung [70]. Infusion of an endothelin receptor antagonist mitigated the decrease in oxygen tension and pulmonary neutrophil infiltration during reperfusion. However, endothelin receptor blockade did not completely prevent pulmonary damage, perhaps because only one of two known endothelin receptor antagonists was used in this study [70].

A second proinflammatory substance produced by pulmonary endothelial cells is the phospholipid platelet activating factor [20, 71]. Although platelet activating factor can induce vasodilatation in some vascular beds [20], it also causes the release of various leukotrienes and thromboxanes, all of which are vasoconstrictors [72]. Platelet activating factor is a strong stimulator of neutrophil exocytosis, migration, and superoxide production [73]. In addition, it induces airway constriction, pulmonary hypertension, and edema in isolated lungs, independent of platelets [74]. The net effect of platelet activating factor activity is a significant increase in vascular permeability and lung injury. In experimental lung [75] and heart-lung [76] transplant models, platelet activating factor antagonists significantly improved lung function during reperfusion. Platelet activating factor antagonists have been used in a small number of patients undergoing clinical lung transplantation (personal communication, Mr John Dark, November 1995), but the results of this trial have yet to be reported.

Aside from endothelin-1 and platelet activating factor, other substances can have a vasoconstrictor, thrombogenic, and proinflammatory effect in the setting of pulmonary ischemia-reperfusion injury. Recently, platelet-derived growth factor has been identified as a peptide vasoconstrictor released by endothelial cells in response to shear stress and hypoxia [69, 77]. In addition, superoxide radicals produced by neutrophils and endothelial cells cause the rapid inactivation of nitric oxide, thus promoting vasoconstriction and inflammation [20]. Decreased nitric oxide levels along with chemotactic factors such as leukotriene B₄ and C5a promote neutrophil recruitment and adherence to dysfunctional endothelium, amplifying the early events that promote cell injury during reperfusion [20].

	Strategies to Maintain Endothelial Cell Function During Ischemia-Reperfusion Injury

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
Cyclic Adenosine Monophosphate Supplementation
Cyclic AMP is an important intracellular second messenger that maintains endothelial cell function and inhibits the induction of procoagulant activity by various cytokines [78, 79]. When cultured pulmonary endothelial cells were exposed to hypoxia, adenylate cyclase activity and cyclic AMP levels decreased, in concert with an increase in endothelial permeability [80]. This change in endothelial cell barrier function was prevented by the addition of cyclic AMP analogues [80]. In addition, agents that increased intracellular cyclic AMP levels decreased pulmonary capillary permeability after ischemia-reperfusion injury in an isolated, blood-perfused rabbit lung model [81]. Furthermore, administration of a cyclic AMP analogue or use of a phosphodiesterase inhibitor resulted in improved lung function after 6 hours of hypothermic preservation in rats [82]. Given these impressive results in small animal models and the multifaceted beneficial effects of cyclic AMP on leukocyte-endothelial cell interactions [78], investigation of cyclic AMP supplementation of pulmonary flush solutions in a large animal model of ischemia-reperfusion injury is indicated.

Recent work in a canine left lung transplant model has demonstrated that a continuous prostaglandin E₁ infusion in the recipient, starting before reperfusion, was associated with improved oxygenation and less lung edema after transplantation [83]. There were no differences between prostaglandin E₁-treated animals and the control group in pulmonary vascular hemodynamics or graft neutrophil sequestration. The authors of that study speculated that prostaglandin E₁ improved posttransplantation lung function by virtue of its "cytoprotective effect." Nonetheless, previous work has indicated that prostaglandins exert many of their effects by activating adenyllate cyclase and increasing the intracellular production of cyclic AMP [63]. Further studies should be performed to elucidate the mechanisms by which prostaglandin E₁ induces its cytoprotective effects and to determine whether the cytoprotection engendered by prostaglandin E₁ is dependent on cyclic AMP.

Role of the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway in Lung Preservation
Endogenous nitric oxide maintains pulmonary vascular homeostatic properties by regulating neutrophil adherence, microvascular permeability, platelet aggregation, and vasomotor tone [84–86]. Endogenous and exogenous nitric oxide modulate the expression of the potent vasoconstrictors endothelin-1 and platelet-derived growth factor-ß by endothelium under basal conditions and during hypoxia [87]. Nitric oxide exerts its effects via activation of guanylate cyclase and the resultant formation of cyclic GMP [20, 64]. Recent studies have documented in a rat orthotopic lung transplant model that both nitric oxide and cyclic GMP levels decreased markedly at the onset of reperfusion [88]. Supplementation of the lung preservation solution with a cyclic GMP analogue resulted in improved oxygenation, decreased pulmonary vascular resistance, reduced neutrophil infiltration, and improved recipient survival [88, 89].

An alternative approach to cyclic GMP supplementation of lung preservation solutions is the stimulation of guanylate cyclase activity by exogenous nitric oxide, nitroglycerin, or nitroprusside. The ability of these agents to increase cyclic GMP levels was first noted almost 20 years ago [90]. Recently, inhaled nitric oxide has been used as a potent and selective pulmonary vasodilator in neonatal pulmonary hypertension [91], in children with pulmonary hypertension after the correction of congenital heart defects [92], in adult cardiac surgical patients [93], and in patients with adult respiratory distress syndrome [94]. In the setting of lung transplantation, nitric oxide is theoretically attractive because of its ability to quench superoxide radicals and protect pulmonary endothelial cell function. Nonetheless, the use of nitric oxide can have a "dark side" as a result of its combination with superoxide to form peroxynitrite [95]. Peroxynitrite can generate the highly toxic hydroxyl anion and is a strong oxidant in its own right; it readily catalyzes membrane lipid peroxidation, reacts with metals to form toxic nitrosylating species, and oxidizes sulfhydryl groups on cellular proteins [95, 96]. In a rat lung transplant model, inhaled nitric oxide failed to prevent hypoxemia, increased pulmonary vascular resistance, and pulmonary neutrophil infiltration after 6 hours of hypothermic storage, whereas addition of cyclic GMP to the flush solution had a marked pulmonary protective effect [89]. Moreover, the timing of nitric oxide delivery was found to be critical in an in vivo rat model of normothermic lung ischemia [97]. Inhaled nitric oxide delivered at the onset of reperfusion worsened injury at 30 minutes but reduced lung permeability and pulmonary neutrophil sequestration at 4 hours [97]. The increased lung injury at 30 minutes in this model could be avoided either by delaying nitric oxide therapy for 10 minutes or by treating the rats with superoxide dismutase before reperfusion, which indicates that the toxic effects of nitric oxide were due to its interaction with superoxide anions in the first few minutes of reperfusion. Recent work in a canine model of 18-hour lung preservation showed that inhaled nitric oxide, administered continuously at 60 to 70 parts per million during reperfusion, significantly improved oxygenation, although the oxygen tension/inspired oxygen fraction ratio decreased to less than 300 mm Hg toward the end of reperfusion [98]. There was a significant reduction in graft neutrophil infiltration when the lung was analyzed 6 hours after the onset of reperfusion [98].

In the setting of clinical lung transplantation, inhaled nitric oxide has been increasingly employed in the treatment of established postoperative graft dysfunction [99, 100]. In the first study, nitric oxide administration was begun in the intensive care unit at a dose of 80 parts per million in 6 patients with lung graft dysfunction; this dose resulted in a significant decrease in pulmonary artery pressure, pulmonary vascular resistance, and intrapulmonary shunt and in a trend toward improved oxygenation [99]. In the second study, nitric oxide was administered to 15 patients who manifested an oxygen tension/inspired oxygen fraction ratio less than 150 mm Hg early after transplantation. Inhaled nitric oxide at a starting dose of 40 to 60 parts per million resulted in rapid improvement of arterial oxygenation and pulmonary artery pressure without systemic hemodynamic effects [100]. In an additional study from the same center, the routine use of nitric oxide was found to be of no benefit, and in fact paradoxically worsened oxygenation, in 21 patients with no evidence of early graft dysfunction [101]. These results indicate that inhaled nitric oxide therapy should be offered only to patients who exhibit significant lung graft dysfunction early postoperatively. Furthermore, such patients should receive the lowest maintenance dose of nitric oxide that is effective and should undergo close monitoring of nitrogen dioxide and methemoglobin levels so as to limit toxicity.

In view of the potential deleterious effects of inhaled nitric oxide when administered routinely at the onset of reperfusion, recent animal studies have focused on the pulmonary protective effect of nitric oxide donors such as nitroglycerin and nitroprusside. In rat lung transplant experiments using a short preservation time, nitroglycerin added to the Ringer's lactate pulmonary flush solution significantly improved oxygenation, pulmonary blood flow, and recipient survival after transplantation [102]. Subsequent experiments using a longer ischemic interval and Euro-Collins flush solution found that the beneficial physiologic effects of nitroglycerin were concentration dependent and were associated with a marked decrease in neutrophil and platelet infiltration into lung grafts [86]. Hydralazine, added to the Euro-Collins flush solution as a direct-acting vasodilator, caused greater vasodilatation than did nitroglycerin but was associated with poor graft function after transplantation [86]. These findings suggested that it is the endothelial protective, antineutrophil, and antiplatelet effects of nitroglycerin that caused enhanced lung preservation in this model, rather than vasodilatation alone at the time of harvest [86].

Aside from nitroglycerin, nitroprusside is a potent nitric oxide donor that also has the potential to prevent posttransplantation lung graft dysfunction. In a canine model of prolonged lung graft storage, nitroprusside added to the flush solution and infused continuously during reperfusion resulted in improved oxygenation during 6 hours of reperfusion and in significantly decreased pulmonary neutrophil sequestration [103]. Endothelial cell culture experiments have confirmed that during hypoxia transcription of the genes for the vasoconstrictors endothelin-1 and platelet-derived growth factor can be dramatically reduced within 30 minutes of exposure to nitroprusside [69]. These results suggested that nitroglycerin and nitroprusside may be effective not only by virtue of their direct endothelial protective, antineutrophil, and antiplatelet actions, but also by inhibiting the synthesis of pulmonary vasoconstrictors by endothelial cells. Clinical trials involving the addition of nitroglycerin and nitroprusside to pulmonary flush solutions, as well as recipient therapy with these agents, need to be performed to ascertain if these interventions can decrease postoperative lung graft dysfunction. If nitroglycerin or nitroprusside proves effective, the need for inhaled nitric oxide therapy, with its potential deleterious effects early during reperfusion, may be obviated.

	Additional Strategies to Improve Lung Graft Preservation

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
New Pulmonary Flush Solutions
Since the publication of previous review articles on lung preservation, laboratory work has shown that high-potassium storage solutions impair vascular endothelial cell function [104]. Studies during the past 4 years have demonstrated that low-potassium–dextran pulmonary flush solution provides excellent 12-hour lung preservation in dogs [105], pigs [106], and primates [107]. The addition of 1% glucose to low-potassium–dextran solution promoted the continuation of aerobic metabolism during storage and resulted in normal oxygenation after 24 hours of preservation [108]. To our knowledge, no prospective, randomized trial comparing a low-potassium–dextran solution with modified Euro-Collins solution has yet been reported.

To date, the only published clinical trial contrasting two different lung preservation solutions was a nonrandomized study of modified Euro-Collins solution versus University of Wisconsin solution [109]. Despite a significantly longer graft ischemic time in the University of Wisconsin group, chest radiographic evidence of lung injury was less severe on the first postoperative day in these patients. There were no significant differences in the arterial/alveolar oxygen tension ratio between the two patient groups, indicating that despite the longer ischemic time the lung preservation achieved by University of Wisconsin solution was comparable with that achieved with Euro-Collins solution [109]. Subsequent animal experiments in which the constituents of University of Wisconsin solution were sequentially removed demonstrated that the major factor responsible for the efficacy of this solution in rat lung graft preservation was the impermeant trisaccharide raffinose [110]. Further studies in an isolated rat lung model showed that enrichment of University of Wisconsin solution with vasoactive intestinal peptide markedly prolonged the duration of successful lung preservation, probably due to its antiinflammatory actions via a cyclic AMP-mediated mechanism [111]. Further work on improving the pulmonary protective properties of University of Wisconsin solution is required, given its promise in experimental studies and in the clinical trial reported above.

Pentoxifylline
Pentoxifylline is a methylxanthine derivative that has been used as a hemorrheologic agent for the treatment of peripheral vascular disease [112]. In vitro studies have demonstrated that pentoxifylline has a marked inhibitory effect on neutrophils, particularly neutrophils that have been previously exposed to inflammatory cytokines [113]. Studies on the mechanism of pentoxifylline's effect on neutrophils have demonstrated a likely cyclic AMP-mediated mechanism [113]. In the lungs, pentoxifylline reduced neutrophil oxidant production and decreased neutrophil-dependent pulmonary dysfunction [114]. In a model of normothermic rat lung ischemia, pentoxifylline administered before reperfusion significantly reduced microvascular injury and attenuated pulmonary neutrophil sequestration [115]. After lung transplantation in dogs, pentoxifylline significantly improved oxygenation and decreased lung edema after 18 hours of hypothermic preservation [116]. In view of its myriad antineutrophil effects and beneficial hemorrheologic properties, as well as its long track record of use in humans, pentoxifylline should be further investigated in the preservation of clinical lung grafts for transplantation.

In summary, most of the agents that have been recently reported to improve lung preservation have exerted their effects by increasing the concentration of intracellular cyclic AMP (prostaglandins, pentoxifylline) or cyclic GMP (nitric oxide, nitroglycerin, nitroprusside). Increased intracellular levels of these second messengers promote the integrity of the pulmonary endothelium during graft storage and during the critical early minutes and hours of reperfusion.

	Role of Alveolar Type II Cells and Pulmonary Surfactant in Lung Preservation

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
The pulmonary alveolar epithelium is composed of two cell types, elongated type I cells, which cover most of the alveolar surface, and cuboidal type II cells, which predominate in the alveolar corners [117]. Both type I and II cells exist in close proximity to pulmonary capillary endothelial cells (Fig 3). It is the type II alveolar pneumocyte that synthesizes, stores, and secretes pulmonary surfactant [117, 118]. The process by which surfactant is formed and excreted by the type II pneumocyte is shown in Figure 4. By decreasing surface tension at the critical air-blood interface in the lungs, surfactant promotes alveolar stability at low lung volumes and protects against pulmonary edema under physiologic conditions and during lung injury [117, 118]. In addition to its phospholipid component, surfactant contains at least four distinct surfactant-associated proteins that play an important role in regulating its biophysical activity and in counteracting the inhibition of surfactant by serum proteins in the airway [117].

View larger version (52K): [in this window] [in a new window]   Fig 3. . Electron microscopic section of a human alveolar wall, showing the typical appearance of epithelial type I cells (I), epithelial type II cells (II), and capillary endothelial cells (E) (bar = 4 µm). (Reproduced with permission from Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER. Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis 1982;126:332–7.)

View larger version (58K): [in this window] [in a new window]   Fig 4. . Formation and excretion of pulmonary surfactant in the type II pneumocyte. The surfactant material is packaged as lamellar bodies, which contain phospholipid bilayers with a high content of disaturated phosphatidylcholines. In the lining layer of the alveolus, the lamellar bodies are converted into a unique structure known as tubular myelin. Tubular myelin serves as a reservoir of surfactant molecules, which are available for adsorption to the air-blood interface to form a monolayer of surfactant lipids. Repeated compressions of this monolayer during breathing lead to a squeezing out of unsaturated lipids, resulting in a monolayer enriched in disaturated phosphatidylcholines, which is capable of producing a very low surface tension. Once utilized, surfactant lipids are recycled as small vesicles by type II cells for reuse in surfactant production (ER = endoplasmic reticulum; G = Golgi apparatus; LB = lamellar bodies; M = monolayer; TM = tubular myelin.) (Reproduced with permission from Possymayer F, Yu SH, Weber JM, Harding PGR. Pulmonary surfactant. Can J Biochem Cell Biol 1984;62:1121–33.)

Alterations in Surfactant During Lung Injury and Lung Transplantation
The changes in endogenous pulmonary surfactant have been extensively studied in animal models of acute lung injury [122] as well as in patients with the acute respiratory distress syndrome [123]. In both conditions there were decreased levels of phosphatidylcholine and phosphatidylglycerol and increased levels of the cell membrane lipid sphingomyelin and its degradation product lysophosphatidylcholine. In addition, lung injury in animals and in patients with the acute respiratory distress syndrome is associated with an increased ratio of the poorly functioning surfactant small aggregate forms to the superiorly functioning large surfactant aggregate forms in the airspace [122]. Furthermore, decreased concentrations of the surfactant-associated proteins A and B have been reported in patients with the acute respiratory distress syndrome [123].

Work in our laboratory has shown that sphingomyelin levels were increased and phosphatidylglycerol and surfactant-associated protein A levels were decreased after 12 hours of lung graft storage and 6 hours of reperfusion in dogs [124]. These surfactant alterations occurred to a lesser degree in the native (nontransplanted) lung of recipient dogs and were associated with significant hypoxemia during reperfusion. In rat lung grafts transplanted after warm ischemic times of 60 to 120 minutes, the concentration of phosphatidylcholine decreased and the concentration of serum proteins (which inhibit surfactant activity) increased progressively in the airway according to the severity of lung injury [125]. Furthermore, the in vitro function of surfactant from transplanted grafts decreased in parallel with prolongation of the ischemic time. It is thus evident that the endogenous surfactant system undergoes profound alterations after pulmonary ischemia and transplantation that are qualitatively similar to the changes in surfactant that occur in nontransplant lung injury models.

Exogenous Surfactant Therapy in Lung Transplantation
The lung injury literature is replete with studies showing that exogenous surfactant therapy can mitigate pulmonary dysfunction in a wide array of experimental models [122]. In vitro studies have documented that exogenous surfactant phospholipids can decrease cytokine secretion by stimulated human alveolar macrophages, probably by a pretranslational mechanism [126]. Work in our laboratory has demonstrated that exogenous surfactant administered into the airway of recipient dogs immediately after transplantation can restore normal lung function in select animals even after 38 hours of storage [127]; however, the physiologic response to the instilled surfactant was not consistent in this model. A subsequent study showed that treatment of lung donors with exogenous surfactant before 36 hours of graft storage was associated with less severe lung injury than waiting to administer the surfactant to transplant recipients [128]. Combined donor and recipient exogenous surfactant treatment resulted in an increased recovery of exogenous surfactant in transplanted lungs and was associated with decreased protein leak and a superior physiologic response during reperfusion [128].

Studies in a rat lung transplant model have demonstrated that the instillation of surfactant into transplanted lungs just before reperfusion markedly improved oxygenation and dynamic compliance in grafts stored for 6 hours and, to a lesser degree, 20 hours [129]. In isolated rabbit lungs preserved for 24 hours, exogenous surfactant administered 5 minutes before reperfusion improved pulmonary compliance but not oxygen tension, lung edema, or pulmonary leukocyte sequestration during reperfusion [130]. These reports suggested that for surfactant to have a maximum impact on lung injury after prolonged storage, donor surfactant therapy is probably essential.

Further studies need to be performed to determine whether exogenous surfactant therapy can downregulate cytokine production in vivo and whether surfactant can salvage injured lung grafts so that they may be used for transplantation. A case report of the successful treatment of a patient with early postoperative lung graft dysfunction with aerosolized synthetic surfactant has recently been published [131]. A clinical trial of exogenous surfactant therapy in lung transplant donors is a logical next step to the studies in experimental animals that have been performed during the past 3 years. Moreover, the use of isolated alveolar type II cell cultures [132] as a screening test for the assessment of proposed new pulmonary flush and storage solutions should be encouraged.

	Use of Compromised Lungs for Transplantation

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
The salvage of lungs that do not meet the classic criteria for donor acceptance has been recognized as an important challenge [1]. Until recently, the limits of viability of experimental lung grafts that were compromised before harvest had not been assessed. Recent work in rat lungs with endotoxin-induced injury has confirmed satisfactory aerodynamic function of these grafts after 6, but not 12, hours of preservation [133]. Additional work is required to mitigate the injury in damaged lung grafts before harvest to allow satisfactory pulmonary function even after a prolonged interval of storage.

Recent studies have focused on the use of lung grafts from non–heart-beating donors as a means to expand the donor pool. Laboratory work from over a quarter of a century ago documented that canine lungs could tolerate 3 to 4 hours of warm ischemia in situ as long as they continued to be ventilated during the ischemic interval [134]. In 1991 the University of North Carolina group demonstrated that lungs from non–heart-beating donor animals functioned well when they were harvested after an hour of in situ warm ischemia followed by 4 hours of cold storage and an additional hour of anastomotic time [135]. Subsequent work from the same laboratory documented that preharvest ventilation [136] or inclusion of the oxygen free radical scavenger dimethylthiourea in the pulmonary flush solution [137] improved the function of cadaver lung grafts after 2 to 4 hours of warm ischemia. Further experiments showed that if rat lungs were continuously ventilated with oxygen during 12 hours of warm ischemia, only 26% of parenchymal cells were nonviable, versus 77% in nonventilated rats [138]. These studies demonstrated that modification of the preharvest or harvest conditions could have a major impact on the preservation of lungs from non–heart-beating donors.

In all of the initial experiments using cadaver lungs, lung donors were heparinized before circulatory arrest, a practice that does not usually occur in the clinical situation of donor death. A recent study has confirmed that treatment of nonheparinized donor lungs with high-dose urokinase improved their subsequent function after 2 hours of in situ warm ischemia followed by transplantation [139]. The authors of that study hypothesized that urokinase promoted the dissolution of pulmonary thrombi in donor lungs and may also have prevented the formation of additional pulmonary thrombi after reperfusion. In a chronic survival study using porcine lungs harvested 0, 15, and 30 minutes postmortem, no significant differences in oxygen tension or pulmonary vascular hemodynamics were noted among groups at the 1-week postoperative assessment, although dynamic airway compliance was significantly lower in the 30-minute warm ischemic group [140]. Further survival studies using lung grafts that have been subjected to longer intervals of warm ischemia before harvest are essential to define the effects of these ischemic times on long-term graft function.

One major limitation of the above studies is the fact that all donor animals had normal hemodynamics and lung function before the onset of warm in situ lung ischemia. In the clinical situation most cadaver donors usually experience significantly deranged hemodynamics in the hours preceding their death. Circulatory shock triggers a severe form of endothelial dysfunction in many organs [20] and has also been shown to promote pulmonary neutrophil sequestration [17] and the development of pulmonary ultrastructural lesions [16]. In a recent study from the University of Toronto [141], donor rats were subjected to 1 hour of preharvest hemorrhagic shock (mean blood pressure, 30 to 40 mm Hg). The animals were then killed and underwent 2 to 3 hours of warm in situ ischemia before flushing. After a brief storage interval, the lungs were perfused in a previously validated isolated rat lung model. Pulmonary edema developed within 10 minutes of reperfusion in all of the lungs that had experienced 1 hour of hypotension before 3 hours of warm in situ ischemia, whereas lungs that had been subjected to 3 hours of warm ischemia with no preceding hypotension fared well [141]. The authors of that study concluded that a relatively brief interval of hypotension before death severely impaired cadaver lung viability. Because the animals used in that experiment were not heparinized, further studies using urokinase or other thrombolytic agents were proposed to assess the ability of these agents to promote the dissolution of postmortem pulmonary thrombi. Additional strategies to preserve endothelial and alveolar type II cell function before storage should also be investigated in an attempt to salvage these severely injured lung grafts.

	Summary

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
Until the advent of xenotransplantation, the practice of lung transplantation will be constrained by a shortage of donor organs. Significant progress has been made during recent years in elucidating the multiple biochemical derangements that occur during ischemia-reperfusion lung injury. The myriad cellular and molecular events that occur during this injury result in significant endothelial and alveolar type II cell dysfunction. Strategies to preserve posttransplantation lung function should be rationalized on the basis of maintaining the integrity of these cells. Additional work to increase our understanding of the molecular mechanisms of lung injury before, during, and after transplantation is required to develop optimal strategies to minimize the occurrence of postoperative lung graft dysfunction. Ideally, such mechanistic studies should characterize ischemia-reperfusion lung injury simultaneously at the whole-animal, organ, cellular, and molecular levels [30, 31].

It is imperative that innovative work from the experimental laboratory be translated into clinical reality via prospective, randomized trials. Techniques to improve the preservation of both pulmonary endothelial and epithelial cells should be investigated clinically, because a combination of treatment modalities will likely prove necessary to minimize pulmonary ischemia-reperfusion injury. The next few years promise to be an exciting era in which the results of innovative laboratory research in this field enter widespread clinical application to improve patient outcomes after lung transplantation.

	Acknowledgments

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
We acknowledge the assistance of Drs Anthony M. Jevnikar, Bhagirath Singh, and Fred Possmayer, who reviewed the manuscript before its submission. We also thank Heather L. Motloch for her expertise in typing and preparing the manuscript.

Supported by grants from the Heart and Stroke Foundation of Ontario and the Multi-Organ Transplant Service, London Health Sciences Centre, University Campus.

	Footnotes

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 
A complete list of 210 references on lung preservation is available from the author on request.

Address reprint requests to Dr Novick, London Health Sciences Centre, University Campus, PO Box 5339, London, Ont, Canada N6A 5A5.

	References

Top Footnotes Abstract Introduction Donor Lung Injury Before... Mechanisms of Pulmonary Ischemia... Pulmonary Ischemia-Reperfusion... Endothelial Dysfunction During... Strategies to Maintain... Additional Strategies to Improve... Role of Alveolar Type... Use of Compromised Lungs... Summary Acknowledgments References

 

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