Free radical—mediated vascular injury in lungs preserved at moderate hypothermia

doi:10.1016/0003-4975(95)00620-Z

The Annals of Thoracic Surgery

Volume 60, Issue 5, November 1995, Pages 1376-1381

https://doi.org/10.1016/0003-4975(95)00620-Z Get rights and content

Background.

Early allograft dysfunction remains a frequently encountered problem in clinical lung transplantation. Lung ischemia-reperfusion injury is associated with increased vascular permeability, which may be due in part to oxygen (O₂) free radicals. However, it is not clear whether O₂ free radicals are produced during ischemia under storage conditions in clinical lung transplantation.

Methods.

Using an isolated ex vivo rabbit lung model, we studied the effects of preservation temperature on pulmonary capillary filtration coefficient (K_f) and lipid peroxidation in rabbit lungs inflated with 100% O₂ after preservation with or without the O₂ free radical scavenger dimethylthiourea. New Zealand white rabbits weighing 2.7 to 3.1 kg were intubated and ventilated with room air or 100% O₂ (tidal volume = 25 mL). After heparinization and sternotomy, the pulmonary artery was flushed with low-potassium—dextran—1% glucose solution (200 mL). The heart-lung block was excised, submerged, and stored for 24 hours at 1° or 10°C. After 24-hour preservation, the heart-lung block was suspended from a strain-gauge force transducer and ventilated with room air. The pulmonary artery cannula was connected to a reservoir of hetastarch solution. The lungs were flushed briefly with the hetastarch solution, and the reservoir was raised sequentially at 8-minute intervals to achieve 1.0 to 1.5 mm Hg increments in pulmonary artery pressure. Lung weight gain, airway pressure, pulmonary artery pressure, and left atrial pressure were measured continuously. The slope of steady-state lung weight gain was used to determine K_f (g · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹ wet weight).

Results.

Twenty-four—hour lung preservation at both 1° and 10°C increased K_f. A similar increase in K_f was observed in lungs stored at 1°C while inflated with 100% O₂. However, a significant increase in K_f was observed when lungs inflated with 100% O₂ were stored at 10°C. This increase in K_f was ameliorated by dimethylthiourea. Thiobarbituric acid—reactive substance levels were increased in lungs stored at 10°C while inflated with 100% O₂. This finding was eliminated by dimethylthiourea.

Conclusions.

These results indicate that free radical injury occurs during the ischemic phase when lungs are stored at moderate hypothermia while inflated with 100% O₂.

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Thus, aerobic metabolism can continue, albeit at a reduced rate due to hypothermia; this can delay cell death and prevent the accumulation of cellular metabolites. Although the optimum oxygenation threshold is unclear, high oxygen concentrations might induce the production of oxygen free radicals, increasing the risk of PGD during reperfusion.66 Thus, most groups inflate lungs with a fraction of inspired oxygen of 50% before retrieval and transportation.
Although lung transplantation has become a life-saving option for patients with end-stage lung disease, this intervention is hampered by a shortage of lungs in view of the growing number of people on the waiting list. Lungs are retrieved from only a small percentage of multiorgan donors, and the transplantation and intensive-care communities have recognised the need to develop innovative methods to expand the donor pool. Advancements in lung-preservation techniques in the preretrieval and postretrieval periods have increased the pool of available donors, and novel research and discoveries in this area have steadily improved post-transplantation adverse events. This Review summarises current best practice and the latest research on intensive-care management of a potential lung donor. We also discuss lung-preservation techniques, including advancements in normothermic ex-vivo lung perfusion, and the potential for a personalised medicine approach to the organ.
Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation
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However, multiple studies have described that because of unique structure and function, the lung becomes a vulnerable target during IR/I [62]. Interestingly, accumulation of toxic metabolites from aerobic metabolism and free radical injury may occur when the lungs are inflated with oxygen [63,64]. Alveolar oxygen helps maintain aerobic metabolism and prevents hypoxic ROS formation, which have a key role in causing pulmonary IR injury [65].
Organ transplantation is the only choice for treatment of end-stage disease. The ischemia reperfusion injury (I/RI) occurring after cold ischemia is an unavoidable injury during transplantation, which is also one of the main causes of graft failure. Multiple mechanisms have been postulated to explain tissue injury that occurs after I/RI. It is well-known that ischemic preconditioning (IPC), a short period of ischemia followed by reperfusion, arouses the endogenous mechanism of protection against a sustained ischemic insult. Can ischemic preconditioning alone really protect organs from ischemia reperfusion injury in transplantation?
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Deep hypothermia during ischemia improves functional recovery and reduces free-radical generation in isolated reperfused rat heart
2004, Journal of Heart and Lung Transplantation
We investigated the influence of deep hypothermia (4°C) during ischemia–reperfusion in the isolated rat heart model.
Isolated, perfused rat hearts underwent either 30 minutes of normothermic ischemia (control group) or 30 minutes of hypothermic ischemia (hypothermia-treated group), followed by 30 minutes of reperfusion in both groups. We recorded functional parameters and used electron spin resonance (ESR) spectroscopy to detect ascorbyl radicals, as markers of free-radical production, in samples of coronary effluents.
Functional parameters were stable in the 2 groups during pre-ischemic and ischemic periods. During reperfusion, coronary flow, left diastolic ventricular pressure, left ventricular developed pressure, and heart rate more rapidly recovered to values close to those obtained during the pre-ischemic period in the hypothermia-treated group than in the control group. Moreover, the post-ischemic contracture observed in the control group did not appear in the hypothermia-treated group. Finally, ESR analysis showed that the post-ischemic release of ascorbyl radicals decreased in the hypothermia-treated group.
These results demonstrate that the protective effect of hypothermia against functional injury caused by ischemia–reperfusion may decrease the free-radical burst at reperfusion.
Do vitamins C and E attenuate the effects of reactive oxygen species during pulmonary reperfusion and thereby prevent injury?
2002, Annals of Thoracic Surgery
Citation Excerpt :
Baker and colleagues [9] showed that the addition of a water-soluble α-tocopherol to a preservation solution prolonged ischemic viability of vascular endothelial cells, and improved but did not normalize postischemic lung function in an isolated perfused rat lung model. Others tested radical scavengers such as dimethylthiourea or N-acetylcysteine and found them to be beneficial, although protection still remained incomplete [10, 11]. The chemiluminometric results of this study clearly show one of theoretically possible reasons for this incomplete protection: the used vitamins blocked radical release by PMNs, certainly a major source during injury; however, they were not able to scavenge the remaining free ROS in whole blood, nor were they able to prevent their production from other sources.
Background. We established an in vivo pig model of standardized lung ischemia to analyze pulmonary reperfusion injury. Enhanced chemiluminescence measurement (CM) allowed immediate quantification of reactive oxygen species (ROS) and subsequent lipid peroxidation. In such model we analyzed efficacy of vitamins C and E to prevent reperfusion injury.
Methods. After left lateral thoracotomy in group I (n = 6), normothermic lung ischemia was maintained for 90 minutes followed by a 5-hour reperfusion period. In group II, animals (n = 6) underwent ischemia as in group I, but received vitamins (preoperative IV bolus C = 1 g, E = 0.75 g, then continuous infusion (125 mg/h) each throughout the study). In Group III, animals (n = 6) underwent sham surgery and served as controls. Hemodynamic variables and gas exchange were assessed. The CM was performed for injury quantification in blood samples and to determine activation of isolated PMNs. The Wilcox rank test was used for statistical analysis.
Results. During reperfusion, all animals in group I developed significant pulmonary edema with significant loss of pulmonary function. The addition of vitamins (group II) improved oxygenation and almost abolished pulmonary inflammatory cell infiltration; however, as in group I, pulmonary compliance still tended to decline and the number of circulating leucocytes increased. The CM showed that, compared with group I, vitamins reduced O₂⁻ basic release by PMNs significantly (460% to 170%, p < 0.05; control 165%), but could not prevent an increase of free ROS in whole blood similar to group I (443% to 270%, p = ns, control 207%). With regard to lipid peroxidation only a trend of reduction was observed (117% to 105%, p = ns, control 100%).
Conclusions. Differentiated analysis by CM demonstrated that vitamins C and E inhibited PMN activation but were not able to prevent radical production by other sources. This offers a potential explanation why radical scavengers like vitamins only attenuate but ultimately do not prevent reperfusion injury.

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Free radical—mediated vascular injury in lungs preserved at moderate hypothermia

Background.

Methods.

Results.

Conclusions.

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Anal Biochem

Methods Enzymol

Ann Thorac Surg

J Thorac Cardiovasc Surg

Free Radic Biol Med

Oxygen-derived free radicals in postischemic tissue injury

N Engl J Med

Ischemia-reperfusion injury: role of oxygen-derived free radicals

Acta Physiol Scand

Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury

Am J Physiol