Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration

doi:10.1016/j.transproceed.2004.11.079

Transplantation Proceedings

Volume 37, Issue 1, January–February 2005, Pages 379-381

https://doi.org/10.1016/j.transproceed.2004.11.079 Get rights and content

Abstract

Chronic allograft dysfunction remains the major obstacle for long-term successful transplantation. To date there is no effective treatment. Overexpression of protective genes has provided increased graft function and survival. This mechanism has been implicated in the process of graft accommodation. One of these genes that has been shown to mediate protective effects decodes the enzyme heme oxygenase-1 (HO-1), and an HO-1 downstream product, carbon monoxide (CO). Using an established model of kidney chronic allograft rejection in the rat, we investigated the impact of methylene chloride (MC), a CO donor, as a therapeutic tool to reduce chronic graft deterioration. We showed that donor and long-term recipient treatment with MC improved graft function and reduced histological signs of chronic rejection. Carbon monoxide may be a promising agent to improve graft quality and long-term graft function.

Section snippets

Material and methods

Fisher 344 (3 months old, 200 to 230 g, RT1^1v1) kidneys were transplanted orthotopically into bilaterally nephrectomized Lewis rats (3 months old, 200 to 230 g, RT1¹, CyA 1.5 mg/kg/d × 10 days). MC was applied to recipients for either a short-term (10 days) or a long-term (6 months) period. Methylene chloride diluted in olive oil was given orally (100 mg/kg/d). CO was measured indirectly, by determination of carbox hemoglobin (COHb) percentage in capillary blood. Non–MC-treated animals served

Results

All animals survived the observation period. The regimen of 100 mg/kg/d oral MC was well tolerated; no behavioral changes were noted. After 6 months, autopsy failed to reveal macroscopic changes or tumors in the long-term treated group. The peak COHb (5.53% ± 2.1%) was reached at 2 hours after administration of MC (100 mg/kg orally) and the levels of COHb were maintained above the basal level for up to 24 hours. Both recipients and donors treated with MC showed less proteinuria (control = 60 ±

Discussion

It is known that early graft damage can increase graft immunogenicity and exert a major impact on short- and long-term transplant outcomes. Donor treatment has been proposed as an important approach to promote cytoprotection and modulate graft immunogenicity thereby preventing further graft injury. Exogenous administration of CO, a downstream product of HO-1 metabolism, may ameliorate the consequences of I/R.2, 3, 4 CO has been shown to have antioxidant, antiapoptotic, anti-inflammatory, and

References (4)

R. Buelow et al.
Protection of grafts by hemoxygenase-1 and its toxic product carbon monoxide
Am J Transplant
(2001)
S.G. Tullius et al.
Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single donor treatment with cobalt protoporphyrin (CoPP) for the induction of Heme oxygenase-1
Transplantation
(2002)

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Cited by (34)

Application of carbon monoxide in kidney and heart transplantation: A novel pharmacological strategy for a broader use of suboptimal renal and cardiac grafts
2021, Pharmacological Research
Citation Excerpt :
This implies that CO is a chief mediator of the pharmacological protection against cold renal IRI, and is partly via activation of the sGC/cGMP pathway. It is important to note that short-term treatment (10 days) of organ donors prior to organ procurement and long-term (6 months) recipients with 100 mg/kg/day of methylene chloride (CO donor) prevented chronic graft rejection and improved graft function in a rat model of kidney allograft rejection [79], which further supports the evidence of renal graft protection by CO. In the same vein, pharmacological induction of HO-1 with intraperitoneal administration of 5 mg/kg cobalt protoporphyrin before organ harvesting attenuated activation of caspase-3 and increased expression of Bcl-xL, leading to preservation of renal graft function and inhibition of post-reperfusion apoptosis following 45 h of SCS in 4 °C UW solution.
Carbon monoxide (CO) was historically regarded solely as a poisonous gas that binds to hemoglobin and reduces oxygen-carrying capacity of blood at high concentrations. However, recent findings show that it is endogenously produced in mammalian cells as a by-product of heme degradation by heme oxygenase, and has received a significant attention as a medical gas that influences a myriad of physiological and pathological processes. At low physiological concentrations, CO exhibits several therapeutic properties including antioxidant, anti-inflammatory, anti-apoptotic, anti-fibrotic, anti-thrombotic, anti-proliferative and vasodilatory properties, making it a candidate molecule that could protect organs in various pathological conditions including cold ischemia-reperfusion injury (IRI) in kidney and heart transplantation. Cold IRI is a well-recognized and complicated cascade of interconnected pathological pathways that poses a significant barrier to successful outcomes after kidney and heart transplantation. A substantial body of preclinical evidence demonstrates that CO gas and CO-releasing molecules (CO-RMs) prevent cold IRI in renal and cardiac grafts through several molecular and cellular mechanisms. In this review, we discuss recent advances in research involving the use of CO as a novel pharmacological strategy to attenuate cold IRI in preclinical models of kidney and heart transplantation through its administration to the organ donor prior to organ procurement or delivery into organ preservation solution during cold storage and to the organ recipient during reperfusion and after transplantation. We also discuss the underlying molecular mechanisms of cyto- and organ protection by CO during transplantation, and suggest its clinical use in the near future to improve long-term transplantation outcomes.
Oxygenation of the Transplanted Kidney
2019, Seminars in Nephrology
Citation Excerpt :
Interestingly, carbon monoxide does not need to be applied as an inhalation gas. The group of Stefan Tullius88 used the prodrug methylene chloride in rat renal transplantation. In the liver, methylene chloride is metabolized, releasing carbon monoxide, which binds to blood hemoglobin to induce functional anemia.
Summary: Although kidney oxygen tensions are heterogenous, and mostly below renal vein level, the nephron is highly dependent on aerobic metabolism for active tubular transport. This renders the kidney particularly susceptible to hypoxia, which is considered a main characteristic and driver of acute and chronic kidney injury, albeit the evidence supporting this assumption is not entirely conclusive. Kidney transplants are exposed to several conditions that may interfere with the balance between oxygen supply and consumption, and enhance hypoxia and hypoxic injury. These include conditions leading to and resulting from brain death of kidney donors, ischemia and reperfusion during organ donation, storage and transplantation, postoperative vascular complications, vasoconstriction induced by immunosuppression, and impaired perfusion resulting from interstitial edema, inflammation, and fibrosis. Acute graft injury, the immediate consequence of hypoxia and reperfusion, results in delayed graft function and increased risk of chronic graft failure. Although current strategies to alleviate hypoxic/ischemic graft injury focus on limiting injury (eg, by reducing cold and warm ischemia times), experimental evidence suggests that preconditioning through local or remote ischemia, or activation of the hypoxia-inducible factor pathway, can decrease hypoxic injury. In combination with ex vivo machine perfusion such approaches hold significant promise for improving transplantation outcomes.
Nonmetallic carbon monoxide releasing molecules (CORMs)
2017, Organic and Biomolecular Chemistry
Carbon monoxide (CO) is a gasotransmitter that plays important roles in regulating cell functions and has shown therapeutic effects in clinic studies. CO releasing molecules (CORMs), which allow controlled release of CO in physiological conditions, have been intensively studied in the past decade. While most CORMs are metal complexes, several nonmetallic CORMs have also been developed and most of them were reported in recent years. The major advantages of nonmetallic CORMs are potentially low toxicity and easy modification for property tuning. Syntheses, CO-release mechanisms, biological behaviors, and physicochemical properties of these nonmetallic CORMs are reviewed here. The first part of this short review covers the nonmetallic CORMs that do not require irradiation to release CO, which includes methylene chloride, CORM-A1 and its derivatives, amine carboxyboranes, and bimolecular CORMs. The second part focuses on the CORMs that release CO under irradiation (PhotoCORMs) including unsaturated cyclic diketones, xanthene carboxylic acids, meso-carboxy BODIPYs, and hydroxyflavones. Future prospects are discussed at the end of this review.
Inhalation of carbon monoxide reduces skeletal muscle injury after hind limb ischemia-reperfusion injury in mice
2012, American Journal of Surgery
The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 expression, and improve indexes of tissue integrity and inflammation after hind limb ischemia reperfusion.
C57BL6 mice inhaling CO (250 ppm) or room air were subjected to 1.5 hours of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time, 4.5 or 7.5 h). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were killed at either the end of CO treatment or at 24 hours' reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis.
CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were reduced significantly (P < .05) in mice treated with CO for 7.5 hours. Tubulin, heme oxygenase, and adenosine triphosphate levels were higher in CO-treated mice.
Inhaled CO protected muscle from structural injury and energy depletion after ischemia reperfusion.
An old dream revitalised: preconditioning strategies to protect surgical flaps from critical ischaemia and ischaemia-reperfusion injury
2008, Journal of Plastic, Reconstructive and Aesthetic Surgery
Citation Excerpt :
The resulting metabolites are biliverdin, an antioxidant, Fe++, and carbon monoxide, a potent vasodilator.83 The protection from ischaemic injury of these HSPs has been reported for a variety of organs and tissues, including the heart,84 the brain,85 the liver86 and the kidney.87 In experimental flap surgery, Koenig et al. were the first to report an improved flap survival upon preconditioning with supraphysiological heat.88
The prevention of ischaemia and the adequate restitution of blood flow to ischaemic tissue are pivotal to halt the progression of cellular injury associated with decreased oxygen and nutrient supply. Accordingly, the search for novel strategies which aim at preventing ischaemia-reperfusion-induced tissue damage is still of major interest in flap surgery. Preconditioning represents an elegant approach to render the tissue more resistant against deleterious ischaemic insults. For many decades, ‘surgical delay’ has been the standard method of tissue preconditioning. During the last 10 years, ischaemic preconditioning was added to the repertoire of plastic surgeons to protect flaps from ischaemic necrosis. The invasiveness and expenditure of time of these procedures, however, have always been major drawbacks, hindering a wide distribution in clinical practice. Consequently, the motivation has all along been to further refine and simplify protective strategies. Recent experimental studies have now shown that efficient protection from ischaemic necrosis can also be achieved by remote preconditioning or pretreatment with chemical agents and growth factors, which mimic the action of surgical delay and ischaemic preconditioning. In addition, the local application of unspecific stressors, including both heating and cooling, have been shown to effectively improve flap microcirculation and, thus, tissue survival. In view of successful translational research, it is now time that the efficacy of these novel preconditioning procedures is proven in prospective randomised clinical trials.
Heme Oxygenase 1: Does It Have a Role in Renal Cytoprotection?
2008, American Journal of Kidney Diseases
Citation Excerpt :
Thus, the multiple pathways leading to transplant injury potentially could be modified positively by increased HO-1 expression, and this is supported by experimental evidence. Animal models of renal transplantation showed protective effects of HO-1 expression in attenuation of IR injury, immunomodulation, and minimization of chronic damage.88-93 There is evidence that at least some of these effects are secondary to the production of CO and/or biliverdin.57,58,94
Heme oxygenase (HO) was first identified as the rate-limiting enzyme in the degradative pathway of heme, but is now recognized to be involved in diverse biological processes. Different isoforms of HO exist; HO-1 (HMOX1) is ubiquitously present in mammalian tissue with low constitutive expression under physiological conditions, but is upregulated in response to a variety of potentially noxious stimuli. HO-1, an integral component of an important cytoprotective mechanism, mediates its action through removal of heme, the generation of heme breakdown reaction products (biliverdin, free iron, and carbon monoxide), and modulation of key cellular molecules. Data from experimental models in which HO-1 was induced or inhibited, together with observations in genetically modified animals, showed a beneficial effect of HO-1 in several pathways leading to kidney injury. The discovery of a functional guanosine thymine tandem repeat polymorphism in the promoter region of the human HO-1 gene has stimulated clinical investigations in a variety of diseases. However, despite theoretical and experimental support for an important pathophysiological role for HO-1, the relevance of this polymorphism in native kidney or renal transplant function is equivocal. This article reviews the molecular genetics of HO-1, its myriad cytoprotective effects allied to how these are mediated, and relates these findings to experimental and clinical evidence of HO-1 involvement in renal disease.

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Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration

Abstract

Section snippets

Material and methods

Results

Discussion

Am J Transplant

Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single donor treatment with cobalt protoporphyrin (CoPP) for the induction of Heme oxygenase-1

Transplantation