Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration
Section snippets
Material and methods
Fisher 344 (3 months old, 200 to 230 g, RT11v1) 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
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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 ResearchCitation 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.
Oxygenation of the Transplanted Kidney
2019, Seminars in NephrologyCitation 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.
Nonmetallic carbon monoxide releasing molecules (CORMs)
2017, Organic and Biomolecular ChemistryInhalation of carbon monoxide reduces skeletal muscle injury after hind limb ischemia-reperfusion injury in mice
2012, American Journal of SurgeryAn old dream revitalised: preconditioning strategies to protect surgical flaps from critical ischaemia and ischaemia-reperfusion injury
2008, Journal of Plastic, Reconstructive and Aesthetic SurgeryCitation 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
Heme Oxygenase 1: Does It Have a Role in Renal Cytoprotection?
2008, American Journal of Kidney DiseasesCitation 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