Abstract
Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / chemistry
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Adenosine / pharmacokinetics
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Adenosine / pharmacology
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Allopurinol / chemistry
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Allopurinol / pharmacokinetics
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Allopurinol / pharmacology
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Animals
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Antimetabolites / analysis
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Antimetabolites / pharmacokinetics
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Antimetabolites / pharmacology*
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Carbon Monoxide / analysis
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Carbon Monoxide / pharmacokinetics
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Carbon Monoxide / pharmacology*
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Disease Models, Animal
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Glutathione / chemistry
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Glutathione / pharmacokinetics
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Glutathione / pharmacology
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Graft Survival / drug effects
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Insulin / chemistry
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Insulin / pharmacokinetics
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Insulin / pharmacology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / ultrastructure
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Intestine, Small / blood supply*
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Intestine, Small / metabolism
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Intestine, Small / transplantation*
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Male
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Microscopy, Electron, Transmission
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Organ Preservation
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Organ Preservation Solutions / chemistry
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Organ Preservation Solutions / pharmacokinetics
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Organ Preservation Solutions / pharmacology*
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Organ Transplantation / adverse effects*
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Raffinose / chemistry
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Raffinose / pharmacokinetics
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Raffinose / pharmacology
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Rats
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Rats, Inbred Lew
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Reperfusion Injury / etiology
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Reperfusion Injury / metabolism
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Reperfusion Injury / prevention & control*
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Treatment Outcome
Substances
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Antimetabolites
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Insulin
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Organ Preservation Solutions
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University of Wisconsin-lactobionate solution
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Allopurinol
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Carbon Monoxide
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Glutathione
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Adenosine
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Raffinose