title: Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.
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.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pennsylvania, USA. anakao@imap.pitt.edu
authors.forename: A
authors.initials: A
authors.lastname: Nakao
authors.forename: H
authors.initials: H
authors.lastname: Toyokawa
authors.forename: A
authors.initials: A
authors.lastname: Tsung
authors.forename: M A
authors.initials: MA
authors.lastname: Nalesnik
authors.forename: D B
authors.initials: DB
authors.lastname: Stolz
authors.forename: J
authors.initials: J
authors.lastname: Kohmoto
authors.forename: A
authors.initials: A
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Tomiyama
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Yang
authors.forename: M P
authors.initials: MP
authors.lastname: Fink
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.forename: A M K
authors.initials: AM
authors.lastname: Choi
authors.forename: N
authors.initials: N
authors.lastname: Murase
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000493:Allopurinol / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D007328:Insulin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007421:Intestine, Small / Q000098:blood supply* / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D046529:Microscopy, Electron, Transmission; D009926:Organ Preservation; D019188:Organ Preservation Solutions / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016377:Organ Transplantation / Q000009:adverse effects*; D011887:Raffinose / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000963:Antimetabolites; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D002248:Carbon Monoxide; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose