title: Beneficial effects of perioperative low-dose inhaled carbon monoxide on pulmonary allograft survival in MHC-inbred CLAWN miniature swine.
abstract: BACKGROUND
  We have recently reported that perioperative low-dose carbon monoxide (CO) inhalation decreases lung ischemia-reperfusion injury in miniature swine. The aims of this study were to establish a large animal model of pulmonary allograft rejection using polymerase chain reaction-typed major histocompatibility complex (MHC)-inbred CLAWN miniature swine and to examine the effects of CO on allograft survival.
  
  
  METHODS
  Eleven CLAWN miniature swines received fully MHC-mismatched lungs followed by 12 days of tacrolimus (days 0-11; blood level 35-45 ng/mL). Six recipients received tacrolimus alone (control group). Five recipients were additionally treated with inhaled CO (180 min for donors until graft harvest; 390 min for recipients until 2 hr after reperfusion).
  
  
  RESULTS
  All recipients treated with tacrolimus alone uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. CO treatment was effective in prolonging allograft survival from a mean of 47±7 to 82±13 days (P=0.017), with one CO-treated animal maintaining function until postoperative day 120. Development of antidonor antibodies and donor-specific responsiveness by cell-mediated lympholysis and mixed lymphocyte reaction assays was delayed in animals that received CO therapy. Furthermore, serum concentrations of proinflammatory cytokines (interleukin-1β and -6) 1 day after transplant were significantly decreased in the CO-treated group.
  
  
  CONCLUSIONS
  Fully MHC-mismatched lungs in CLAWN miniature swine were consistently rejected within 63 days, suggesting that this is a robust large animal model ideal for investigating mechanisms and treatment of lung rejection. Perioperative low-dose CO inhalation prolonged graft survival and inhibited antidonor antibody production and was associated with decreased proinflammatory mediators in this model.
authors.affiliation: Xenotransplantation Surgery Section, Frontier Science Research Center, Kagoshima University, Kagoshima, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sahara
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Kentaro
authors.initials: K
authors.lastname: Setoyama
authors.forename: Manei
authors.initials: M
authors.lastname: Oku
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Okumi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Wunimenghe
authors.initials: W
authors.lastname: Oriyanhan
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tasaki
authors.forename: Joseph
authors.initials: J
authors.lastname: Scalea
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
authors.forename: Toru
authors.initials: T
authors.lastname: Bando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000627:therapeutic use*; D002470:Cell Survival; D003165:Complement System Proteins / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007178:Inbreeding; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007518:Isoantibodies / Q000097:blood; D016040:Lung Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D059035:Perioperative Period; D013552:Swine; D013556:Swine, Miniature; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D007518:Isoantibodies; D002248:Carbon Monoxide; D003165:Complement System Proteins; D016559:Tacrolimus