title: Carbon monoxide-releasing molecule attenuates allograft airway rejection.
abstract: Acute rejection after lung transplantation is the main risk factor for the development of bronchiolitis obliterans (BO). Carbon monoxide (CO) can provide anti-inflammatory effects and may serve to limit tissue injury in airway transplant. Here, we tested the ability of carbon monoxide releasing molecule-2 (CORM-2) to prevent airway rejection. Tracheal grafts from BALB/c or C57BL/6 were transplanted to C57BL/6 recipients. Experimental groups were treated with multiple doses of CORM-2. Histopathological evaluation of luminal obliteration was blindly reviewed. Immunohistochemistry and real-time RT-PCR analyses were performed. Allografts treated with CORM-2 revealed a striking reduction of thickening in epithelial and subepithelial airway layers (P < 0.01) at day 7 in orthotopic trachea transplantation model compared with allografts treated with vehicle. In heterotopic trachea transplantation model, CORM-2 treated allografts showed a reduction of luminal obliteration (P < 0.01) at days 14 and 21. There was also a concordant decrease in CD3(+) lymphocytes and macrophages in CORM-2 treated allografts. IFN-γ, IL-2 and IL17A mRNA expressions were reduced dramatically by systemic administration of CORM-2. These data implicate CORM-2-derived CO has an important protective function in experimental BO, and may represent a target for the therapeutic intervention of chronic lung allograft rejection.
authors.affiliation: Section of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kaseda
authors.forename: Takao
authors.initials: T
authors.lastname: Shigenobu
authors.forename: Tai
authors.initials: T
authors.lastname: Hato
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kamiyama
authors.forename: Taichiro
authors.initials: T
authors.lastname: Goto
authors.forename: Mitsutomo
authors.initials: M
authors.lastname: Kohno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
mesh_terms: D064591:Allografts; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology; D002248:Carbon Monoxide / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000494:pharmacology*; D014132:Trachea / Q000637:transplantation*
chemical_list: D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide
keywords: airway obstruction; carbon monoxide; lung transplantation