title: Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis.
abstract: Carbon monoxide (CO) has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles (CO-HbV). We hypothesized that CO-HbV could have a therapeutic effect on idiopathic pulmonary fibrosis (IPF), an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species (ROS). Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced pulmonary fibrosis mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on pulmonary fibrosis can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-β in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of pulmonary fibrosis via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced pulmonary fibrosis mice model. CO-HbV has the potential for use in the treatment of, not only IPF, but also a variety of other ROS and inflammation-related disorders.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Chemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Horinouchi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan; DDS Research Institute, Sojo University, Kumamoto 860-0082, Japan. Electronic address: otagirim@ph.sojo-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D002248:Carbon Monoxide / Q000627:therapeutic use*; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000737:chemistry / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000737:chemistry*
chemical_list: D018925:Chemokines; D006454:Hemoglobins; D018836:Inflammation Mediators; D008055:Lipids; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D053835:Unilamellar Liposomes; D001761:Bleomycin; D002248:Carbon Monoxide
keywords: Antioxidant; Fibrosis; Inflammation; Liposome; Lung