title: Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles.
abstract: Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1α promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1α. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically-applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation.
authors.affiliation: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Stanford BioADD Laboratory, Stanford, CA, USA.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Malkovskiy
authors.affiliation: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Tian
authors.affiliation: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Yon K
authors.initials: YK
authors.lastname: Sung
authors.affiliation: Stanford BioADD Laboratory, Stanford, CA, USA.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Sun
authors.affiliation: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Joe L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Stanford BioADD Laboratory, Stanford, CA, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Manickam
authors.affiliation: Stanford BioADD Laboratory, Stanford, CA, USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Wagh
authors.affiliation: Stanford Cell Sciences Imaging Facility, Stanford, CA, USA.
authors.forename: Lydia-Marie
authors.initials: LM
authors.lastname: Joubert
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Stanford BioADD Laboratory, Stanford, CA, USA.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.affiliation: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy*; D016040:Lung Transplantation / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000637:transplantation
chemical_list: D043925:Angiogenesis Inducing Agents; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D017382:Reactive Oxygen Species; D000072483:Placenta Growth Factor; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D003676:Deferoxamine
keywords: Bioabsorption; Nanoparticle; Oxygenation; Surface treatment; Transplantation; Wound healing