title: Extracellular Adenosine Production by ecto-5'-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis.
abstract: Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5'-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately 3-fold. Histologic evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P < 0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacologic strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. Cancer Res; 76(10); 3045-56. ©2016 AACR.
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wirsdörfer
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: de Leve
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Federica
authors.initials: F
authors.lastname: Cappuccini
authors.affiliation: Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Therese
authors.initials: T
authors.lastname: Eldh
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alina V
authors.initials: AV
authors.lastname: Meyer
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gau
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Linda F
authors.initials: LF
authors.lastname: Thompson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas.
authors.forename: Ning-Yuan
authors.initials: NY
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas.
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Clinic, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Institute of Anatomy, Medical Faculty Carl Custav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kasper
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.affiliation: Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Ritchey
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: Department of Infection Immunology, Institute of Medical Microbiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.affiliation: Department of Radiation Oncology, University Hospital Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stuschke
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany. verena.jendrossek@uni-due.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
mesh_terms: D015720:5'-Nucleotidase / Q000502:physiology*; D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D058851:GPI-Linked Proteins; D012333:RNA, Messenger; D015720:5'-Nucleotidase; C548242:Nt5e protein, mouse; D000241:Adenosine