title: Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis.
abstract: Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling.
  
  
  
  A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided.
  
  
  
  Administration of FG-3019 prevented (∼50%-80%) or reversed (∼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation ( P < .01). Importantly, when antibody treatment was initiated at 16 weeks after thoracic irradiation, FG-3019 reversed established lung remodeling and restored lung function. CTGF blockade abrogated M2 polarized macrophage influx, normalized radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression.
  
  
  
  These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Departments of Radiation Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bickelhaupt
authors.affiliation: Departments of Cardiology, University Hospital Center, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Departments of Radiation Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Timke
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Wirkner
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Dadrich
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Flechsig
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tietz
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pföhler
authors.affiliation: Departments of Experimental Surgery, University Hospital Center, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gross
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Peschke
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Line
authors.initials: L
authors.lastname: Hoeltgen
authors.affiliation: Departments of Cardiology, University Hospital Center, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Departments of Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Departments of Radiation Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Nils H
authors.initials: NH
authors.lastname: Nicolay
authors.affiliation: Departments of Hematology and Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Saffrich
authors.affiliation: Departments of Radiation Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Departments of Molecular Biology, FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Sternlicht
authors.affiliation: Departments of Molecular Biology, FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Seeley
authors.affiliation: Drug Research, FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.affiliation: Departments of Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Departments of Radiation Oncology, University Hospital Center, Heidelberg, Germany.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D059630:Mesenchymal Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D011654:Pulmonary Edema / Q000517:prevention & control; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects / Q000528:radiation effects; D011832:Radiation Injuries / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D017564:Radiation Pneumonitis / Q000517:prevention & control; D011878:Radiotherapy / Q000009:adverse effects; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C526317:CCN2 protein, human; D055513:Connective Tissue Growth Factor; C560078:pamrevlumab