title: LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-β and BMP-associated proinflammatory and proangiogenic signals.
abstract: OBJECTIVE
  Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-β signaling is considered to play an important role.
  
  
  METHODS
  We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-β receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts.
  
  
  RESULTS
  Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-β signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals.
  
  
  CONCLUSIONS
  Small-molecule inhibitors of the TGF-β receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis.
authors.affiliation: Radiation Oncology, German Cancer Research Center and University Hospital Center Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Flechsig
authors.forename: Monika
authors.initials: M
authors.lastname: Dadrich
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bickelhaupt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Jenne
authors.forename: Kai
authors.initials: K
authors.lastname: Hauser
authors.forename: Carmen
authors.initials: C
authors.lastname: Timke
authors.forename: Peter
authors.initials: P
authors.lastname: Peschke
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hahn
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yingling
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
authors.forename: Ute
authors.initials: U
authors.lastname: Wirkner
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D042501:Angiogenic Proteins / Q000502:physiology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002478:Cells, Cultured; D054893:Cone-Beam Computed Tomography; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D017564:Radiation Pneumonitis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051899:Smad2 Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D042501:Angiogenic Proteins; D019485:Bone Morphogenetic Proteins; D018836:Inflammation Mediators; C530108:LY2109761; D011720:Pyrazoles; D011758:Pyrroles; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I