LY2109761 Attenuates Radiation-Induced Pulmonary Murine Fibrosis via Reversal of TGF-β and BMP-Associated Proinflammatory and Proangiogenic Signals

• Published in: Clinical cancer research 2012-07, Vol.18 (13), p.3616-3627
• Main Authors: FLECHSIG, Paul, DADRICH, Monika, LAHN, Michael, WIRKNER, Ute, HUBER, Peter E, BICKELHAUPT, Sebastian, JENNE, Jurgen, HAUSER, Kai, TIMKE, Carmen, PESCHKE, Peter, HAHN, Eric W, GRÖNE, Hermann-Josef, YINGLING, Jonathan
• Format: Article
• Language: English
• Subjects: Angiogenic Proteins - physiology; Animals; Antineoplastic agents; Biological and medical sciences; Bone Morphogenetic Proteins - physiology; Cells, Cultured; Cone-Beam Computed Tomography; Female; Fibroblasts - metabolism; Fibroblasts - radiation effects; Gene Expression Profiling; Humans; Inflammation Mediators - physiology; Lung - diagnostic imaging; Lung - pathology; Lung - radiation effects; Medical sciences; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Phosphorylation; Pneumology; Protein Processing, Post-Translational - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrroles - pharmacology; Pyrroles - therapeutic use; Radiation Injuries, Experimental - diagnostic imaging; Radiation Injuries, Experimental - drug therapy; Radiation Injuries, Experimental - pathology; Radiation Pneumonitis - diagnostic imaging; Radiation Pneumonitis - drug therapy; Radiation Pneumonitis - pathology; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; Respiratory system : syndromes and miscellaneous diseases; Smad2 Protein - metabolism; Transcription, Genetic; Transforming Growth Factor beta - physiology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2855

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. 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. 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. 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.