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  • THORACIC IRRADIATION  (1)
  • TRANSIT  (1)
  • 1
    Keywords: LUNG ; PATHWAYS ; MICE ; CANCER-THERAPY ; FACTOR-BETA-1 ; GLIOBLASTOMA ; TRANSFORMING-GROWTH-FACTOR ; KINASE INHIBITOR LY2109761 ; NORMAL TISSUE-INJURY ; THORACIC IRRADIATION
    Abstract: PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signaling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-beta 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-beta 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. CONCLUSION: Small-molecule inhibitors of the TGF-beta receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis.
    Type of Publication: Journal article published
    PubMed ID: 22547771
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  • 2
    Keywords: IMAGES ; segmentation ; DISEASE ; INTERSTITIAL-CELLS ; GASTROINTESTINAL MOTILITY ; DYNAMIC MR ; TRANSIT ; CAJAL ; INTESTINAL MOTILITY
    Abstract: Small bowel motility analyses using magnetic resonance imaging (MRI) could reduce current invasive techniques in animal studies and comply with the 'three Rs' rule for human animal experimentation. Thus we investigated the feasibility of in vivo small bowel motility analyses in mice using dynamic MRI acquisitions. All experimental procedures were approved by the institutional animal care committee. Six C57BL/6 mice underwent MRI without additional preparation after isoflurane anaesthetization in the prone position on a 4.7 T small animal imager equipped with a linear polarized hydrogen birdcage whole-body mouse coil. Motility was assessed using a true fast imaging in a steady precession sequence in the coronal orientation (acquisition time per slice 512 ms, in-plane resolution 234 x 234 microm, matrix size 128 x 128, slice thickness 1 mm) over 30 s corresponding to 60 acquisitions. Motility was manually assessed measuring the small bowel diameter change over time. The resulting motility curves were analysed for the following parameters: contraction frequency per minute (cpm), maximal contraction amplitude (maximum to minimum [mm]), luminal diameter (mm) and luminal occlusion rate. Small bowel motility quantification was found to be possible in all animals with a mean small bowel contraction frequency of 10.67 cpm (SD +/- 3.84), a mean amplitude of the contractions of 1.33 mm (SD +/- 0.43) and a mean luminal diameter of 1.37 mm (SD +/- 0.42). The mean luminal occlusion rate was 1.044 (SD +/- 0.45%/100). The mean duration needed for a single motility assessment was 185 s (SD +/- 54.02). Thus our study demonstrated the feasibility of an easy and time-sparing functional assessment for in vivo small bowel motility analyses in mice. This could improve the development of small animal models of intestinal diseases and provide a method similar to clinical MR examinations that is in concordance with the 'three Rs' for humane animal experimentation.
    Type of Publication: Journal article published
    PubMed ID: 25266965
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