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  • 13-DEFICIENT MICE  (1)
  • FACTOR-BETA-1  (1)
  • 1
    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: IRRADIATION ; SURVIVAL ; Germany ; INHIBITION ; LUNG ; MODEL ; imaging ; EXPOSURE ; DRUG ; computed tomography ; MICE ; FAMILY ; REDUCTION ; MRI ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; TARGET ; MOUSE ; radiosurgery ; resistance ; EXTRACELLULAR-MATRIX ; tomography ; COMPUTED-TOMOGRAPHY ; GROWTH-FACTOR-BETA ; inflammation ; INJURY ; FEATURES ; fibrosis ; ONCOLOGY ; MATRIX METALLOPROTEINASES ; DEFICIENT MICE ; SCIENCE ; KNOCKOUT MOUSE ; development ; ionizing radiation ; methods ; PHASE ; proteases ; matrix metalloproteinase ; INDUCED LUNG FIBROSIS ; outcome ; HEPATIC STELLATE CELLS ; PULMONARY FIBROSIS ; 13-DEFICIENT MICE ; MMP13 ; Volume computed tomography
    Abstract: Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMPI 3 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57BI/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis. (C) 2010 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 20457355
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