Radiation Enteropathy

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Martin Hauer-jensen - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic potential of natural plant products and their metabolites in preventing Radiation Enteropathy resulting from abdominal or pelvic irRadiation.
    International journal of radiation biology, 2019
    Co-Authors: Rupak Pathak, Sumit K. Shah, Martin Hauer-jensen
    Abstract:

    Radiation-induced gastrointestinal injury or Radiation Enteropathy is an imminent risk during Radiation therapy of abdominal or pelvic tumors. Despite remarkable technological advancements in image-guided Radiation delivery techniques, the risk of intestinal injury after radiotherapy for abdominal or pelvic cancers has not been completely eliminated. The irradiated intestine undergoes varying degrees of adverse structural and functional changes, which can result in transient or long-term complications. The risk of development of Enteropathy depends on dose, fractionation, and quality of Radiation. Moreover, the patients' medical condition, age, inter-individual sensitivity to Radiation and size of the treatment area are also risk factors of Radiation Enteropathy. Therefore, strategies are needed to prevent radiotherapy-induced undesirable alteration in the gastrointestinal tract. Many natural plant products, by virtue of their plethora of biological activities, alleviate the adverse effects of Radiation-induced injury. The current review discusses potential roles and possible mechanisms of natural plant products in suppressing Radiation Enteropathy. Natural plant products have the potential to suppress intestinal Radiation toxicity.

  • Fibrinogen deficiency suppresses the development of early and delayed Radiation Enteropathy.
    World journal of gastroenterology, 2017
    Co-Authors: Junru Wang, Rupak Pathak, Sarita Garg, Martin Hauer-jensen
    Abstract:

    Fibrinogen deficiency suppresses the development of early and delayed Radiation Enteropathy

  • Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
    2016
    Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensen
    Abstract:

    Radiation therapy in the treatment of cancer is dose limited by Radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-b1) in intestinal and cardiac Radiation injury, we studied the influence of pharmacological induction of TGF-b1 with xaliproden (SR 57746A) in rat models of Radiation Enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-b induction may enhance Radiation injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation injury. In the Radiation Enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-b1 levels by 300 % and significantly induced expression of TGF-b1 and TGF-b1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-b1 induction. Similarly, in the RIHD model induction of TGF-b1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-b1 in biological mechanisms of Radiation-induce

  • Correction: Radiation Enteropathy—pathogenesis, treatment and prevention
    Nature Reviews Gastroenterology & Hepatology, 2014
    Co-Authors: Martin Hauer-jensen, James W. Denham, H. Jervoise N. Andreyev
    Abstract:

    Nat. Rev. Gastroenterol. Hepatol. 11, 470–479 (2014); doi:10.1038/nrgastro.2014.46 In the version of this article originally published online and in print, the definition for PAS was listed incorrectly as para-aminosalicylic acid instead of periodic acid–Schiff in the legend for Figure 3. The error has been corrected for the HTML and PDF versions of the article.

  • Radiation Enteropathy--pathogenesis, treatment and prevention.
    Nature reviews. Gastroenterology & hepatology, 2014
    Co-Authors: Martin Hauer-jensen, James W. Denham, H. Jervoise N. Andreyev
    Abstract:

    Radiation Enteropathy remains an important obstacle to uncomplicated cancer cures after Radiation therapy of pelvic and abdominal malignancies. Moreover, the prevalence of Radiation Enteropathy in the population exceeds that of IBD. This Review introduces the clinical problem of Radiation Enteropathy, discusses contemporary concepts in pathogenesis, current therapeutic options and strategies for development of new radioprotective agents.

Junru Wang - One of the best experts on this subject based on the ideXlab platform.

  • Fibrinogen deficiency suppresses the development of early and delayed Radiation Enteropathy.
    World journal of gastroenterology, 2017
    Co-Authors: Junru Wang, Rupak Pathak, Sarita Garg, Martin Hauer-jensen
    Abstract:

    Fibrinogen deficiency suppresses the development of early and delayed Radiation Enteropathy

  • Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
    2016
    Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensen
    Abstract:

    Radiation therapy in the treatment of cancer is dose limited by Radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-b1) in intestinal and cardiac Radiation injury, we studied the influence of pharmacological induction of TGF-b1 with xaliproden (SR 57746A) in rat models of Radiation Enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-b induction may enhance Radiation injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation injury. In the Radiation Enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-b1 levels by 300 % and significantly induced expression of TGF-b1 and TGF-b1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-b1 induction. Similarly, in the RIHD model induction of TGF-b1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-b1 in biological mechanisms of Radiation-induce

  • Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
    PloS one, 2013
    Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensen
    Abstract:

    Radiation therapy in the treatment of cancer is dose limited by Radiation injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-β1) in intestinal and cardiac Radiation injury, we studied the influence of pharmacological induction of TGF-β1 with xaliproden (SR 57746A) in rat models of Radiation Enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-β induction may enhance Radiation injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation injury. In the Radiation Enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-β1 levels by 300% and significantly induced expression of TGF-β1 and TGF-β1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-β1 induction. Similarly, in the RIHD model induction of TGF-β1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-β1 in biological mechanisms of Radiation-induced adverse remodeling in the intestine and the heart.

  • Inhibition of protease-activated receptor 1 ameliorates intestinal Radiation mucositis in a preclinical rat model.
    International journal of radiation oncology biology physics, 2012
    Co-Authors: Junru Wang, Louis M. Fink, Ashwini Kulkarni, Madhu Chintala, Martin Hauer-jensen
    Abstract:

    Purpose To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on Radiation Enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. Methods and Materials Rats underwent fractionated X-irRadiation (5 Gy × 9) of a 4-cm small-bowel segment. Early Radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irRadiation. The effect of PAR1 inhibition on development of chronic intestinal Radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irRadiation, or continuously until termination of the experiment 26 weeks after irRadiation. Results Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal Radiation injury ( P =.002), number of myeloperoxidase-positive ( P =.03) and proliferating cell nuclear antigen-positive ( P =.04) cells, and collagen III accumulation ( P =.005). In contrast, there was no difference in delayed Radiation Enteropathy in either the 2- or 26-week administration groups. Conclusion Pharmacological blockade of PAR1 seems to reduce early Radiation mucositis but does not affect the level of delayed intestinal Radiation fibrosis. Early Radiation Enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal Radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.

  • Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine
    International journal of radiation oncology biology physics, 2010
    Co-Authors: Junru Wang, Marjan Boerma, Ashwini Kulkarni, Morley D. Hollenberg, Martin Hauer-jensen
    Abstract:

    Purpose Protease-activated receptor-2 (PAR 2 ) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR 2 is strikingly upregulated and exhibits increased activation in response to intestinal irRadiation. We examined the mechanistic significance of Radiation Enteropathy development by assessing the effect of exogenous PAR 2 activation. Methods and Materials Rat small bowel was exposed to localized single-dose Radiation (16.5 Gy). The PAR 2 agonist (2-furoyl-LIGRLO-NH 2 ) or vehicle was injected intraperitoneally daily for 3 days before irRadiation (before), for 7 days after irRadiation (after), or both 3 days before and 7 days after irRadiation (before-after). Early and delayed Radiation Enteropathy was assessed at 2 and 26 weeks after irRadiation using quantitative histologic examination, morphometry, and immunohistochemical analysis. Results The PAR 2 agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irRadiation, administration of the PAR 2 agonist was associated with more severe mucosal injury and increased intestinal wall thickness in all three treatment groups ( p 2 agonist also exacerbated the Radiation injury score, serosal thickening, and mucosal inflammation ( p 2 did not affect Radiation-induced intestinal injury at 26 weeks. Conclusion The results of the present study support a role for PAR 2 activation in the pathogenesis of early Radiation-induced intestinal injury. Pharmacologic PAR 2 antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.

Konrad K. Richter - One of the best experts on this subject based on the ideXlab platform.

  • Radiation-induced granulocyte transmigration predicts development of delayed structural changes in rat intestine.
    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2001
    Co-Authors: Konrad K. Richter, Junru Wang, Magne K. Fagerhol, Martin Hauer-jensen
    Abstract:

    Abstract We examined whether early Radiation-induced granulocyte transmigration (assessed by the fecal transferrin excretion ELISA assay) predicts subsequent development of (consequential) chronic Radiation Enteropathy. After accounting for the effect of Radiation dose, transferrin excretion remained an independent predictor of overall tissue injury, intestinal fibrosis, and mucosal ulcers, but not TGF-β immunoreactivity.

  • upregulation and spatial shift in the localization of the mannose 6 phosphate insulin like growth factor ii receptor during Radiation Enteropathy development in the rat
    Radiotherapy and Oncology, 1999
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Martin Hauerjensen
    Abstract:

    Abstract Background and purpose : Transforming growth factor β 1 (TGF- β 1) appears to play an important role in the pathogenesis of chronic Radiation-induced fibrosis in the intestine and several other organs. TGF- β 1 is secreted as a non-biologically active complex and its function depends on activation. In vitro data suggest that the mannose 6-phosphate/insulin-like growth factor- β (M6P/IGF-II) receptor is involved in the mechanism of TGF- β 1 activation. Thus, we used a rat model of Radiation Enteropathy to examine the potential role of the M6P/IGF-II receptor in the in vivo regulation of TGF- β 1 activity and localization. Materials and methods : A scrotal hernia containing a loop of small intestine was created in male rats. The intestine in the scrotum was exposed to 0, 12, or 21 Gy single dose X-Radiation. Groups of rats were euthanized 1 day and 2, 6 and 26 weeks after irRadiation. Histopathologic injury was assessed with a Radiation injury score (RIS). Computerized image analysis was used to identify M6P/IGF-II receptor-positive cells and to quantify extracellular matrix-associated TGF- β 1 immunoreactivity. Changes in urokinase plasminogen activator (uPA), tissue-like plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) immunoreactivity were also assessed. Results : In normal (sham-irradiated) intestine, M6P/IGF-II immunoreactivity was confined to relatively weak, but specific epithelial staining. Irradiated intestine exhibited a highly significant time- and dose-dependent increase in the number of M6P/IGF-II receptor-positive cells ( P β 1 in areas of histopathologic injury. There were highly significant associations between the number of M6P/IGF-II receptor-positive stromal cells and TGF- β 1 immunoreactivity ( P P P P Conclusions : M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF- β 1 activity and responsible for the tissue specificity of TGF- β 1 action after irRadiation.

  • Upregulation and spatial shift in the localization of the mannose 6-phosphate/insulin-like growth factor II receptor during Radiation Enteropathy development in the rat.
    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 1999
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Martin Hauer-jensen
    Abstract:

    Abstract Background and purpose : Transforming growth factor β 1 (TGF- β 1) appears to play an important role in the pathogenesis of chronic Radiation-induced fibrosis in the intestine and several other organs. TGF- β 1 is secreted as a non-biologically active complex and its function depends on activation. In vitro data suggest that the mannose 6-phosphate/insulin-like growth factor- β (M6P/IGF-II) receptor is involved in the mechanism of TGF- β 1 activation. Thus, we used a rat model of Radiation Enteropathy to examine the potential role of the M6P/IGF-II receptor in the in vivo regulation of TGF- β 1 activity and localization. Materials and methods : A scrotal hernia containing a loop of small intestine was created in male rats. The intestine in the scrotum was exposed to 0, 12, or 21 Gy single dose X-Radiation. Groups of rats were euthanized 1 day and 2, 6 and 26 weeks after irRadiation. Histopathologic injury was assessed with a Radiation injury score (RIS). Computerized image analysis was used to identify M6P/IGF-II receptor-positive cells and to quantify extracellular matrix-associated TGF- β 1 immunoreactivity. Changes in urokinase plasminogen activator (uPA), tissue-like plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) immunoreactivity were also assessed. Results : In normal (sham-irradiated) intestine, M6P/IGF-II immunoreactivity was confined to relatively weak, but specific epithelial staining. Irradiated intestine exhibited a highly significant time- and dose-dependent increase in the number of M6P/IGF-II receptor-positive cells ( P β 1 in areas of histopathologic injury. There were highly significant associations between the number of M6P/IGF-II receptor-positive stromal cells and TGF- β 1 immunoreactivity ( P P P P Conclusions : M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF- β 1 activity and responsible for the tissue specificity of TGF- β 1 action after irRadiation.

  • Cellular Sources of Transforming Growth Factor-β Isoforms in Early and Chronic Radiation Enteropathy
    The American journal of pathology, 1998
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Huaien Zheng, Martin Hauer-jensen
    Abstract:

    The three mammalian transforming growth factor (TGF)-β isoforms (TGF-β1, TGF-β2, and TGF-β3) differ in their putative roles in Radiation-induced fibrosis in intestine and other organs. Furthermore, tissue specificity of TGF-β action may result from temporal or spatial changes in production and/or activation. The present study examined shifts in the cell types expressing TGF-β mRNA relative to TGF-β immunoreactivity and histopathological injury during Radiation Enteropathy development. A 4-cm loop of rat small intestine was locally exposed to 0, 12, or 21-Gy single doses of x-irRadiation. Sham-irradiated and irradiated intestine were procured 2 and 26 weeks after irRadiation. Cells expressing the TGF-β1, TGF-β2, or TGF-β3 transcripts were identified by in situ hybridization with digoxigenin-labeled riboprobes. Intestinal wall TGF-β immunoreactivity was measured using computerized image analysis, and structural Radiation injury was assessed by quantitative histopathology. Normal intestinal epithelium expressed transcripts for all three TGF-β isoforms. Two weeks after irRadiation, regenerating crypts, inflammatory cells, smooth muscle cells, and mesothelium exhibited increased TGF-β1 expression and, to a lesser degree, TGF-β2 and TGF-β3 expression. Twenty-six weeks after irRadiation, TGF-β2 and TGF-β3 expression had returned to normal. In contrast, TGF-β1 expression remained elevated in smooth muscle, mesothelium, endothelium, and fibroblasts in regions of chronic fibrosis. Extracellular matrix-associated TGF-β1 immunoreactivity was significantly increased at both observation times, whereas, TGF-β2 and TGF-β3 immunoreactivity exhibited minimal postRadiation changes. Intestinal Radiation injury is associated with overexpression of all three TGF-β isoforms in regenerating epithelium. Radiation Enteropathy was also associated with sustained shifts in the cellular sources of TGF-β1 from epithelial cells to cells involved in the pathogenesis of chronic fibrosis. TGF-β2 and TGF-β3 did not exhibit consistent long-term changes. TGF-β1 appears to be the predominant isoform in Radiation Enteropathy and may be more important in the mechanisms of chronicity than TGF-β2 and TGF-β3.

  • Changes in Transforming Growth Factor β1 Gene Expression and Immunoreactivity Levels during Development of Chronic Radiation Enteropathy
    Radiation research, 1998
    Co-Authors: Martin Hauer-jensen, Junru Wang, Konrad K. Richter, Ching-ching Sung, Etsuko Abe, James W. Hardin
    Abstract:

    Chronic intestinal Radiation injury is associated with locally increased TGF-beta1 immunoreactivity that correlates with morphological alterations. However, the underlying mechanisms are not known. This study examined changes in intestinal TGF-beta1 immunoreactivity, steady-state TGF-beta1 mRNA levels, and cellular localization of TGF-beta1 mRNA during development of chronic Radiation Enteropathy in a rat model. A loop of small bowel was fixed inside the scrotum of orchiectomized male rats. The intestine was subsequently exposed locally to 0, 12 or 21 Gy X Radiation. Intestine was procured at 24 h and 2, 6 and 26 weeks and subjected to histopathological analysis, quantitative immunohistochemistry with computerized image analysis, assessment of steady-state TGF-beta1 mRNA levels with quantitative reverse transcriptase polymerase chain reaction, and identification of cell types expressing TGF-beta1 mRNA with in situ hybridization. Intestine from the 21-Gy group exhibited more histopathological injury and increased TGF-beta immunoreactivity 2-26 weeks after irRadiation compared to the 12-Gy group and sham-irradiated controls. TGF-beta1 mRNA in irradiated intestine increased up to six times relative to controls at 24 h and 2 weeks, was less at 6 weeks, and did not differ from controls at 26 weeks. In situ hybridization detected TGF-beta1 mRNA in epithelial and Paneth cells in control intestine. Irradiated intestine exhibited additional TGF-beta1 mRNA in inflammatory and fibroblast-like cells. We conclude that there is a Radiation-induced shift in the cellular sources of TGF-beta1, and that Tgfb1 gene expression is increased mainly during the early phases of Radiation Enteropathy, preceding the increase in immunoreactivity and histopathological injury. Translational or post-translational mechanisms are likely involved in sustaining increased TGF-beta1 immunoreactivity levels during the chronic phase of Radiation Enteropathy.

Ching-ching Sung - One of the best experts on this subject based on the ideXlab platform.

  • The synthetic somatostatin analogue, octreotide, ameliorates acute and delayed intestinal Radiation injury
    International journal of radiation oncology biology physics, 1999
    Co-Authors: Junru Wang, Ching-ching Sung, Huaien Zheng, Martin Hauer-jensen
    Abstract:

    Abstract Purpose: Reducing intraluminal proteolytic activity attenuates intestinal Radiation toxicity. This study assessed whether pharmacological inhibition of exocrine pancreatic secretion protects against early and delayed Radiation Enteropathy in a preclinical rat model. Methods and Materials: Rat ileum was sham-irradiated or exposed to 16 once-daily 4.2 Gy fractions of X-Radiation. Vehicle or somatostatin analogue (octreotide, 2 μg/kg/hr) were administered from 2 days prior to 10 days after the end of irRadiation. Mucosal injury was monitored noninvasively by assessment of granulocyte transmigration. Radiation injury was assessed at 2 weeks (early phase) and 26 weeks (chronic phase) using quantitative histopathology, immunohistochemistry, and morphometry. Results: Octreotide decreased granulocyte transmigration ( p p = 0.0002), attenuated structural injury at 2 weeks ( p = 0.04) and 26 weeks ( p = 0.02), preserved mucosal surface area at 2 weeks ( p = 0.0008) and 26 weeks ( p = 0.0008), and reduced intestinal wall thickening at 26 weeks ( p = 0.002). Octreotide did not affect granulocyte transmigration, histology, or mucosal surface area in sham-irradiated controls. Conclusion: These results demonstrate the importance of consequential mechanisms in the pathogenesis of chronic Radiation Enteropathy. Short-term octreotide administration ameliorates acute Radiation-induced mucosal injury, as well as chronic structural changes, and should be subject to further preclinical and clinical testing.

  • upregulation and spatial shift in the localization of the mannose 6 phosphate insulin like growth factor ii receptor during Radiation Enteropathy development in the rat
    Radiotherapy and Oncology, 1999
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Martin Hauerjensen
    Abstract:

    Abstract Background and purpose : Transforming growth factor β 1 (TGF- β 1) appears to play an important role in the pathogenesis of chronic Radiation-induced fibrosis in the intestine and several other organs. TGF- β 1 is secreted as a non-biologically active complex and its function depends on activation. In vitro data suggest that the mannose 6-phosphate/insulin-like growth factor- β (M6P/IGF-II) receptor is involved in the mechanism of TGF- β 1 activation. Thus, we used a rat model of Radiation Enteropathy to examine the potential role of the M6P/IGF-II receptor in the in vivo regulation of TGF- β 1 activity and localization. Materials and methods : A scrotal hernia containing a loop of small intestine was created in male rats. The intestine in the scrotum was exposed to 0, 12, or 21 Gy single dose X-Radiation. Groups of rats were euthanized 1 day and 2, 6 and 26 weeks after irRadiation. Histopathologic injury was assessed with a Radiation injury score (RIS). Computerized image analysis was used to identify M6P/IGF-II receptor-positive cells and to quantify extracellular matrix-associated TGF- β 1 immunoreactivity. Changes in urokinase plasminogen activator (uPA), tissue-like plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) immunoreactivity were also assessed. Results : In normal (sham-irradiated) intestine, M6P/IGF-II immunoreactivity was confined to relatively weak, but specific epithelial staining. Irradiated intestine exhibited a highly significant time- and dose-dependent increase in the number of M6P/IGF-II receptor-positive cells ( P β 1 in areas of histopathologic injury. There were highly significant associations between the number of M6P/IGF-II receptor-positive stromal cells and TGF- β 1 immunoreactivity ( P P P P Conclusions : M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF- β 1 activity and responsible for the tissue specificity of TGF- β 1 action after irRadiation.

  • Upregulation and spatial shift in the localization of the mannose 6-phosphate/insulin-like growth factor II receptor during Radiation Enteropathy development in the rat.
    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 1999
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Martin Hauer-jensen
    Abstract:

    Abstract Background and purpose : Transforming growth factor β 1 (TGF- β 1) appears to play an important role in the pathogenesis of chronic Radiation-induced fibrosis in the intestine and several other organs. TGF- β 1 is secreted as a non-biologically active complex and its function depends on activation. In vitro data suggest that the mannose 6-phosphate/insulin-like growth factor- β (M6P/IGF-II) receptor is involved in the mechanism of TGF- β 1 activation. Thus, we used a rat model of Radiation Enteropathy to examine the potential role of the M6P/IGF-II receptor in the in vivo regulation of TGF- β 1 activity and localization. Materials and methods : A scrotal hernia containing a loop of small intestine was created in male rats. The intestine in the scrotum was exposed to 0, 12, or 21 Gy single dose X-Radiation. Groups of rats were euthanized 1 day and 2, 6 and 26 weeks after irRadiation. Histopathologic injury was assessed with a Radiation injury score (RIS). Computerized image analysis was used to identify M6P/IGF-II receptor-positive cells and to quantify extracellular matrix-associated TGF- β 1 immunoreactivity. Changes in urokinase plasminogen activator (uPA), tissue-like plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) immunoreactivity were also assessed. Results : In normal (sham-irradiated) intestine, M6P/IGF-II immunoreactivity was confined to relatively weak, but specific epithelial staining. Irradiated intestine exhibited a highly significant time- and dose-dependent increase in the number of M6P/IGF-II receptor-positive cells ( P β 1 in areas of histopathologic injury. There were highly significant associations between the number of M6P/IGF-II receptor-positive stromal cells and TGF- β 1 immunoreactivity ( P P P P Conclusions : M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF- β 1 activity and responsible for the tissue specificity of TGF- β 1 action after irRadiation.

  • Cellular Sources of Transforming Growth Factor-β Isoforms in Early and Chronic Radiation Enteropathy
    The American journal of pathology, 1998
    Co-Authors: Junru Wang, Konrad K. Richter, Ching-ching Sung, Huaien Zheng, Martin Hauer-jensen
    Abstract:

    The three mammalian transforming growth factor (TGF)-β isoforms (TGF-β1, TGF-β2, and TGF-β3) differ in their putative roles in Radiation-induced fibrosis in intestine and other organs. Furthermore, tissue specificity of TGF-β action may result from temporal or spatial changes in production and/or activation. The present study examined shifts in the cell types expressing TGF-β mRNA relative to TGF-β immunoreactivity and histopathological injury during Radiation Enteropathy development. A 4-cm loop of rat small intestine was locally exposed to 0, 12, or 21-Gy single doses of x-irRadiation. Sham-irradiated and irradiated intestine were procured 2 and 26 weeks after irRadiation. Cells expressing the TGF-β1, TGF-β2, or TGF-β3 transcripts were identified by in situ hybridization with digoxigenin-labeled riboprobes. Intestinal wall TGF-β immunoreactivity was measured using computerized image analysis, and structural Radiation injury was assessed by quantitative histopathology. Normal intestinal epithelium expressed transcripts for all three TGF-β isoforms. Two weeks after irRadiation, regenerating crypts, inflammatory cells, smooth muscle cells, and mesothelium exhibited increased TGF-β1 expression and, to a lesser degree, TGF-β2 and TGF-β3 expression. Twenty-six weeks after irRadiation, TGF-β2 and TGF-β3 expression had returned to normal. In contrast, TGF-β1 expression remained elevated in smooth muscle, mesothelium, endothelium, and fibroblasts in regions of chronic fibrosis. Extracellular matrix-associated TGF-β1 immunoreactivity was significantly increased at both observation times, whereas, TGF-β2 and TGF-β3 immunoreactivity exhibited minimal postRadiation changes. Intestinal Radiation injury is associated with overexpression of all three TGF-β isoforms in regenerating epithelium. Radiation Enteropathy was also associated with sustained shifts in the cellular sources of TGF-β1 from epithelial cells to cells involved in the pathogenesis of chronic fibrosis. TGF-β2 and TGF-β3 did not exhibit consistent long-term changes. TGF-β1 appears to be the predominant isoform in Radiation Enteropathy and may be more important in the mechanisms of chronicity than TGF-β2 and TGF-β3.

  • Changes in Transforming Growth Factor β1 Gene Expression and Immunoreactivity Levels during Development of Chronic Radiation Enteropathy
    Radiation research, 1998
    Co-Authors: Martin Hauer-jensen, Junru Wang, Konrad K. Richter, Ching-ching Sung, Etsuko Abe, James W. Hardin
    Abstract:

    Chronic intestinal Radiation injury is associated with locally increased TGF-beta1 immunoreactivity that correlates with morphological alterations. However, the underlying mechanisms are not known. This study examined changes in intestinal TGF-beta1 immunoreactivity, steady-state TGF-beta1 mRNA levels, and cellular localization of TGF-beta1 mRNA during development of chronic Radiation Enteropathy in a rat model. A loop of small bowel was fixed inside the scrotum of orchiectomized male rats. The intestine was subsequently exposed locally to 0, 12 or 21 Gy X Radiation. Intestine was procured at 24 h and 2, 6 and 26 weeks and subjected to histopathological analysis, quantitative immunohistochemistry with computerized image analysis, assessment of steady-state TGF-beta1 mRNA levels with quantitative reverse transcriptase polymerase chain reaction, and identification of cell types expressing TGF-beta1 mRNA with in situ hybridization. Intestine from the 21-Gy group exhibited more histopathological injury and increased TGF-beta immunoreactivity 2-26 weeks after irRadiation compared to the 12-Gy group and sham-irradiated controls. TGF-beta1 mRNA in irradiated intestine increased up to six times relative to controls at 24 h and 2 weeks, was less at 6 weeks, and did not differ from controls at 26 weeks. In situ hybridization detected TGF-beta1 mRNA in epithelial and Paneth cells in control intestine. Irradiated intestine exhibited additional TGF-beta1 mRNA in inflammatory and fibroblast-like cells. We conclude that there is a Radiation-induced shift in the cellular sources of TGF-beta1, and that Tgfb1 gene expression is increased mainly during the early phases of Radiation Enteropathy, preceding the increase in immunoreactivity and histopathological injury. Translational or post-translational mechanisms are likely involved in sustaining increased TGF-beta1 immunoreactivity levels during the chronic phase of Radiation Enteropathy.

Marie-catherine Vozenin-brotons - One of the best experts on this subject based on the ideXlab platform.

  • Pravastatin Inhibits the Rho/CCN2/Extracellular Matrix Cascade in Human Fibrosis Explants and Improves Radiation-Induced Intestinal Fibrosis in Rats
    Clinical Cancer Research, 2007
    Co-Authors: Valerie Haydont, C Bourgier, Marc Pocard, A Lusinchi, Jocelyne Aigueperse, Denis Mathe, Jean Bourhis, Marie-catherine Vozenin-brotons
    Abstract:

    Purposes: Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action. Experimental Design: Rho and ROCK activities were monitored in human explants presenting Radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from Radiation Enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic Radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d pravastatin in the drinking water. Results: The results obtained with human explants show that pravastatin specifically inhibits Rho activity in submucosal mesenchymal cells. Pravastatin also elicits ROCK inhibition, and subsequent CCN2 production in human explants and smooth muscle cells isolated from Radiation Enteropathy. Inhibition of type I collagen and fibronectin does occur, showing that pravastatin modulates the secretory phenotype of mesenchymal cells. Lastly, curative pravastatin administration improves Radiation Enteropathy in rats. This structural improvement is associated with decreased deposition of CCN2 and subsequent decreased extracellular matrix deposition. Conclusion: Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in Radiation-induced Enteropathy, and is easily transferable into the clinic.

  • Pravastatin Inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves Radiation-induced intestinal fibrosis in rats.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2007
    Co-Authors: Valerie Haydont, C Bourgier, Marc Pocard, A Lusinchi, Jocelyne Aigueperse, Denis Mathe, Jean Bourhis, Marie-catherine Vozenin-brotons
    Abstract:

    Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action. Rho and ROCK activities were monitored in human explants presenting Radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from Radiation Enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic Radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d pravastatin in the drinking water. The results obtained with human explants show that pravastatin specifically inhibits Rho activity in submucosal mesenchymal cells. Pravastatin also elicits ROCK inhibition, and subsequent CCN2 production in human explants and smooth muscle cells isolated from Radiation Enteropathy. Inhibition of type I collagen and fibronectin does occur, showing that pravastatin modulates the secretory phenotype of mesenchymal cells. Lastly, curative pravastatin administration improves Radiation Enteropathy in rats. This structural improvement is associated with decreased deposition of CCN2 and subsequent decreased extracellular matrix deposition. Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in Radiation-induced Enteropathy, and is easily transferable into the clinic.

  • Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves Radiation-induced intestinal fibrosis in rats
    Clinical Cancer Research, 2007
    Co-Authors: Valerie Haydont, C Bourgier, Marc Pocard, A Lusinchi, Jocelyne Aigueperse, Denis Mathe, Jean Bourhis, Marie-catherine Vozenin-brotons
    Abstract:

    Purposes: Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action. Experimental Design: Rho and ROCK activities were monitored in human explants presenting Radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from Radiation Enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic Radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d pravastatin in the drinking water. Results: The results obtained with human explants show that pravastatin specifically inhibits Rho activity in submucosal mesenchymal cells. Pravastatin also elicits ROCK inhibition, and subsequent CCN2 production in human explants and smooth muscle cells isolated from Radiation Enteropathy. Inhibition of type I collagen and fibronectin does occur, showing that pravastatin modulates the secretory phenotype of mesenchymal cells. Lastly, curative pravastatin administration improves Radiation Enteropathy in rats. This structural improvement is associated with decreased deposition of CCN2 and subsequent decreased extracellular matrix deposition. Conclusion: Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in Radiation-induced Enteropathy, and is easily transferable into the clinic. © 2007 American Association for Cancer Research.

  • Successful Mitigation of Delayed Intestinal Radiation Injury Using Pravastatin is not Associated with Acute Injury Improvement or Tumor Protection
    International journal of radiation oncology biology physics, 2007
    Co-Authors: Valerie Haydont, Agnès François, C Bourgier, Jocelyne Aigueperse, Jean Bourhis, Olivier Gilliot, Sofia Rivera, Marie-catherine Vozenin-brotons
    Abstract:

    Purpose To investigate whether pravastatin mitigates delayed Radiation-induced Enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition. Methods and Materials Mitigation of delayed Radiation-induced Enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irRadiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14 days, 15 weeks, and 26 weeks after irRadiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments. Results Pravastatin improved delayed Radiation Enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irRadiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from Radiation injury. Conclusion Pravastatin provides effective protection against delayed Radiation Enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.