Radiation-induced enteropathy: Molecular basis of pentoxifylline–vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition

Hamama, Saad; Gilbert-Sirieix, Marie; Vozenin, Marie-Catherine; Delanian, S.

doi:10.1016/j.radonc.2012.08.023

Cited by 39 publications

(32 citation statements)

References 45 publications

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“…Patients with pre-RT CRP or post-RT CRP levels greater than 2 mg/L or patients experienced an increase in CRP levels greater than 1 mg/L have a higher risk for grade 2+ EASRs at week 6. This is supported by a previous study that expression of human CRP in mice was correlated with up-regulation of the TGF-β/Smad3 signaling pathway, which has been associated with RT-induced fibrosis or moist desquamation of the skin (22). Other risk factors, such as obesity and breast volume, have been related to late effects (23).…”

Section: Discussionsupporting

confidence: 79%

Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in Patients with Breast Cancer

Rodriguez-Gil

Takita

Wright

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Post-surgery adjuvant radiotherapy (RT) significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life and treatment outcomes. Methods We evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs in 159 breast cancer patients undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed at weeks 3 and 6 using the National Cancer Institute Common Toxicity Criteria (v3.0). Association between EASRs and CRP levels were assessed using logistic regression models after adjusting for potential confounders. Results RT-induced grade 2+ EASRs were observed in 8 (5%) and 80 (50%) patients at weeks 3 and 6 (end of RT), respectively. At the end of RT, significantly higher proportion of African Americans developed grade 3 EASRs (13.8% vs. 2.3% in others); grade 2+ EASRs were significantly associated with: change of CRP>1 mg/L (OR=2.51; 95%CI=1.06, 5.95, p=0.04), obesity (OR=2.08; 95%CI=1.03, 4.21, p=0.04), or combined both factors (OR=5.21; 95%CI=1.77, 15.38, p=0.003). Conclusion This is the first study to demonstrate that an inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. Impact Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced adverse effects and improve quality of life in breast cancer patients undergoing RT.

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Section: Discussionsupporting

confidence: 79%

Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in Patients with Breast Cancer

Rodriguez-Gil

Takita

Wright

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In congruence with the current study, inhibition of TGF-β with a soluble TGF-β type II receptor resulted in a reduction in the radiation injury score, enhanced mucosal surface area, and reduced intestinal wall fibrosis in a mouse model of radiation enteropathy [29]. Hence, inhibition of TGF-β1 signaling may reduce clinical manifestations of radiation enteropathy [43].…”

Section: Discussionsupporting

confidence: 85%

Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

et al. 2013

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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.

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“…PTX is a xanthine derivative that acts by inhibiting TNF-α, IL-1, fibroblast growth factor, TGF-β as well as the SMAD pathway, whereas Vit E is known to counteract TGF-β and the SMAD signaling (203). In a study with 40 patients PTX was shown to provide significant protection against the early and late adverse late effects of RT in the lung (204).…”

Section: Therapeutic Approaches For Radiation-induced Pneumopathymentioning

confidence: 99%

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

Wirsdörfer¹,

Jendrossek²

2016

Front. Immunol.

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Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease.

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Radiation-induced enteropathy: Molecular basis of pentoxifylline–vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition

Cited by 39 publications

References 45 publications

Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in Patients with Breast Cancer

Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in Patients with Breast Cancer

Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

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