Elucidation of gastrointestinal dysfunction in response to irradiation using metabolomics.
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ABSTRACT:
SUBMITTER: Salah M
PROVIDER: S-EPMC7393574 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Because radiotherapy (RT) can induce diaphragm dysfunction, this study investigated the protective effect of inspiratory muscle training (IMT) on RT-induced diaphragm damage in patients with esophageal cancer during concurrent chemoradiotherapy (CCRT) in a preclinical setting, and an animal model was designed to confirm and explore the underlying mechanism. Six subjects who underwent CCRT were randomly enrolled in the control or concurrent-IMT group (n=3 per group). The training intensity was set to 30% maximal effort. The diaphragmatic function and functional exercise capacity were assessed weekly during the course of CCRT. Furthermore, Sprague-Dawley (SD) rats were randomly assigned to receive IMT using the tracheal banding method over a 1-week period (n=6) or the sham group (n=6). After training was completed, 5-Gy RT was applied to the diaphragm. All the rats were sacrificed 24 h following RT, and their diaphragms were removed and examined for contractile function, antioxidant capacity, and oxidative injury. In patients receiving IMT, the diaphragm activation efficiency and fatigability and the functional exercise capacity were improved during the CCRT course. The animals belonging to the training group demonstrated significantly higher peak twitch (P<0.01) and tetanus tension (P<0.001), less fatigue (P=0.04), lower protein carbonyl levels (P<0.01) and higher Cu/Zn-SOD and Mn-SOD mRNA expression levels (both P<0.05) compared with those belonging to the control group. Preclinical human and animal models show that the IMT-conditioned diaphragm exhibits better resistance to off-target irradiation damage, but studies with a larger patient sample size are warranted to confirm the applicability of this concept in clinical practice.
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Project description:Background and Purpose:Up to 50-60% of all cancer patients receive radiotherapy as part of their treatment strategy. However, the mechanisms accounting for increased vascular risks after irradiation are not completely understood. Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis. Materials and Methods:Assays for apoptosis, cellular metabolism, mitochondrial DNA content, functionality and morphology were used to compare the response of endothelial cells to a single 2 Gy dose of X-rays under basal conditions or after pharmacological treatments that either reduced (EtBr) or increased (rosiglitazone) mitochondrial content. Results:Exposure to ionizing radiation caused a persistent reduction in mitochondrial content of endothelial cells. Pharmacological reduction of mitochondrial DNA content rendered endothelial cells more vulnerable to radiation-induced apoptosis, whereas rosiglitazone treatment increased oxidative metabolism and redox state and decreased the levels of apoptosis after irradiation. Conclusion:Pre-existing mitochondrial damage sensitizes endothelial cells to ionizing radiation-induced mitochondrial dysfunction. Rosiglitazone protects endothelial cells from the detrimental effects of radiation exposure on mitochondrial metabolism and oxidative stress. Thus, our findings indicate that rosiglitazone may have potential value as prophylactic for radiation-induced atherosclerosis.
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