Abstract
Introduction. Ionizing radiation can lead to radiation damage to healthy pancreatic tissue, with the development of signs of post-radiation pancreatitis. Electron irradiation potentially has the most “sparing” effect on healthy tissue, but data on this are sparse. The search for means to protect healthy tissues from the effects of ionizing radiation remains relevant. Thus, the use of agents with antioxidant properties (N-acetylcysteine) can potentially slow down the development of post-radiation pancreatitis.
The aim of the study: assessment of the inflammatory response in the pancreas after administration of N-acetylcysteine in a radiation-induced pancreatitis model.
Methods. Wistar rats (n=120) were divided into four groups: I (n=30) – control; II (n=30) – irradiation with electrons in a total irradiation dose of 25 Gy; III (n=30) – pre-irradiation administration of N-acetylcysteine before electron irradiation; IV (n=30) – administration of N-acetylcysteine. Animals were removed from the experiment on the 7th, 30th and 90th days. A morphological assessment of pancreatic fragments and an immunohistochemical study with antibodies to pro- (IL-1, IL-6) and anti-inflammatory (IL-10) cytokines, markers of T-lymphocytes (CD3) and macrophages (CD68) were carried out.
Results. At all stages of the experiment, high levels of expression of pro- and anti-inflammatory cytokines were observed in the electron irradiation group with a slight increase in the number of CD3+ T-lymphocytes and CD68+ macrophages. In the group of pre-radiation administration of N-acetylcysteine, increased levels of immunolabeling were also found when conducting reactions with antibodies to pro- and anti-inflammatory cytokines, however, by the third month of the experiment, practically no CD3+ and CD68+ immunocompetent cells were noted in this group.
Conclusion. Pancreatic local electron irradiation at a total dose of 25 Gy in the early stages leads to the development of a stromal-vascular inflammatory reaction with a capillary-parenchymal block with practically no cellular inflammatory infiltration. At the same time, pre-radiation administration of N-acetylcysteine partially prevents the development of post-radiation pancreatitis.
Authors and affiliations
G.A. Demyashkin(1, 2), D.A. Atyakshin(3), D.I. Ugurchieva(2), V.A. Yakimenko(2),M.A. Vadyukhin(2),, S.N. Koryakin(1)
1-Medical Radiological Research Center named after A.F. Tsyba – branch of the Federal State Budgetary Institution
“National Medical Research Center of Radiology”, st. Koroleva, 4, Obninsk, 249036, Russian Federation;
2-Federal State Autonomous Educational Institution of Higher Education I.M.Sechenov First Moscow State Medical University
of the Ministry of Health of the Russian Federation (Sechenov University), Trubetskaya st., 8/2, Moscow, 119048, Russian Federation;
3RUDN University named after Patrice Lumumba, Miklouho-Maklaya st., 6, Moscow, 117198, Russian Federation
References
Seifert L., Werba G., Tiwari S., Giao Ly N.N., Nguy S., Alothman S., Alqunaibit D., Avanzi A., Daley D., Barilla R., Tippens D., Torres-Hernandez A., Hundeyin M., Mani V.R., Hajdu C., Pellicciotta I., Oh P., Du K., Miller G. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice. Gastroenterology. 2016; 150 (7): 1659–72.e5. DOI:10.1053/j.gastro.2016.02.070
Schröter P., Hartmann L., Osen W., Baumann D., Offringa R., Eisel D., Debus J., Eichmüller S.B., Rieken S. Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line. Sci Rep. 2020; 10 (1): 686. DOI:10.1038/s41598-020-57456-2
Wydmanski J., Polanowski P., Tukiendorf A., Maslyk B. Radiation-induced injury of the exocrine pancreas after chemoradiotherapy for gastric cancer. Radiother Oncol. 2016; 118 (3): 535–9. DOI: 10.1016/j.radonc.2015.11.033
Baek J.Y., Lim D.H., Oh D., Nam H., Kim J.J., Lee J.H., Min B.H., Lee H. Increased Risk of Diabetes after Definitive Radiotherapy in Patients with Indolent Gastroduodenal Lymphoma. Cancer Res Treat. 2022; 54 (1): 294–300. DOI:10.4143/crt.2021.073
Mercantepe F., Tümkaya L., Mercantepe T., Yilmaz Rakici S. The effects of coenzyme Q10 (CoQ10) on ionizing radiation-induced pancreatic β-cell injury. Endocrinol Res Pract. 2023; 27 (3): 127–34. DOI: 10.5152/erp.2023.23245
Leung P.S., Chan Y.C. Role of oxidative stress in pancreatic inflammation. Antioxid Redox Signal. 2009; 11 (1): 135–65. DOI: 10.1089/ars.2008.2109
Bacarella N., Ruggiero A., Davis A.T., Uberseder B., Davis M.A., Bracy D.P., Wasserman D.H., Cline J.M., Sherrill C., Kavanagh K. Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates. Int. J. Radiat Oncol. Biol. Phys. 2020; 106 (4): 878–86. DOI:10.1016/j.ijrobp.2019.11.034
Schoonbroodt D., Zipf A., Hermann G., Jung M. Histological findings in chronic pancreatitis after abdominal radiotherapy. Pancreas. 1996; 12: 313–5.
. Демяшкин Г.А., Дубовая Т.К., Угурчиева Д.И., Вадюхин М.А., Ахмедова П.С., Симагина В.К. Морфофункциональная характеристика поджелудочной железы после введения N-ацетилцистеина в модели острого постлучевого панкреатита. Морфология. 2023; 161 (2): 15–22. DOI: 10.17816/morph.623166. [Demyashkin G.A., Dubovaya T.K., Ugurchieva D.I., Vadyukhin M.A., Akhmedova P.S., Simagina V.K. Morphofunctional characteristics of the pancreas after N-acetylcysteine administration in an acute postradiation pancreatitis model. Morphology 2023; 161 (2): 15–22. DOI:10 .17816/morph.623166 (in Russian)]
. Calvo F.A., Serrano J., Cambeiro M., Aristu J., Asencio J.M., Rubio I., Delgado J.M., Ferrer C., Desco M., Pascau J. Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies. Cancers (Basel). 2022; 14 (15): 3693. DOI:10.3390/cancers14153693
Zhou R., Bu W., Fan Y., Du Z., Zhang J., Zhang S., Sun J., Li Z., Li J. Dynamic Changes in Serum Cytokine Profile in Rats with Severe Acute Pancreatitis. Medicina (Kaunas). 2023; 59 (2): 321. DOI:10.3390/medicina59020321
Attia A.A., Hamad H.A., Fawzy M.A., Saleh S.R. The Prophylactic Effect of Vitamin C and Vitamin B12 against Ultraviolet-C-Induced Hepatotoxicity in Male Rats. Molecules. 2023; 28 (11): 4302. DOI:10.3390/molecules28114302
. Topcu A., Mercantepe F., Rakici S., Tumkaya L., Uydu H.A., Mercantepe T. An investigation of the effects of N-acetylcysteine on radiotherapy-induced testicular injury in rats. Naunyn Schmiedebergs Arch Pharmacol. 2019; 392 (2): 147–57. DOI: 10.1007/s00210-018-1581-6
Sia J., Szmyd R., Hau E., Gee H.E. Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer. Front Cell Dev Biol. 2020; 8: 41. DOI: 10.3389/fcell.2020.00041
Jiao Y., Cao F., Liu H. Radiation-induced Cell Death and Its Mechanisms. Health Phys. 2022; 123 (5): 376–86. DOI:10.1097/HP.0000000000001601
Moustafa E.M., Moawed F.S.M., Abdel-Hamid G.R. Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats. Dose Response. 2020; 18 (4): 1559325820970810. DOI: 10.1177/1559325820970810
. Fertey J., Thoma M., Beckmann J., Bayer L., Finkensieper J., Reißhauer S., Berneck B.S., Issmail L., Schönfelder J., Casado J.P., Poremba A., Rögner F.H., Standfest B., Makert G.R., Walcher L., Kistenmacher A.K., Fricke S., Grunwald T., Ulbert S. Automated application of low energy electron irradiation enables inactivation of pathogen- and cell-containing liquids in biomedical research and production facilities. Sci Rep. 2020; 10 (1): 12786. DOI: 10.1038/s41598-020-69347-7
Cameron S., Schwartz A., Sultan S., Schaefer I.M., Hermann R., Rave-Fränk M., Hess C.F., Christiansen H., Ramadori G. Radiation-induced damage in different segments of the rat intestine after external beam irradiation of the liver. Exp. Mol. Pathol. 2012; 92 (2): 243–58. DOI: 10.1016/j.yexmp.2011.11.007
Bertho A., Iturri L., Brisebard E., Juchaux M., Gilbert C., Ortiz R., Sebrie C., Jourdain L., Lamirault C., Ramasamy G., Pouzoulet F., Prezado Y. Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy. Int. J. Radiat Oncol. Biol. Phys. 2023; 115 (2): 426–39. DOI: 10.1016/j.ijrobp.2022.08.011
Wang Z., Shen L., Wang J., Shan B., Zhang L., Lu F., Guo X., Li X. Immunostimulatory effect of a composition isolated from white peony root oral liquid in the treatment of radiation-induced esophagitis. Exp Ther Med. 2013; 6 (4): 1010–4. DOI: 10.3892/etm.2013.1227
Lin L., Xie S., Zhao Y., Liang Z., Wu Q., Fang M., Teng X., Shi B., Yang Y., Chen B. Ultrasound-induced destruction of heparin-loaded microbubbles attenuates L-arginine-induced acute pancreatitis. Eur. J. Pharm Sci. 2023; 180: 106318. DOI: 10.1016/j.ejps.2022.106318
. Lu C.L., Wang Y., Yuan L., Li Y., Li X.Y. The angiotensin-converting enzyme 2/angiotensin (1–7)/Mas axis protects the function of pancreatic β cells by improving the function of islet microvascular endothelial cells. Int. J. Mol. Med. 2014; 34 (5): 1293–300. DOI: 10.3892/ijmm.2014.1917
Mercantepe F., Topcu A., Rakici S., Tumkaya L., Yilmaz A. The effects of N-acetylcysteine on radiotherapy-induced small intestinal damage in rats. Exp Biol Med (Maywood). 2019; 244 (5): 372–9. DOI: 10.1177/1535370219831225
. Mansour H.H., Hafez H.F., Fahmy N.M., Hanafi N. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats. Biochem Pharmacol. 2008; 75 (3): 773–80. DOI: 10.1016/j.bcp.2007.09.018