Radyasyona Spesifik Organ Sistem Yanıtları, Normal Doku Genel Tepkileri
Özet
İyonizan radyasyon, tümör dokusunu hedeflerken çevre normal dokularda akut ve geç dönem hasarlara yol açar. Bu süreçte vasküler endotel ve progenitor hücre ölümüyle tetiklenen ikincil mekanizmalar, fonksiyonel yetersizlikleri ve fibrozisi beraberinde getirir. Dokularda gelişen aşırı reaktif oksijen türleri (ROS) üretimi, antioksidan savunma sistemlerini baskılayarak hücresel yapıları tahrip eder. Eş zamanlı olarak salınan proinflamatuar sitokinler (IL-1, IL-6, TNF-α) ve profibrotik faktörler (TGF-ß), kronik inflamasyonu kalıcı hale getirir. Hücresel boyutta organ özgüllüğü gösteren bu toksisite; ciltte deskuamasyon ve dermal fibrozis, gastrointestinal sistemde mukozal bariyer ihlali ve ishal, akciğerlerde ise hayatı tehdit eden pnömoni ve obliteratif fibrozis şeklinde klinik bulgular verir. Beyinde ise kan-beyin bariyerinin bozulması ile hipokampal nörogenez baskılanmakta ve kognitif disfonksiyonlar tetiklenmektedir. Mesane, kalp, karaciğer ve böbrekler gibi hayati organlarda da mikrovasküler tromboz, iskemi ve parankimal hücre kaybı kalıcı organ hasarlarını uyarır. Bu komplikasyonları hafifletmek adına, prostaglandin sentezini bloke eden antiinflamatuar ajanlar, serbest radikalleri temizleyen SOD mimetikleri ile anti-fibrotik koşulları destekleyen statinler ve ACE inhibitörleri (ramipril, kaptopril) gibi koruyucu tedavi stratejileri klinik pratikte aktif olarak tercih edilmektedir.
Ionizing radiation, while targeting tumor tissue, causes acute and late-term damage in surrounding normal tissues. In this process, secondary mechanisms triggered by vascular endothelial and progenitor cell death lead to functional deficits and fibrosis. Excessive reactive oxygen species (ROS) production in tissues overwhelms antioxidant defense systems, damaging cellular structures. Simultaneously released proinflammatory cytokines (IL-1, IL-6, TNF-α) and profibrotic factors (TGF-ß) perpetuate chronic inflammation. Showing organ specificity at the cellular level, this toxicity presents clinically as desquamation and dermal fibrosis in the skin; mucosal barrier breach and diarrhea in the gastrointestinal system; and life-threatening pneumonitis and obliterative fibrosis in the lungs. In the brain, disruption of the blood-brain barrier suppresses hippocampal neurogenesis, triggering cognitive dysfunctions. In vital organs such as the bladder, heart, liver, and kidneys, microvascular thrombosis, ischemia, and parenchymal cell loss stimulate permanent organ injury. To mitigate these complications, protective treatment strategies—including anti-inflammatory agents blocking prostaglandin synthesis, SOD mimetics scavenging free radicals, and statins and ACE inhibitors (ramipril, captopril) promoting anti-fibrotic conditions—are actively utilized in clinical practice.
Referanslar
Otsuka S, Coderre JA, Micca PL, et al. Depletion of neural precursor cells after local brain irradiation is due to radiation dose to the parenchyma, not the vasculature. Radiat Res. 2006; 165:582-91.
Schuller BW, Binns PJ, Riley KJ, et al. Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells. Proc Natl Acad Sci U S A. 2006;103:3787-92.
Rhee SG, Chae HZ, Kim K. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med. 2005;38:1543-52.
Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and spesific therapeutic target? Int J Radiat Oncol Biol Phys. 2000; 47:277-90.
Anscher MS, Maks LB, Shafman TD, et al. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:988-95.
Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected aganist cutaneous injury induced by iyonizing radiation. Am J Pathol. 2002;160:1057-68.
Janko M, Ontiveros F, Fitzgerald TJ, et al. IL-1 generated subsequent to radiatıon-induced tissue injury contributes to the pathogenesis of radiodermatitis. Radiat Res. 2012;178:166-72.
Nawroth I, Alsner J, Behlke MA, et al. Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis. Radioother Oncol. 2010;97:143-8.
Lybimova N, Hopewell JW. Experimental evidence to support the hypothesis that damage to vascular endothelium plays the primary role in the development of late radiatıon-induced CNS injury. Br J Radiol. 2004;77:488-92.
Li YQ, Ballinger JR, Nordal RA, et al. Hypoxıa in radiation-induced blood –spinal cord barrier breakdown. Cancer Res. 2001;61:3348-54.
Nordal RA, Nagy A, Pintilie M, et al. Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury : a role for vascular endothelial growth factor. Clin Cancer Res. 2004;10:3342-53.
Gonzalez J, Kumar AJ, Conrad CA, et al.. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. 2007;67:323-6.
Bastianutto C, Mian A, Symes J, et al. Local radiotherapy induced homing of hematopoietic stem cells to the irradiated bone marrow. Cancer Res. 2007;67:10112-6.
Thanasegaran S, Ito S, Nishio N, Uddin MN, Sun Y, Isobe KI. Recruitment of Gr1+ CD11b+ F4/80+ Population in the Bone Marrow and Spleen by Irradiation-Induced Pulmonary Damage. Inflammation. 2015;38(2):465-75.
Yarnold J, Brotons MC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol. 2010;97:149-61.
Ahmed EA, Agay D, Schrock G, et al. Persistent DNA damage after high dose in vivo gamma exposure of miniping skin. PLoS One. 2012;7e39521.
Wang J, Zheng H, Ou X, et al. Hirudin ameliorates intestinal radiation toxicity in the rat: support for trombin inhibition as strategy to minimize side effects after radiatıon therapy and as countermeasure aganist radiation exposure. J Thromb Haemost. 2004; 2:2027-35.
Paris F, Funks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001;293:293-7.
Sekine l, Sumi M, Ito Y, et al. Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients. Radiother Oncol. 2006;80:93-7.
Mizumatsu S, Monje ML, Morhardt DR, et al. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63:4021-7.
Kermen F, Sultan S, Sacquet J, et al. Consolidation of an olfactory memory trace in the olfactory bulb is required for learning-induced survival of adult –born neurons and long-term memory. PLoS One. 2010;5:e12118.
Toni N, Laplagne DA, Zhao C,et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci. 2008;11:901-7.
Snyder JS, Ferrante SC, Cameron HA. Late maturation of adult-born neurons in the temporal dentate gyrus. PLoS One. 2012;7:e48757.
Rola R, Raber J, Rizk A, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol. 2004;188:316-30.
Jenrow KA, Brown SL, Lapanowski K, et al. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res. 2013;179:549-56.
Acharya MM, Martirosian V, Christie LA, et al. Long-term cognitive effects of human stem cell transplantation in the irradiated brain. Int J Radiat Biol. 2014;90:816-20.
Liang L, Hu D, Liu W, et al. Celecoxib reduces skin damage after radiation: selective reduction of chemokine and receptor mRNA expression in irradiated skin but not in irradiated mammary tumor. Am J Clin Oncol. 2003;26:S114-21.
Di Maggio FM, Minafra L, Forte GI, et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm. (2015) 12:14.
Baskar R, Dai J, Wenlong N, et al. Biological response of cancer cells to radiation treatment. Front Mol Biosci. (2014) 1:24.
Zwaans BMM, Chancellor MB, et al. Modeling and treatment of radiation cystitis. Urology. 2016; 88:14–21.
Jaal J, Dörr W. Radiation induced late damage to the barrier function of small blood vessels in mouse bladder. J Urol. 2006; 176:2696–700.
Jaal J, Dörr W. Early and long-term effects of radiation on intercellular adhesion molecule 1 (ICAM-1) expression in mouse urinary bladder endothelium. Int J Radiat Biol. 2005; 81:387–95.
Dörr W, Beck-Bornholdt H-P. Radiation-induced impairment of urinary bladder function in mice: fine structure of the acute response and consequences on late effects. Radiat Res. 1999; 151:461–7.
Jaal J, Dörr W. Radiation-induced damage to mouse urothelial barrier. Radiother Oncol. 2006; 80:250–6.
Bentzen SM. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer. 2006; 6:702–13.
Zwaans BMM, Krueger S, Bartolone SN, et al. Modeling of chronic radiation-induced cystitis in mice. Adv Radiat Oncol. 2016; 1:333–43.
Hatoum OA, Otterson MF, Kopelman D, et al. Radiation inducesendothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species. Arterioscler Thromb Vasc Biol. 2006;26:287–94.
Gaya AM, Ashford RF. Cardiac complications of radiation therapy. Clin Oncol (R Coll Radiol). 2005;17:153–9.
Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease:current knowledge and future prospects. Int J Radiat Oncol Biol Phys . 2010;76:656–65
Abramson JS, Digumarthy SR, Reingold JS, et al. Case records of the Massachusetts General Hospital. Case 24-2010. A 56-year-old woman with a history of Hodgkin’s lymphoma and sudden onset of dyspnea and shock. N Engl J Med. 2010;363:664–75.
Wethal T, Lund MB, Edvardsen T, et al. Valvular dysfunction and left ventricular changes in Hodgkin’s lymphoma survivors. A longitudinal study. Br J Cancer. 2009;101:575–81.
van Rijswijk S, Huijbregts MA, Lust E, et al. Mini-review on cardiac complications after mediastinal irradiation for Hodgkin lymphoma. Neth J Med. 2008;66:234–7.
Sagrista-Sauleda J, Angel J, Sanchez A, et al. Effusive-constrictive pericarditis. N Engl J Med. 2004;350: 469–75.
Boerma M, Kruse JJ, van Loenen M, et al. Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation. Strahlenther Onkol. 2004;180:109–16.
McEniery PT, Dorosti K, Schiavone WA, et al. Clinical and angiographic features of coronary artery disease after chest irradiation. Am J Cardiol. 1987;60:1020–4.
Nellessen U, Zingel M, Hecker H, et al. Effects of radiation therapy on myocardial cell integrity and pump function: which role for cardiac biomarkers? Chemotherapy. 2010;56:147–52.
Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol. 1996;27:766–73.
Heidenreich PA, Hancock SL, Vagelos RH, et al. Diastolic dysfunction after mediastinal irradiation. Am Heart J. 2005; 150:977–82.
Larsen RL, Jakacki RI, Vetter VL, et al. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. Am J Cardiol. 1992;70:73–7.
Regaud C, Blanc J. Actions des rayons X sur les diverses generations de la lignèe spermatique: extreme sensibilitè des spermatogonies á ces rayons. Compt Rend Soc de Biol. 1906;61-165.
De Felice F, Marchetti C, Marampon F, et al. Radiation effects on male fertility. Andrology. 2019; 72-7.
Meistrich ML, Hunter NR, Suzuki N, et al. Gradual regeneration of mouse testicular stem cells after exposure to ionizing radiation. Radiat Res. 1978;74:349-362.
Biedka M, Kuzba-Kryszak T, Nowikiewicz T, et al. Fertility impairment in radiotherapy. Contemp Oncol. 2016;20:199-204.
Suzuki E, Fujita D, Takahashi M, et al. Adult stem cells as a tool for kidney regeneration. Word J Nephrol. 2016;5:43-52.
Withers HR, Mason KA, Thames HD Jr. Late radiation response of kidney assayed by tubule cell survival. Br J Radiol. 1986;59:587-595.
Robbins ME, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol. 2004; 80: 251–259.
Christiansen H, Saile B, Neubauer-Saile K, et al. Irradiation leads to susceptibility of hepatocytes to TNF-alpha mediated apoptosis. Radiother Oncol. 2004; 72: 291–296
Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011; 25: 195–206
Sempoux C, Horsmans Y, Geubel A, et al. Severe radiation-induced liver disease following localized radiation therapy for biliopancreatic carcinoma: activation of hepatic stellate cells as an early event. Hepatology. 1997; 26: 128–134.
Zhang J, Zhou S, Zhou Y, et al. Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model. PLoS ONE. 2014; 9: e114670.
DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Di.s 2002; 22: 27–42.
Anscher MS, Crocker IR, Jirtle RL. Transforming growth factor-beta 1 expression in irradiated liver. Radiat Res. 1990; 122: 77–85.
Carmona-Cuenca I, Roncero C, Sancho P, et al. Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity. J Hepatol. 2008; 49: 965–976.
Verdelho Machado M, Diehl AM. Role of Hedgehog signaling pathway in NASH. Int J Mol Sci. 2016; 17: E857.
Taysi S, Koc M, Buyukokuroglu ME, et al. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J Pineal Res. 2003; 34: 173–177
Leiper AD. Late effects of total body irradiation. Arch Dis Child. 1995; 72:382–385.
Singh VK, Brown DS, Kao TC. Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor. Int J Radiat Biol. 2010;86:12-21.
Kulkarni S, Singh PK, Ghosh SP, et al. Granulocyte colony-stimulating factor antibody abrogates radioprotective efficacy of gamma-tocotrienol, a promising radiation countermeasure. Cytokine. 2013;62:278-85.
Singh VK, Beattie LA, Seed TM. Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures. J Radiat Res. 2013;54:973-88.
Avraham T, Yan A, Zampell JC, et al. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-beta1-mediated tissue fibrosis. Am J Physiol Cell Physiol.2010;299:C589-605.
Lee JW, Tutella JP, Zoumalan RA, et al. Inhibition of Smad3 expression in radiation –induced fibrosis using a novel method for topical transcutaneous gene therapy. Arch Otolaryngol Head Neck Surg. 2010;136:714-9.
Brown SL, Kolozsvary A, Jenrow KA, et al. TNF alfa receptor antagonist mitigates radiation induced acute and sub-acute skin injury in mice (poster PS4-47). In: Presented at the 58th Annual Meeting of the Radiation Research Society; 2012 4;Puerto Rico.
Delanian S, Baillet F, Huart J, et al. Successful treatment of radiation-induced fibrosis using liposomal Cu/Zu superokxide dismutase: clinical trial. Radiother Oncol. 1994;32:12-20.
Rosenthal RA, Fish B, Hill RP, et al. Salen Mn complexes mitigate radiation injury in normal tissues. Anticancer Agents Med Chem. 2011;11:359-72.
Yan S, Brown SL, Kolozsvary A, et al. Mitigation of radiation-induced skin injury by AAV2-mediated MnSOD gene therapy. J Gene Med. 2008;10:1012-8.
Chan AW, Bhatt DL, Chew DP, et al. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation. 2003;107:1750-6.
Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through spesific inflammatory pathways. Circulation. 2003;108:426-31.
Lu D, Goussev A, Chen J,et al. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma. 2004;21:21-32.
Jenrow KA, Liu J, Brown SL et al. Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis. J Neurooncol. 2011;101:449-56.
Liu YH, Yang XP, Sharov VG, et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926-35.
Ward WF, Kim YT, Molteni A, et al. Radiation-induced pulmonary endothelial dysfunction in rats: modification by an inhibitor of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys. 1988;15:135-40.
Moulder JE, Fish BL, Regner KR, et al. Angiotensin II blockade reduces radiation-induced proliferation in experimental radiation nephropathy. Radiat Res. 2002;157:393-401.
Kim JH, Brown SL, Kolozsvary A, et al. Modification of radiation injury by ramipril, inhibitor of angiotensin –converting enzyme, on optic neuropathy in the rat. Radiat Res. 2004;161:137-42.
Ryu S, Kolozsvary A, Jenrow KA, et al. Mitigation of radiation –induced optic neuropaty in rats by ACE inhibitor ramipril: importance of ramipril dose and treatment time. J Neurooncol. 2007;82:119-24.
