Fig. 8.14 ). Damage to DNA caused by ionizing radiation that is not precisely repaired leads to mutations, which can manifest years or decades later as cancer. Ionizing radiation can cause many types of damage in DNA, including single-base damage, singleand double-strand breaks, and crosslinks between DNA and protein. In surviving cells, simple defects may be reparable by various enzyme repair systems contained in mammalian cells (see Chapter 6). These repair systems are linked to cell-cycle regulation through proteins such as ATM (ataxia-telangiectasia mutated) that initiate signal transduction after the damage, and p53, which can transiently arrest the cell cycle to allow for DNA repair or to trigger apoptosis of cells that are irreparable. However, double-strand breaks may persist without repair, or the repair of lesions may be imprecise (error prone), creating mutations. If cell-cycle checkpoints are not functioning (for instance, because of mutations in TP53), cells with abnormal and unstable genomes survive
Inhibition of Failed or Additional cell division aberrant repair transforming
Fetus or germ cells: teratogenesis Carcinogenesis events Cell death
Fig. 8.14 EffectsofionizingradiationonDNAandtheirconsequences.TheeffectsonDNAcanbedirector,mostimportant,indirect,throughfreeradicalformation.
and may expand as abnormal clones to form tumors eventually.
A common consequence of cancer radiotherapy is the development of fibrosis in the irradiated field (
Fig. 8.15 ). Fibrosis may occur weeks or months after irradiation, leading to the replacement of dead parenchymal cells by connective tissue and the formation of scars and adhesions (see Chapter 3). As already mentioned, ionizing radiation causes vascular damage and consequent tissue ischemia. Vascular damage, the killing of tissue stem cells by ionizing radiation, and the release of cytokines and chemokines that promote an inflammatory reaction all contribute to fibroblast activation and the development of radiation-induced fibrosis.
Fig. 8.15 Vascularchangesandfibrosisofsalivaryglandsproducedbyradiationtherapyoftheneckregion.(A)Normalsalivarygland;(B)fibrosiscausedbyradiation;(C)fibrosisandvascularchangesconsistingoffibrointimalthickeningandarteriolarsclerosis.V, Vessellumen;I, thickenedintima.(A–C, Courtesy of Dr. Melissa Upton,Department of Pathology,University of Washington,Seattle,Washington.) http://ebooksmedicine.net
BRAIN • Adult – resistant SKIN • Atrophy, cancerGONADS MARROW • Granulocytopenia • Anemia • Lymphopenia
Fig. 8.16 Overviewofthemajormorphologicconsequencesofradiationinjury.Earlychangesoccurinhourstoweeks;latechangesoccurinmonthstoyears.ARDS, Acuterespiratorydistresssyndrome.
MORPHOLOGYCellssurvivingradiantenergydamageshowawiderangeofstructuralchanges in chromosomes, includingdeletions,breaks,translocations,andfragmentation.Themitoticspindleoftenbecomesdisorderly,andpolyploidyandaneuploidymaybeencountered.Nuclear swelling andcondensationandclumpingofchromatinmayappear;breaksinthenuclearmembranealsomaybenoted.Apoptosis mayoccur.Cellswithabnormalnuclearmorphologymaybeproducedandpersistforyears,includinggiantcellswithpleomorphicnucleiormorethanonenucleus.Atextremelyhighdoselevelsofradiantenergy,featuresthatforetellimpendingcelldeath,suchasnuclearpyknosis,appearquickly.