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Cellular Mechanisms of Radiation Injury.

The acute effects of ionizing radiation range from overt necrosis at high doses (>10 Gy), killing of proliferating cells at intermediate doses (1 to 2 Gy), and no histopathologic effect at

doses less than 0.5 Gy. Subcellular damage does occur at these lower doses, primarily targeting DNA; however, most cells show adaptive and reparative responses to low doses of ionizing

radiation. If cells undergo extensive DNA damage or if they are unable to repair this damage, they undergo apoptosis ( Chapter 7 ). Surviving cells may show delayed effects of radiation

injury: mutations, chromosome aberrations, and genetic instability. These genetically damaged cells may become malignant; tissues with rapidly proliferating cell populations are

especially susceptible to the carcinogenic effects of ionizing radiation. Most cancers induced by ionizing radiation have occurred after doses greater than 0.5 Gy. Acute cell death,

especially of vascular endothelial cells, can cause delayed organ dysfunction several months or years after radiation exposure. In general, this delayed injury is caused by a combination of

atrophy of parenchymal cells, ischemia due to vascular damage, and fibrosis.[53] Acute and delayed effects of ionizing radiation are listed in Table 9-17 , and their mechanisms are

described next.

Acute Effects.

Ionizing radiation can produce a variety of lesions in DNA, including DNA-protein cross-links, cross-linking of DNA strands, oxidation and degradation of bases, cleavage of sugarphosphate

bonds, and single-stranded or double-stranded DNA breaks. This damage may be produced directly by particulate radiation, x-rays, or gamma rays or indirectly by oxygenderived

free radicals or soluble products derived from peroxidized lipids.[54] Even relatively low doses of ionizing radiation (less than 0.5 Gy) induce alterations in gene expression in some

target cell populations. Free radicals generated directly or indirectly by exposure to ionizing radiation may produce oxidant stress that activates transcription factors (such as NF-kB) that

increase gene expression.[55] DNA damage itself stimulates the expression of several genes involved in DNA repair, cell-cycle arrest, and apoptosis. As discussed in Chapter 7 , the tumorsuppressor

gene p53 is activated after many different forms of DNA damage. The end-points resulting from activation of this p53-mediated DNA damage response are discussed in Chapter

7 . Briefly, activation of p53 induces cell-cycle arrest, DNA repair and, in some cases, apoptosis. Apoptosis of microvascular endothelial cells may be the primary target of acute radiation

in the GI tract, resulting in secondary damage to intestinal crypt stem cells[56] and the GI syndrome (see Table 9-18 ).

Fibrosis.

An important delayed complication of ionizing radiation, usually at doses used for cancer therapy, is replacement of normal parenchymal tissue by fibrosis, resulting in scarring and loss of

function. These fibrotic changes may be secondary to ischemic injury caused by vascular damage, death of parenchymal cells, or deletion of stem cells.[57] The mechanisms responsible for



fibrosis have been explored in a murine model of radiation-induced pulmonary fibrosis using microarray analysis of gene expression. Up-regulation of chemokines that recruit

inflammatory cells to the lungs as well as cytokines and growth factors involved in fibroblast activation and collagen deposition are central components of radiation-induced fibrosis.[58] As

described in Chapter 3 , these chemokines, cytokines, and growth factors also play important roles in wound healing.

TABLE 9-17-- Acute Injury and Delayed Complications Caused by Ionizing Radiation


Date: 2016-04-22; view: 978


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