05. Radiation Toxicity

 Radiation Toxicity

Medical effects of radiation exposure can be divided into two categories known as Acute Radiation Syndrome (ARS) and Delayed Effects of Acute Radiation Exposure (DEARE)Acute radiation exposure consists of health effects that immediately exposure of the body to a relatively high dose (>2-5Gy) delivered with high dose rate. ARS is visible as three syndromes based on the radiosensitivity of organs. Those are Hematopoietic syndrome (occurring after exposure 0.7-10Gy), Gastrointestinal syndrome (usually greater than 10 Gy), and Cardiovascular/Central nervous system syndrome ( dose greater than >50 Gy).DEARE is visible months or years after the radiation exposure symptoms such as prolonged gastrointestinal dysfunction, skin injury, renal failure, and lung injury.

Radiation-induced damage occurs from long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines which damage the recovery and repopulation of stem cells. The limitations of conventional radiotherapy depend on radiation damage to surrounding healthy tissues and localized therapeutic beam into well-defined targets. Normal tissue injury induced with depletion of parenchymal or vascular endothelial cells and failure to replace damaged cells from progenitor cells is located on primary targets which have radiation-induced DNA or cell structure damages. In contrast, this use has therapeutic effects which damage cancer cells also. Vascular endothelial cell and tissue stem and progenitor cell death leads to much greater cell loss, tissue damage, fibrosis, and necrosis

Generation of Reactive Oxygen Species.

Normal production of ROS family by reaction calatayed by NADPH oxidase with electrons supplied by NADPH but in normal conditions, antioxidant systems defend cells against ROS damage but during prolonged radiation exposure which induces indirect action produce tremendous amount of ROS and overwhelming antioxidants systems resulting damaged cell structures. Vascular damage caused for tissue hypoxia and increase ROS production including fibrosis and even neoplastic transformation. ROS are cleared with superoxide dismutase, catalase, aldehyde dehydrogenase and glutathione peroxidase, and antioxidants vitamins. Catalase production initiated by rough endoplasmic reticula mans concentrated into peroxisomes located next to mitochondria throughout reacts with hydrogen peroxide and converts into water.

Cytokines and Chemokines

After radiation exposure, tissues and organs are affected by various inflammatory actions which release chemokines and cytokines against radiation-induced impact. Some of the major chemokines are interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β responsible for skin, brain, and lung. Activation of TGF-β cause for epithelial cell growth, mesenchymal cell proliferation, extracellular matrix production, and also radiation-induced fibrosis. TNF-α and IL-1 initiate releasing matrix metalloproteins (MMPs) which degrade basal membrane and extracellular matrix. During radiosurgery, the release of cytokines and chemokines begins tumor angiogenesis and reduces the hypoxic state, and increases the radiosensitivity of the tumor-localized area.

Bone Marrow-Derived Cells and Normal Tissue Injury

Parenchymal cell loss and vascular endothelial damage may increase hypoxia and are the major cause of late effects associated with radiation injury. Vascular damage is repaired by Angiogenesis and vasculogenesis. Angiogenesis is accomplished by the proliferation and migration of resident endothelial cells. which is stimulated by growth factors and cytokines. Vasculogenesis describes the de navo formation of blood vessels by the recruitment of cells that can sever as endothelial progenitor cells. Macrophages also play a significant role in tissue repair by regulating tissue homeostasis, coordination of immune response, inflammation, resolution, and repair. Macrophages mainly visible tissues damaged by radiation cause an increase in the release of inflammatory cytokines.MArcrophages are characterized by two types such as classically activated pro–inflammatory (M1) and alternatively activated anti-inflammatory (M2), M1 is activated to promote inflammation, extracellular matrix destruction, apoptosis, and fibrosis, and M2 promotes extracellular construction, cell proliferation, angiogenesis and facilitate wound healing. Obtained Data demonstrate activation of macrophages after irradiation-induced within 3 days in a single dose of 30 Gy in mie and persisting for more than 2 months thereafter.

Radiation Skin Injury

Skin damage by irradiation is mainly characterized by loss of basal epithelial cells and effects are acute or prolonged late effects. The Basel layer is repopulated through the proliferation of surviving clonogenic cells despite symptoms varying from dry desquamation, and ulceration to necrosis on radiation dose. Usually greater than a single dose of 20-25Gy or fractionated dose of 70 Gy or higher caused histopathological findings at chronic stages such s telangiectasia, dens dermal fibrosis, sebaceous and sweat gland atrophy, loss of hair follicles, and also increase skin depigmentation, melanin deposition, and skin ulcers. Loss of stem and progenitor cells of the basal and dermal cells leading a fibrotic process and damage is irreversible by reducing the replacement of differentiated functional cells resulting in loss of homeostasis increase apoptosis and necrosis of irradiated skin area.

Gastrointestinal injury

Radiation-induced gastrointestinal injury, Acute side effects consist of nausea, vomiting, diarrhea, increased stool frequency, loss of appetite, and abdominal and rectal pain and also chronic effects develops after 3 or 4 months of manifesting diarrhea, changes in bowel habits, fecal incontinence, pain, and blood loss depending of the volume of irradiated in the intestine. The intestinal epithelium is a highly proliferative tissue. Microvascular injury causes the main role in acute effects and structural damage in the intestine. Prescribe of anticoagulant drugs during and after the higher dose treatment reduce intestinal damage and accelerated epithelial regeneration.

Lung injuries

Radiation-induced lung damage is divided into two sub-syndromes called pneumonitis and chronic fibrosis. Pneumonitis is based on acute effects of radiation within 3 months which loss of mucosal cell lining and diminish defense mechanism cause for inflammation of alveoli. Radiation-induced fibrosis is develop after months to years leading to respiratory dysfunction and decreased quality of life. increasing circulation of myofibroblasts caused for accumulation of collagen and other extracellular matrix components. Inflammatory cells also generate ROS and activation of NADH oxidase caused chronic late effects.

Brain injury

During radiation exposure, the brain is intimate both in acute and chronic effects characterized by fatigue, dizziness, and signs of increased intracranial pressure. Acute side effects depend on damage to the blood-brain barrier leading to secondary edema. Late effects manifested with irreversible neurological consequences such as demyelination of neurons, necrosis of brain parenchyma, dysfunction of cranial nerves, and eventually short-term memory loss. But acute effects can be reversed after 2 to 3 weeks with steroid therapy but radiation necrosis is irreversible and very difficult to treat which causes paralysis. Most of the brain-located cells are not proliferate and express acute effects with high repair ability but have to maintain radiation below the threshold which reduces late effects when treating cancer with radiation therapy.

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Sachindra Lochana