Mechanisms of normal tissue radiation responses Flashcards
Which of the following cytokines is generally considered both anti-inflammatory and immunosuppressive?
A. Interleukin 1
B. Interleukin 6
C. Interleukin 8
D. Interleukin 10
E. Tumor necrosis factor alpha (TNF⍺)
D
IL-10 is produced by a variety of different cell types, particularly monocytes/macrophages and lymphocytes. It is a major anti-inflammatory cytokine that inhibits the initiation and effector phases of cellular immune responses as well as a variety of inflammatory responses. The other cytokines (IL-1, IL-6, IL-8, and TNF⍺) are all considered pro-inflammatory. There is considerable overlap between the activities of TNF⍺ and IL-1. TNF⍺ is secreted mainly by activated monocytes/macrophages and has profound pro-inflammatory effects. It also stimulates the secretion of many other cytokines, including IL-1, IL-6, and IL-8. IL-1 is also a key mediator of host response to infection and inflammation. The main cellular sources of IL-1 are cells of the monocyte and macrophage lineage. Similar to TNF⍺, IL-1 induces several secondary cytokines, including IL-6 and IL-8. Upon stimulation by IL-1 and/or TNF⍺, IL-6 and IL-8 are produced by a large number of different cell types, including monocytes, fibroblasts, endothelial cells and epithelial cells.
Studies with laboratory animals have shown that all of the following interventions can reduce lethality after total body irradiation, EXCEPT:
A. Fluid and electrolyte therapy
B. Inhibitors of poly(ADP-ribose) polymerase (PARP)
C. Antibiotics
D. Probiotics
E. Blood product administration
B
The radiation dose-dependent lethality and reduction in gut crypt cell survival is significantly potentiated, not reduced, in PARP-deficient mice and in mice treated with a PARP inhibitor. Treatment with fluids, electrolytes, antibiotics, and blood products is part of the standard supportive care after exposure to total body irradiation. Manipulation of the gut ecosystem through administration of probiotics has been demonstrated to prevent radiation-induced enteritis in animals.
With regard to the retreatment tolerance of previously-irradiated normal tissues, which of the following statements is FALSE?
A. The lung is capable of long-term recovery after doses that are below the tolerance dose for radiation pneumonitis
B. Re-irradiation of the mucosa does not produce a more severe acute reaction compared to mucosa that has not been previously irradiated
C. The spinal cord is capable of moderate long-term recovery after irradiation
D. Re-irradiation tolerance of the kidney increases with increasing time interval between treatments, indicating continuous repair of subthreshold damage
E. The onset of late bladder damage occurs much earlier in animals that were re-irradiated following a low sub-tolerance initial radiation dose, as opposed to being treated to tolerance in a single course of therapy
D
In the kidney, the tolerance to retreatment decreases with time, indicating a continuous progression of renal injury in the interval between treatments. Experimental studies in mice given initial radiation doses approximately 30-50% of the biologically effective tolerance dose (BEDt) showed that the lungs could be re-irradiated with doses equivalent to the BEDt provided a sufficient time interval between the first and second treatments had elapsed. Re-irradiation tolerance for acute damage in rapidly dividing mucosal tissues is commonly observed. Rodent and monkey data indicate that, contrary to popular belief, the spinal cord is capable of considerable recovery from the injury caused by an initial radiation treatment and can subsequently be retreated with at least a partial tolerance dose. In the bladder, the latency period before expression of injury is shorter in animals that were re-irradiated, as opposed to being treated to tolerance in a single course of therapy, even after low, sub-tolerance initial radiation doses.
Which of the following statements concerning radiation-induced late effects is TRUE?
A. Most late effects develop primarily as a direct result of endothelial cell killing
B. Most late effects are due to the loss of parenchymal cell clonogens
C. Radiation-induced late effects produce unique pathological responses
D. The development of late effects shares many elements in common with both acute and chronic wound-healing responses in normal tissues
E. Once present, late effects are irreversible
D
Despite the recent surge in interest in radiation-induced late effects, the precise mechanisms responsible for their development and progression remain unclear. Historically, late effects were considered to be a consequence of the radiation-induced killing of either parenchymal or vascular target cell populations, and as such, were thought to be inevitable, progressive, and untreatable. More recent findings suggest that this hypothesis is overly simplistic. Radiation-induced late effects are now viewed as the result of dynamic interactions between multiple cell types within the tissue. The parenchymal cells are no longer viewed as passive bystanders, merely dying as they attempt to divide, but rather are thought to be active participants in an orchestrated, yet limited, response to injury. In general, irradiating late-responding normal tissues leads to an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response in which vascular and parenchymal cell dysfunction and cell loss, associated with chronic overproduction of particular cytokines and growth factors, result in fibrosis and/or necrosis, depending on the particular organ involved. This new paradigm promises novel approaches to the mitigation of radiation-induced normal tissue complications, including the possibility that late effects might be reduced by the application of therapies directed at altering steps in the cascade of events leading to the clinical expression of the injury. There are no pathognomonic features characteristic of irradiated late-responding normal tissues.
With regard to the latency period for the expression of radiation-induced normal tissue injury, which of the following statements is CORRECT?
A. The latency period for early-responding tissues decreases markedly with increasing radiation dose
B. Shortening the overall treatment time by accelerating radiotherapy substantially reduces the latency period for early-responding tissues
C. Shortening the overall treatment by accelerating radiotherapy tends to increase the latency period for late-responding tissues
D. The higher the total radiation dose, the shorter the latency period for many late-responding tissues
E. The latency period for early-responding tissues depends on the rate of vascular endothelial cell turnover
D
Early-responding tissues exhibit radiation-induced injury during or shortly after a course of radiotherapy. Late reactions are manifested months or years following the completion of radiotherapy. The classical model of radiation-induced normal tissue injury hypothesizes that normal tissue injury involves the loss of specific target cell clonogens. In early-responding tissues such as the skin and oral mucosa, clonogenic cell turnover is rapid, as is clonogenic cell death. Thus, the latency period, i.e., the period before the expression of radiation-induced injury, is short. This latency period is fixed in early-responding tissues, since it depends on the time it takes for cells to move from the stem cell compartment through the transit compartment, and finally to the terminally-differentiated, non-dividing parenchymal cell that is lost through normal wear and tear. In contrast, target cell turnover is slow or non-existent in late-responding tissues and therefore the latency period is long. Shortening the overall treatment time may cause greater cell depletion and increase the severity of early reactions since the time available for cell repopulation would be limited under these circumstances. This might result in more pronounced “consequential” late effects; however, the latent period for these late effects would, if anything, decrease, rather than increase. According to classical theory, the decrease in the latency period with dose for late effects was thought to be due to the enhanced cell killing resulting from the use of higher doses. It is now recognized that this cell killing likely plays only a limited role in the development of most late responses. In contrast, it is thought that when irradiation of a tissue may give rise to a late radiation reaction, there is initially an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response. Vascular and parenchymal cell dysfunction and cell loss then occur which are accompanied by a chronic overproduction of particular cytokines and growth factors, ultimately resulting in the manifestation of radiation toxicity. Thus, it is now thought that the process ultimately leading to the development of late radiation effects actually begins relatively quickly after irradiation. Presumably, the speed and/or intensity of this process is somewhat dose dependent such that the length of time necessary before a late effect is observed clinically decreases with increasing dose. There is no relationship between the latency period for early-responding tissues and endothelial cell turnover; if anything, the latter has been considered a target cell for injuries in late-responding tissues.
For normal tissues such as spinal cord, a small dosimetric hotspot could be disastrous in terms of increasing the likelihood for a serious late complication. However, a small volume receiving a high dose during lung irradiation may not lead to any late sequelae. The best explanation for this observation is that:
A. The spinal cord has a large functional reserve, but the lung does not
B. Target cells in the lung are better able to repair radiation damage than their counterparts in the spinal cord
C. Surviving clonogens in the lung can repopulate rapidly, whereas those in the spinal cord cannot
D. Migration of cells from outside the irradiated volume helps to augment lung function, but this process does not occur in the spinal cord
E. The putative functional subunits in the lung are arranged in parallel, whereas those in the spinal cord are arranged in series
E
The reason a large dose to a small length of the spinal cord may cause severe radiation injury, such as myelopathy, is that the inactivation of even a single functional subunit (FSU) can disrupt the function of the entire organ for tissues whose FSUs are arranged in a serial fashion. In contrast, a high dose to a small volume of the lung may have little impact because the remainder of the lung will continue to function normally because its FSUs are arranged in parallel.
Radiation effects in the nervous system typically arise as a consequence of damage to:
A. Axons
B. Neurons
C. Oligodendrocytes and glial cells
D. The perikaryon
E. Dendrites
C
The effects of radiation on the nervous system arise primarily as a consequence of damage to oligodendrocytes and glial cells. Although radiation likely does cause some damage to neurons as well, this alone does not seem to manifest itself as a frank nervous system injury.
Which of the following statements is TRUE concerning irradiation of the salivary glands?
A. Serous acinar cells die only by mitotic catastrophe after irradiation
B. The serous acinar cells of the parotid and submaxillary glands are considered the target cells for radiation-induced salivary gland damage
C. Salivary dysfunction is a late radiation effect rarely observed earlier than six months following treatment
D. Mucous cells are more radiosensitive than serous cells
E. Dose fractionation results in significant sparing of serous cells
B
The serous acinar cells of the parotid and submaxillary glands are considered to be the targets for radiation-induced salivary gland damage. Serous acinar cells typically die by apoptosis and not mitotic catastrophe following irradiation. Salivary dysfunction is an early radiation response that often begins while radiotherapy is still ongoing. Mucous cells are more radioresistant than serous cells. Fractionation results in relatively little sparing from radiation-induced killing of serous cells, as is typical for cells with a pro-apoptotic tendency.
Which statement concerning transforming growth factor beta 1 (TGF-β1) and basic fibroblast growth factor (bFGF/FGF2) is TRUE?
A. The pro-fibrotic activities and role in radiation-induced fibrosis of TGF-β1 are mediated by SMAD3
B. Stimulation of TGF-β1 synthesis should improve the therapeutic ratio
C. bFGF has been shown to sensitize endothelial cells to radiationinduced apoptosis
D. The serum concentration of TGF-β1 always decreases following lung
irradiation
E. TGF-β1 promotes the radiation-induced inflammatory response
A
Transforming growth factor beta 1 (TGF-β1) plays a central role in radiation-induced fibrosis as it causes epithelial to mesenchymal cell trans-differentiation and promotes the influx of fibroblasts as well as the production of extracellular matrix. TGF-β1 activates SMAD proteins, including SMAD3, which modulates the transcription of target genes with pro-fibrotic activities. It is thought that stimulation of TGF-β1 synthesis causes fibrosis and would therefore decrease the therapeutic ratio.
Basic fibroblast growth factor (bFGF/FGF2) has been shown to protect (not sensitize) endothelial cells from radiation-induced apoptosis. In addition, TGF-β1 has anti-inflammatory activity. The clinical interpretation of serum TGF-β1 levels during thoracic irradiation is complex; on the one hand, levels are elevated in patients who develop radiation pneumonitis while, on the other hand, lung tumors may self-generate TGF-β1 causing levels to fall during treatment).
Regarding radiation fibrosis, which of the following statements is TRUE?
A. Fibrosis occurs in only a select few tissues and organs
B. The severity of late fibrosis can be predicted based on radiotherapy treatment parameters and is not tissue-dependent
C. Radiation fibrosis is typically inhomogenous; some affected areas could be densely collagenous whereas others may have only a few fibrous bands, despite both areas having received the same dose
D. Irradiated bone marrow commonly develops regions of fibrosis
E. Increases in collagen deposition are associated with down-regulation of fibrogenic cytokines.
C
Fibrosis is one of the most common late radiation effects and can be noted in a majority of irradiated tissues and organs. Although the appearance of fibrosis is both time- and dose-dependent, its extent and severity can vary not only within a single organ, but also across different individuals. Bone marrow is one of the few tissues where fibrosis is rarely seen; in general, fibrosis only appears within the marrow if a tumor or inflammatory lesion was present prior to irradiation. Bone marrow is usually replaced by adipose tissue. Much of the regulation of collagen deposition is mediated through the action of fibrogenic cytokine families and is characterized by the upregulation of such cytokines as TGF-β1.
The cells thought to be responsible for radiation-induced cognitive dysfunction reside in:
A. Medulla oblongata
B. Cerebral cortex
C. Substantia nigra
D. Hippocampus
E. Hypothalamus
D
Radiation-induced cognitive impairment is marked by decreased verbal memory, spatial memory, attention, and novel problem-solving ability. The incidence and severity of radiation-induced cognitive impairment increases over time. The hippocampus houses neuronal stem cells and is one of only two areas where neurogenesis continues after birth. The hippocampus plays an important role in learning and memory consolidation.
The importance of sparing the hippocampus was demonstrated in the phase III NRG-CC001 trial of whole-brain radiotherapy plus memantine, with or with hippocampal avoidance. Patients were randomly assigned to memantine plus whole-brain radiotherapy (30 Gy in 10 fractions) vs memantine plus hippocampal-avoidant whole-brain radiotherapy (30 Gy in 10 fractions). Hippocampal-avoidant whole-brain radiotherapy plus memantine reduced the risk of cognitive function failure by 26% (P = .033).
