Damage Repair and Models for Normal TissuesAditya Juloori, Choamei Xiang, Michael A. Weller, and Jennifer S. Yu

RADIATION DAMAGE REPAIR AND MODELS FOR NORMAL TISSUES

ADITYA JULOORI, CHOAMEI XIANG, MICHAEL A. WELLER, AND JENNIFER S. YU

Question 1

What is the difference between lethal damage, potentially lethal damage, and sublethal damage?

Question 2

Why is a dividing cell more sensitive to radiation than a differentiated cell?

Question 3

What is the importance of the shoulder width on traditional curves for normal tissues?

Question 4

What is the difference between a structurally defined functional subunit (FSU) and a structurally undefined FSU?

Question 1 What is the difference between lethal damage, potentially lethal damage, and sublethal damage?

Answer 1

Lethal damage from radiation is not reversible or reparable and leads to cell death. Potentially lethal damage can be modified by the conditions cells are placed in after being irradiated (observed in cell culture conditions). For example, this has been demonstrated in vitro by putting cells in saline for 6 hours after irradiation in order to plateau the growth curve—these cells then had a higher surviving fraction after radiotherapy than those cells that were not placed in these conditions after radiotherapy. It is hypothesized that tumors with relatively radioresistant histology like melanoma are able to repair this potentially lethal damage. Sublethal damage can be repaired in hours under normal conditions.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Question 2 Why is a dividing cell more sensitive to radiation than a differentiated cell?

Answer 2

The dose of radiation needed to kill a dividing cell is less than that needed to kill a differentiated, nondividing cell. Cell death from radiation is primarily due to mitotic cell death. That is, DNA damage that is left unrepaired induces cells to die as the cell attempts to divide. In contrast, in differentiated cells, a higher dose of radiation is needed to kill cells or impair their function.

Hall EJ, Giaccia AJ. Clinical response of normal tissues. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:327–355.

Question 3 What is the importance of the shoulder width on traditional curves for normal tissues?

Answer 3

Various normal tissues have a wide range of radiosensitivities, with the shoulder length on survival curves being the principal variable. For example, jejunal crypt cells have a large shoulder while bone marrow stem cells have a limited shoulder. The shoulder length is larger for some tissues because of the inherent ability to repair potentially lethal damage.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Question 4 What is the difference between a structurally defined functional subunit (FSU) and a structurally undefined FSU?

Answer 4

Structurally defined FSUs are self-contained and are independent of neighboring units. Clonogenic cells cannot travel between structurally defined FSUs. Examples include nephrons in the kidney or the lobules of the liver and acini in the lung. These structurally defined FSUs are depleted of clonogens with low doses of radiation. Structurally undefined FSUs differ in that clonogenic cells can migrate from one FSU to another in order to repopulate the FSU after irradiation. An example of this would be the spinal cord, the mucosa, and the skin.

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Question 5

What is Casarett’s classification of tissue radiosensitivity based on?

Question 6

What is an H-type population according to the Michalowski classification?

Question 7

What is an F-type population according to the Michalowski classification?

Question 8

What is the role of TGF-β1 in radiation-induced fibrosis in normal tissue?

Question 5 What is Casarett’s classification of tissue radiosensitivity based on?

Answer 5

Cells are divided into four major categories based on histopathological observations, from most sensitive to least resistant. Group I cells divide regularly with no differentiation (e.g., intestinal crypt cells). Group II cells divide regularly with some differentiation between divisions (e.g., myelocytes). Group III cells do not divide regularly and are variably differentiated (e.g., liver). Group IV cells do not divide and are highly differentiated (e.g., nerve cells).

Hall EJ, Giaccia AJ. Radiation carcinogenesis. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:135–153.

Rubin P, Casarett GW. Clinical Radiation Pathology. Vol. 1. Philadelphia, PA: WB Saunders; 1968.

Question 6 What is an H-type population according to the Michalowski classification?

Answer 6

These tissues follow a “hierarchical” model. These are fully functioning cells which are no longer dividing and are differentiated. Examples of tissues/cells that follow this hierarchical model are the bone marrow, the epidermis, and the intestinal epithelium.

Wheldon TE, Michalowski AS. Alternative models for the proliferative structure of normal tissues and their response to irradiation. Br J Cancer. 1986;7(suppl):382–385.

Question 7 What is an F-type population according to the Michalowski classification?

Answer 7

These tissues follow a “flexible” model. These tissues are in organs where the cells do not typically divide unless triggered to do so in response to damage. Examples of this type of tissue include liver, skin, and thyroid. These tissues have no hierarchy and no compartments.

Wheldon TE, Michalowski AS. Alternative models for the proliferative structure of normal tissues and their response to irradiation. Br J Cancer. 1986;7(suppl):382–385.

Question 8 What is the role of TGF-β1 in radiation-induced fibrosis in normal tissue?

Answer 8

TGF-β1 causes the proliferation of fibroblasts and helps differentiate epithelial cells into mesenchymal cells by epithelial-mesenchymal transition; it also causes upregulation of transcription of profibrotic genes.

Boothe DL, Coplowitz S, Greenwood E, et al. Transforming growth factor β-1 (TGF-β1) is a serum biomarker of radiation induced fibrosis in patients treated with intracavitary accelerated partial breast irradiation: preliminary results of a prospective study. Int J Radiat Oncol Biol Phys. 2013;87(5):1030–1036.

Question 9

How has the dose–response relationship for radiation exposure to skin been studied?

Question 10

What parts of the skin are damaged in early and late radiation dermatitis?

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