4.Tissue Response to Radiation

It was pointed out in Chapter 6 that the D₀ for mammalian cclls obtained both in vivo and in vitro is between 1 and 2 Gy, indicating that there is not a substantial difference in the radiosensitivity of mammalian cells. However, it is well known that there is a vast difference in the doses at which different organs and tissues exhibit damage. Reasons for these dose differences must be sought elsewhere. Since cell division is necessary for radiation damage to be expressed, then the time of expression of in jury in an organ must be dependent on the turnover time of the critical target cells — not only if they divide, but when and how often. The term target cell does not imply that radiation is selective for any given cell, but refers to those cells in the tissue that can divide and regenerate the tissue after radiation, i.e., the stem cells. When sufficient numbers of cells are killed and subsequently depleted due to a failure of the stem cells to regenerate after irradiation, overt functional and structural tissue damage occurs. Thus, to understand tissue response to radiation it is important to first have some knowledge of how tissues and organs are organized. This knowledge also is critical to an understanding of how the effects of radiation on different tissues are measured.

1. Tissue Organization

Tissues and organs are made up of two compartments: the parenchymal compartment, containing the cells characteristic of that individual tissue or organ, and the stromal compartment, composed of

connective tissue and vasculature, which makes up the supporting structure of the organ (Fig 7-2).

The parenchymal compartment of tissues and organs may be com­posed of one or more than one category of cells, as defined by Rubin and Casarett. The testis is an example of an organ that contains more than one category of cells: stem cclls — type A spermatogonia (VIM cells); intermediate cells — type В spermatogonia, spermatocytes, and spermatids (DIM cells); and mature, functional cells — spermatozoa (FPM cells). Another example is the hemopoietic system: the bone marrow contains the undifferentiated stem cells, and the circulating blood contains the mature end cell. Two other examples are the skin and the intestinal tract.

In these types of organs where the parenchymal compartment is composed of various cellular populations, cells flow from the stem cell compartment to the differentiated compartment to the end cell compartment as needed (Fig 7-3).

Examples of tissues and organs whose parenchymal compartments are composed of only RPM cells or FPM cells are the liver, muscle, brain, and spinal cord. The hepatic cells of the liver are RPM cells, dividing only when the need exists. If a partial hepatectomy is performed, the hepatic cclls will begin to divide and replace the part of the liver that has been removed. However, most cells of the brain and most muscle cells do not retain the capability of division; these tissues and organs are composed of FPM cells.

compartment (FPM), illustrated by cells of the testis.

Regardless of the population of cells in the parenchymal compartment, all tissues and organs will have a supporting stromal compartment composed of connective tissue and vasculature (multipotential connective tissue cells).

2. Mechanisms of Damage in Normal Tissues

Tables 7-1 and 7-2 indicate that cells in the vasculature are intermediate in sensitivity to radiation, i.e., they arc more sensitive than either the RPM or FPM cells of organs such as the lung, kidney, and spinal cord. For this reason, it had long been suggested that damage in such tissues was a consequence of damage to the vasculature (tissue damage occurred indirectly via vascular narrowing and occlusion, resulting in tissue ischemia), rather than damage to cells specific to that organ (the parenchyma). Recently, however, this hypothesis has been questioned and, in fact, a new classification of normal tissue responses according to the time in which the tissues express injury has been suggested. I his new hypothesis states that the response in all normal tissues is due to killing and subsequent depletion of the critical parenchymal cells of that organ, and that the differences in the time it takes for damage to be expressed are due simply to differences in turnover kinetics of the target cells. The current philosophy, then, is that tissue damage is due to depletion of critical target cells and is not an indirect result of vascular damage. For example, damage is seen in the intestine within a week to 10 days alter irradiation, and is quite predictable based on the turnover kinetics of the stem cells in the crypts (i.e., 12-hour cell cycle). On the other hand, damage in the lung is not expressed for at least 3 months alter irradiation, which, rather than being a consequence of vascular damage, most likely reflects the slow turnover of the critical parenchymal cclls in the lung (perhaps type 2 cells), whose loss results in observable damage.

Based on the difference in turnover kinetics of the critical target cells in different tissues, normal tissues can be divided into two categories: acutely responding and late responding normal tissues. The acutely responding tissues manifest their injury within a few months after radiation

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is completed because they are self-renewal tissues containing rapidly dividing stem cell populations. Examples are the bone marrow, skin, intestine, and testis. On the other hand, late responding normal tissues do not express injury for at least 3 months or longer becausc they contain slowly dividing cell populations. Two examples of the latter are lung and kidney.

Thus, differences in the times within which different tissues express damage after radiation are most likely not an issue of vascular vs. parenchyma, but rather are due simply to the fact that some cells in some tissues, such as the lung, divide more slowly than cells in other tissues, such as the intestine. Table 7-3 lists acutely responding and late responding normal tissues and the known or hypothesized critical target cells.

TABLE 7-3