Pathogenesis

Early radiation effects are usually seen in tissues with a permanent, more or less rapid, cell turnover, such as surface epithelia of the skin or the gastrointestinal tract, or hematopoietic tissue. The patho-genesis of these early reactions is closely related to the proliferative organization of the tissues, with a stringently regulated balance between cell production in the germinal tissue compartment and cell loss from the post-mitotic, functional compartments. Cell production is based on a stem cell population, in which cells on average divide into one stem cell and one transit cell (Fig. 21.2); the latter undergo a limited number of amplifying divisions before differentiation. Radiation impacts on cell production by sterilization (clonogenic, mitotic cell death) of proliferating cells, predominantly of stem cells. In contrast, cell loss, based on the physiological life span of the functional cells and hence largely

Fig. 21.2. Hierarchical proliferative organization of turnover tissues. The entire cell production in turnover tissues is based on tissue stem cells. A stem cell division on average results in one stem cell daughter and one transit cell daughter. This guarantees a constant stem cell number through all cell generations. The transit cells can undergo a limited number of divisions in order to amplify the cellular output per stem cell division. After differentiation, the post-mitotic, functional cells are eventually lost. The lifespan of the functional cells is tissue specific.

Fig. 21.2. Hierarchical proliferative organization of turnover tissues. The entire cell production in turnover tissues is based on tissue stem cells. A stem cell division on average results in one stem cell daughter and one transit cell daughter. This guarantees a constant stem cell number through all cell generations. The transit cells can undergo a limited number of divisions in order to amplify the cellular output per stem cell division. After differentiation, the post-mitotic, functional cells are eventually lost. The lifespan of the functional cells is tissue specific.

independent of radiation exposure, continues at its normal rate. It has to be noted that the sterilized proliferating cells usually undergo a limited number of so-called abortive divisions before terminal differentiation.

As a consequence of the imbalance between cell production and loss, progressive hypoplasia develops, which eventually can result in a complete loss of cells. Clinical effects are observed, if cell density falls below a tissue-specific, minimum cell number, and hence after a tissue-specific but dose-independent latent time (Fig. 21.3). Besides the lifespan of the functional cells, this latency is also substantially influenced by the efficacy of the above-mentioned abortive divisions of the sterilized cells, which represent a significant residual cell production. Reactions of different severity, like dry or moist skin desquamation, are related to different threshold cell numbers.

Healing of early effects, particularly in surface epithelia, occurs mainly on the basis of surviving cells within the irradiated volume; therefore, the time to tissue restoration clearly increases with decreasing numbers of surviving stem cells, i.e., with radiation dose. In other tissues, such as bone marrow, migrating stem cells originating from non-irradiated tissue volumes significantly contribute to tissue healing.

Besides this cellular component of the early reactions, further effects are observed, ranging from vascular, inflammatory changes to increased expression of molecules such as cytokines, adhesion molecules, prostaglandins, and others in endothe-

lial cells, macrophages, etc. These changes can be directly induced by the radiation exposure, or indirectly, by the epithelial changes. Interactions with the epithelial response are currently unclear, but an influence on clinical symptoms, like pain, is obvious.

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