Is it time for a new formalism to categorize normal tissue radiation injury?

Abstract

In many respects, the simple classification of radiation injury as “early” or “late” depending on the timing of its clinical expression, has served us well. Founded on two different, but not mutually exclusive, mechanistic models of injury—the “target cell” and “vascular injury” models—this formalism has provided a structure amenable to reasonably successful quantitative biomathematical modeling, using the very simple parameters of the linear quadratic model. Recently, however, increased knowledge regarding molecular mechanisms of radiation injury has provided us with opportunities to understand their genesis at a more basic level. We therefore believe that the time is ripe to adopt a new formalism for categorizing radiation injury based on fundamental principles, and propose one such formalism for discussion. This is not a semantic issue so much as a means to help develop and refine interventional strategies to avert injury or arrest its development, and to facilitate scientific cross-fertilization and collaboration with other research disciplines. The new formalism holds that lesions producing radiation injury fall into three interacting categories: cytocidal effects, indirect effects, and functional effects. All three types of radiation effects may lead to tissue injury, symptoms, or signs that are expressed after short or long delays. The relationship between this formalism and earlier models of radiation injury is relatively straightforward. “Cytocidal” effects relate to the well-known phenomena characterized by the “target cell” model. Hence, the time between irradiation and manifestation of injury depends on target cell characteristics (radiation sensitivity, repair capacity, proliferation rate, etc.) and tissue organization. In rapid renewal tissues, such as the epithelial surfaces and bone marrow, injury manifests itself clinically within days of first radiation exposure, when cells in the “differentiated” cellular compartment are no longer replaced by cells from the progenitor compartments. These tissues, for obvious reasons, have been dubbed “early-reacting tissues”. Cellular turnover, however, is much slower in connective tissues and organs composed cells of capable of re-entering the cell cycle. Radiation injury may therefore be expressed months or even years after exposure if cell death occurs when cellular division is attempted, and these tissues are said to be “late reacting.” “Indirect” effects are reactive phenomena that occur in response to radiation-induced injury in other cells or tissues, the classic example being parenchymal cell depletion secondary to vascular damage. However “indirect” effects also include such phenomena as the “bystander” effect and tissue reactions to cell lethality such as the effects of vasoactive, procoagulant, and inflammatory mediators, including cytokines, growth factors, and chemokines. Although many of these effects have only been recognized during the past two decades, they do contribute to what are loosely referred to as “consequential mechanisms” of delayed injury. The third category of effects we now propose, termed “functional” effects, lead to injury in ways that do not sit comfortably with the mechanisms underlying either cytocidal or indirect effects. “Functional” effects result from nonlethal effects on different intraand extracellular molecules and changes in gene expression in irradiated cells leading, for example, to direct inactivation of anticoagulant molecules, activation of latent growth factors, and activation of proteases. They include phenomena such as the inhibition of cellular replicative ability and accelerated senescence that lead to decreased tissue vitality. Additional examples are the mechanisms by which tissues can recover from subthreshold injury with time—the concept underlying “forgotten dose.” In most tissues, injury occurs through complex interactions that involve all three types of effects. For example, the acute inflammatory response during and after radiotherapy represents a combination of both functional and indirect effects. Hence, some acute inflammatory phenomena are initiated within hours of the first exposure, when “stress protein” genes are activated (“functional effects”). On the