Radiation tolerance and the new biology: growth factor involvement in radiation injury to the lung.

In this issue of the journal, Rubin, Finklestein, and Shapiro propose a novel hypothesis for the mechanism of radiation-induced injury to pulmonary tissues. The authors report that alveolar macrophages obtained by bronchial lavage from irradiated rabbit lungs exhibit enhanced production and release of TGFcI and TGFP as compared to macrophages obtained from normal lungs. TGFa is known to stimulate fibroblast proliferation, while TGFP induces synthesis and secretion of extracellular matrix components. The investigators suggest that the control of fibroblast proliferation and excessive matrix production, which occur in the lung after exposure to damaging levels of radiation, are mediated via these and other growth factors that are released from parenchymal cells as the result of gene activation by the radiation exposure. These observations provide an insight into mechanisms by which messages exchanged between cells via paracrine loops may mediate specific cellular and tissue responses that lead to the eventual manifestations of radiation damage in normal tissues. In the lung, these events occur during a clinically latent but biologically active period and constitute an early phase in the pathogenesis of radiation injury. The concept that radiation-induced gene products can modulate the radiation response at the tissue level is based on the recent discovery that exposure of mammalian cells to radiation induces the activation and expression of several classes of genes. Hallahan et al. (5) and Witte et al. ( 10) were the first to demonstrate x-ray induction and release of growth factors and cytokines by normal and tumor cells and showed that autocrine or paracrine stimulation of biologically active peptides either induces repair of radiation lesions (2) or enhances x-ray cell killing (4). The effects depend upon the cytokine produced and the specific cell renewal system affected. Several genes have since been shown to be induced or their expression to be altered by ionizing radiation, including early response genes, cell cycle related genes, growth factors and cytokines, and a variety of enzymes and other cellular proteins (2,9). The effector arm of the pleiotropic gene expression after x-irradiation in mammalian cells is not well understood, but it is believed to represent a programmed stress response to radiation injury to DNA which leads to specific cellular responses (1, 2, 8). The pattern of this response seems to be specific for ionizing radiation, as its manifestations and kinetics are apparently distinct from the stress responses to heat shock, hypoxia, or alkylation treatment with melphalan (1, 6). The enhanced production and release of TGFcY and TGFj3 from irradiated alveolar macrophages reported by Rubin, Finklestein, and Shapiro (7) is the first demonstration of prolonged cellular radiation stress response occurring in vivo. One surprising aspect of this phenomenon is the observation that the growth factor stimulation in this in vivo system persists for up to a month following irradiation. Investigations on the kinetics of gene regulation after ionizing irradiation in vitro have shown that while increased transcript levels of growth factor specific mRNA can be detected for several hours after irradiation, they are usually down regulated to normal levels by approximately 12 hr after treatment (2, 3, 8). Enhanced secretion of growth factors into tissue culture media continues for 24-48 hr after irradiation, but subsequently returns to normal (10). The persistent secretion of TGFcx and TGFP by irradiated alveolar macrophages for several weeks after radiation exposure raises the question whether this secretion represents a primary response to a radiation insult, or whether it is secondary to other expressions of radiation tissue damage that continually stimulate alveolar macrophages to produce and secrete local cytokines. The later possibility is supported by the fact that the activated macrophages are not detected in the unirradiated contralateral lung (7).