Volume-dependent expression of in-field and out-of-field effects in the proton-irradiated rat lung.

Abstract

To investigate whether occurrence of early radiation effects in lung tissue depends on local dose only. Twenty-five percent, 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field dose-response curves were obtained 8 weeks after irradiation. The pathohistology of parenchymal inflammation, infiltrates, fibrosis, and vascular damage and the relative expression of proinflammatory cytokines interleukin (IL)-1α, transforming growth factor-β, IL-6, and tumor necrosis factor-α were assessed. For all histologic endpoints, irradiated dose- and volume-dependent in-field and out-of-field effects were observed, albeit with different dynamics. Of note, the out-of-field effects for vascular damage were very similar to the in-field effects. Interestingly, only IL-6 showed a clear dose-dependent increase in expression both in-field and out-of-field, whereas the expression levels of IL-1α, transforming growth factor-β, and tumor necrosis factor-α were either very low or without a clear dose-volume relation. As such, none of the radiation effects studied depended only on local dose to the tissue. The effects of radiation to lung tissue do not only depend on local dose to that tissue. Especially at high-volume irradiation, lung damage seems to present globally rather than locally. The accuracy of predictive modeling may be improved by including nonlocal effects.