Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury.
Recent data from several investigators, including our unit, have provided additional information on the etiology of radiation-induced lung damage. These data suggest that there are two quite separate and distinct mechanisms involved: (a) classical radiation pneumonitis, which ultimately leads to pulmonary fibrosis is primarily due to radiation-induced local cytokine production confined to the field of irradiation; and (b) sporadic radiation pneumonitis, which is an immunologically mediated process resulting in a bilateral lymphocytic alveolitis that results in an "out-of-field" response to localized pulmonary irradiation. Both animal experiments and human studies show that classical radiation pneumonitis has a threshold dose and a narrow sigmoid dose-response curve with increasing morbidity and mortality over a very small dose range. Clinical pneumonitis rarely causes death, whereas in the animal and human studies of classical radiation pneumonitis, all subjects will eventually suffer irreversible pulmonary damage and death. The description of classical radiation pneumonitis is that of an acute inflammatory response to lung irradiation, which is confined to the area of irradiation. Recent studies have also shown that irradiation induces gene transcription and results in the induction and release of proinflammatory cytokines and fibroblast mitogens in a similar fashion to other chronic inflammatory states, and which ultimately results in pulmonary fibrosis. The description of classical radiation pneumonitis does not adequately explain the following observed clinical characteristics: (a) the unpredictable and sporadic onset; (b) the occurrence in only a minority of patients; (c) the dyspnoea experienced, which is out of proportion to the volume of lung irradiated; and (d) the resolution of symptoms without sequelae in the majority of patients. We have demonstrated a bilateral lymphocytic alveolitis of activated T lymphocytes and a diffuse increase in gallium lung scan uptake in patients studied before and 4 to 6 weeks after strictly unilateral lung irradiation. This is suggestive of a hypersensitivity pneumonitis, which gives rise to an "out-of-field" response to localized lung irradiation and hence more accurately describes the clinical picture of radiation pneumonitis. Reevaluation of the mechanisms of pulmonary injury from irradiation suggest that (a) a new term, sporadic radiation pneumonitis, should be introduced to describe the clinical picture of radiation pneumonitis, which is not adequately explained by the classical description and is quite clearly an entirely different process; and (b) that the chronic response to localized lung irradiation that leads to pulmonary fibrosis is largely mediated through the induction and release of tissues cytokines.