Temporal sequence of early alterations in rat lung following thoracic X-irradiation

The temporal patterns of several responses in the lungs of groups of rats administered two different thoracic doses of X-rays (7.5 and 15 Gy) were examined during a time frame within which radiation pneumonitis develops (1-13-week period) in order to assess for potential interrelationships among the responses. Endpoints surveyed included lung gravimetric and volumetric changes, changes in lavaged alveolar macrophage (AM) numbers, interstitial accumulations of mast cells (MC), and alterations in the amounts of lavaged phospholipids (PL), protein (P), and histamine (H). Sham-irradiated rats served as controls. Early (1 week), dose-dependent increases in lavageable PL were not accompanied by increases in lung weights or lavageable P. Elevations in lavaged PL continued for at least 5 weeks after exposure. By this time, lung weights, AM numbers, MC, and lavageable P, but not lavageable H, were all substantially increased in lungs that received the 15 Gy dose, whereas these changes were not observed at the lower dose. At later times (weeks 7 and 9), the hyperpermeability response following the 15 Gy exposure became less pronounced and the PL response also subsided, while lung MC continued to further increase and lavageable H became abnormally elevated. Maximal increases in the lung's permeability status after the 15 Gy exposure was coincidental with maximal increases in AM. An association of increases in AM and lung hyperpermeability, however, was not evident as of week 13 after the 7.5 Gy dose when lung weights and lavageable P were significantly elevated. For the X-ray doses examined, our results suggest that: (1) the early PL response to X-rays is independent of, and precedes, permeability changes in the lung; (2) the time to onset of an X-irradiation-induced increase in lung permeability is dose-dependent; (3) the progressive accumulation of MC in the lung following X-irradiation is dose-dependent; (4) excessive accumulations of interstitial MC after X-irradiation do not necessarily result in an increase in free H; and (5) free H in the lung does not appear to play a prominent role in the hyperpermeable response. Additionally, in conjunction with the findings of other investigators, our study suggests that the MC response to X-rays may be a fundamental component of the fibrogenic response.