The role of endothelial cell damage in the development of radiation injury in the lung was investigated in rats. Vascular permeability-surface area product (PS) was measured as an indicator of the degree of endothelial cell damage in lungs of rats exposed to single dose hemithorax irradiation. Hemithorax irradiation was chosen to simulate clinical radiotherapy, in which only a portion of the lung is irradiated. In addition, it provided a control lung to compare to the irradiated lung. Radiation is postulated to lead to activation of several different biochemical pathways that result in lung injury and fibrosis. Many of these pathways can be specifically blocked with drugs. Thirteen different drugs were studied. Dexamethasone, indomethacin, cromolyn, cyproheptadine, Vitamin D3, theophylline, and diethylcarbamazine were all effective at reducing lung PS on the irradiated side. Dexamethasone, Vitamin D3, and indomethacin also significantly reduced lung PS in the unirradiated lungs and in sham-irradiated rats. Captopril, cobra venom factor, penicillamine, trapidil, epsilon-amino caproic acid, and dapsone had no significant effect on lung PS after hemithorax irradiation. We conclude that the major pathways involved in early post-radiation lung injury involve prostaglandin, leukotriene, and histamine release from macrophages and mast cells. Complement activation, proteolytic enzymes, and neutrophil migration do not seem to be important mediators of early post-radiation lung injury.