PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN THE PATHOGENESIS OF DELAYED RADIATION-DAMAGE IN RAT SPINAL-CORD IN-VIVO

The pathophysiology of radiation-induced damage to the central nervous system (CNS) is poorly understood. Preliminary data suggest that fibr inolytic inhibitors are involved in the development of necrosis. In th is study, cervical spinal cord irradiation was studied in 90 rats by m easuring plasminogen activator inhibitor (PAI)-1 on Days 2, 7, 30, 60, 90, 120, 130, or 145 after irradiation. Paralysis due to radiation ne crosis developed in all animals kept alive for 140 to 150 days. Assay of PAI-1 was by Western blot, enzyme-linked immunosorbent assay (ELISA ), and complex formation with I-125-labeled urokinase. No PAI-1 was de tected in normal spinal cord tissue or in irradiated spinal cord up to Day 90. However, PAI-1 was detected at Day 120 and was marked by elev ated ELISA levels at the time of paralysis. Western blot showed detect able PAI-1 (51 kD) at Day 120 and very significant levels at the time of paralysis. Complex formation with I-125-labeled urokinase was also detected at Day 120 with similar results. Immunohistochemical studies showed that PAI-1 was highly concentrated within and immediately adjac ent to zones of necrosis at 145 days and was absent in normal tissue. This study adds considerable weight to the proposal that PAI-1 is clos ely associated with the pathogenesis of CNS radiation necrosis.