Glucocorticoid-induced, caspase-dependent organ apoptosis early after burninjury

Immune suppression and increased apoptotic loss of circulating lymphocytes have been reported after burn injury. However, little is known about the un derlying mechanisms responsible for the increased apoptosis of lymphoid and parenchymal cells in solid organs and the role played by inflammatory medi ators, such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL ), as well as by glucocorticoids. To evaluate the role of endogenously prod uced glucocorticoids and Fast, mice subjected to a 20% steam burn were pret reated with a glucocorticoid receptor antagonist (mifepristone) or a neutra lizing murine Fas fusion protein. Three and twenty-four hours after burn in jury, histological analysis, caspase-3 activity, and in situ terminal deoxy nucleotidyl transferase dUTP nick-end labeling staining and phenotyping of lymphocyte populations for apoptosis were evaluated. Burn injury increased the number of apoptotic cells and caspase-3 activity in thymus and spleen, but not in other solid organs. Increased apoptosis was seen in several T an d B cell populations from both thymus and spleen. Mifepristone pretreatment significantly reduced the apoptosis and caspase-3 activity after burn inju ry, whereas blocking Fast activity had only minimal effects. We conclude th at corticosteroids, and not Fast, are primarily responsible for the increas ed caspase-3 activity and apoptosis in thymus and spleen cell populations e arly after burn injury.