SIMULTANEOUS ACTIVATION OF GRANULOCYTES AND EXTRATHYMIC T-CELLS IN NUMBER AND FUNCTION BY EXCESSIVE ADMINISTRATION OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes show serious s ide effects such as damage to the gastroduodenal mucosa and dysfunctio n of the liver. Although many investigators have focused on some types of leukocytes, a comprehensive study concerning all types of leukocyt es, especially recently identified extrathymic T cells, remains to be done. When mice were treated with an intraperitoneal injection of indo methacin (50 or 300 mu g/mouse), the number of thymocytes decreased wh ile the number of MNC in various peripheral organs increased, This inc rease in MNC was due mainly to the increase in the numbers of granuloc ytes and extrathymic T cells. Reflecting thymic atrophy, the proportio n of thymus-derived T cells distributed in the periphery decreased. Th e use of other NSAIDs revealed that granulocytosis seen in the periphe ry arose from a selective activation of myelomonocytic cells in the bo ne marrow. Some functional experiments using the Ca2+ influx, iNOS mRN A expression, and autoreactive cytotoxicity as indicators suggested th at granulocytes and extrathymic T cells were in activated states not o nly in number but also in function. Since both granulocytes and extrat hymic T cells become cytotoxic effecters against self-tissues or self- cells when overactivated, these activated leukocytes may be intimately related to the etiology of the tissue damage inducible by NSAIDs (i.e ., adverse drug reaction). (C) 1996 Academic Press, Inc.