THE INDUCTION OF ACCELERATED THYMIC PROGRAMMED CELL-DEATH DURING POLYMICROBIAL SEPSIS - CONTROL BY CORTICOSTEROIDS BUT NOT TUMOR-NECROSIS-FACTOR

Thymic programmed cell death (PCD) or apoptosis (A(o)) is elevated dur ing inflammation by a variety of stressors in vitro (i.e., glucocortic oids, tumor necrosis factor (TNF), prostanoids, etc.), however, little or no information is available concerning its presence in polymicrobi al sepsis. To establish whether or not PCD is accelerated in the thymu s following the onset of sepsis, thymocytes were harvested from C3H/He N mice at 1, 4, 12, and 24 h following cecal ligation and puncture (CL P; to induce sepsis) or Sham-CLP (Sham), and assessed for changes in t hymocyte viable cell yield, increased A(o)+ cells based on FACS analys is (propidium iodide staining) or by evidence of fragmentation of the genomic DNA. The results indicate that at 1 h post-CLP there were no m arked changes in any of these parameters. However, by 4 h post-CLP the percentage of A(o)+ thymocytes increased and the septic mouse genomic DNA exhibited trace amounts of fragmentation. These changes increased in the septic animals cells through both 12 and 24 h. Alternatively, thymic viable cell yield did not significantly decrease until 12 h. Ma rked changes in systemic mediators, corticosterone and TNF, were also detected in septic mouse blood at all time points. In an effort to det ermine the contribution of these two agents to the induction of the ac celerated PCD seen here, mice were randomized to receive either RU-384 86 (11 beta-[p-(dimethylamino)phenyl]-17 beta-hydroxy-17- (1-propynyl) estra-4,9-dien-3-one (Mifepristone); a steroid receptor blocker), poly ethylene glycol (PEG)-(rsTNF-R1)(2) (a TNF inhibitor) immediately foll owing CLP. The decline in viable thymocyte cell yield induced by sepsi s (CLP) was not seen with RU-38486, but was present in PEG-(rsTNF-R1)( 2)-treated mice. Furthermore, RU-38486, unlike PEG-(rsTNF-R1)(2), trea tment markedly decreased the percentage of cells which were A(o)+ as w ell as the extent of DNA fragmentation. Thus, sepsis-induced PCD in th e thymus is not a response to TNF but appears to be controlled in vivo by corticosteriods released after the onset of sepsis.