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 (Ao) is elevated during inflammation by a variety of stressors in vitro (i.e., glucocorticoids, tumor necrosis factor (TNF), prostanoids, etc.), however, little or no information is available concerning its presence in polymicrobial sepsis. To establish whether or not PCD is accelerated in the thymus following the onset of sepsis, thymocytes were harvested from C3H/HeN mice at 1, 2, 12, and 24 h following cecal ligation and puncture (CLP; to induce sepsis) or Sham-CLP (Sham), and assessed for changes in thymocyte viable cell yield, increased Ao + cells based on FACS analysis (propidium iodide staining) or by evidence of fragmentation of the genomic DNA. The results indicate that at 1 h post-CLP there were no marked changes in any of these parameters. However, by 4 h post-CLP the percentage of Ao + 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. Marked changes in systemic mediators, corticosterone and TNF, were also detected in septic mouse blood at all time points. In an effort to determine the contribution of these two agents to the induction of the accelerated PCD seen here, mice were randomized to receive either RU-38486 (11 beta-[p-(dimethylamino)phenyl]-17 beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (Mifepristone); a steroid receptor blocker), polyethylene glycol (PEG)-(rsTNF-R1)2 (a TNF inhibitor) immediately following CLP.(ABSTRACT TRUNCATED AT 250 WORDS)
Ayala
A
A
Department of Surgery, Michigan State University, East Lansing 48824, USA.
Herdon
C D
CD
Lehman
D L
DL
DeMaso
C M
CM
Ayala
C A
CA
Chaudry
I H
IH
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015735:Mifepristone / Q000494:pharmacology; D018805:Sepsis / Q000473:pathology*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone