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Chun-Shiang Chung, PhD; Ying Xin Xu, MD; Weiyang Wang, MD, PhD; Irshad H. Chaudry, PhD; Alfred Ayala, PhD

Arch Surg. 1998;133:1213-1220.

Background  Apoptosis (A_o) is a normal constitutive process that seems to have pathological effects in diseases of immune deficiency and autoimmune disorders, as well as in certain lymphoid tissues during sepsis. Little is known about this process in mucosal lymphoid tissue, such as intestinal intraepithelial lymphocytes (IELs).

Objectives  To determine whether sepsis induces increased A_o in small intestinal IEL, whether this was associated with functional changes in cytokine gene expression in the IEL, and which mediators control this process and their impact on the survival of the mouse with sepsis.

Design  Male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasL^gld (endotoxin-tolerant/Fas ligand [FasL]–deficient) mice were subjected to sepsis (cecal ligation and puncture [CLP]) and IELs were harvested at 4 (early) or 24 hours (late sepsis). Alterations in the cell phenotype and A_o (TUNEL [terminal deoxynucleotidyl transferase–mediated deoxyuridine 5-triphosphate nick-end labeling] assay) were determined by 3-color flow cytometry. Cytokine gene expression was assessed by multiprobe RNase protection assay.

Results  At 4 hours after CLP, only the frequency of IEL which was CD8⁺ decreased markedly. By 24 hours after CLP, the number of CD8⁺and CD4⁺cells decreased while the proportion of double-negative cells showed a marked increase when compared with sham-controls. The percentage of A_o positive in CD8⁺ and CD4⁺ double-positive and double-negative cells increased markedly 24 hours after CLP concomitant with a significant (P<.05 vs sham-controls, Mann-Whitney U test) increase in expression of the IL-2, IL-10, and IL-15 gene. These data collectively suggest that sepsis causes lymphocyte activation–induced A_o that may be mediated by FasL. Additional studies were done to determine if the increased A_o was due to either endotoxin or FasL. The results of studies with endotoxin-tolerant C3H/HeJ or FasL-deficient C3H/HeJ-FasL^gld mice showed an increase in A_o in CD4⁺ and CD8⁺ cells from septic C3H/HeJ but not C3H/HeJ-FasL^gld mice. With regard to septic mortality, our results indicated that there was a marked reduction in mortality in C3H/HeJ-FasL^gld vs C3H/HeJ mice.

Conclusions  We conclude that the phenotypic changes associated with increased A_o may be a reflection of localized immune cell activation due to a FasL-mediated process and not endotoxin. Thus, FasL directly and/or indirectly contributes to higher septic mortality.

From the Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence.

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