Sepsis: prognostic role of apoptosis regulators in gastrointestinal cells

Abstract

Background: Intestinal epithelial cell apoptosis has been reported in sepsis as a mechanism of organ failure. The aim of this study was to clarify the role of apoptosis-regulating proteins (bcl-2, bax, cytochrome-c, and caspase-8) in septic rats by studying their expression in gastric and intestinal epithelial cells.

Methods: Adult Wistar rats were subjected to the cecal ligation and puncture (CLP) model of sepsis and randomly divided into two study groups. Sixty-two animals were sacrificed 6, 12, 24, 36, 48, and 60 h post-procedure, and 50 animals served as the survival study group. Sham-operated animals (n = 40) were used as controls. Gastric and intestinal tissue was excised, and immunohistochemical detection of bcl-2, bax, cytochrome-c, and caspase-8 protein expression was performed.

Results: In gastric mucosa, sepsis induced upregulation of bax and downregulation of caspase-8 expression (p = 0.053 and p = 0.05, respectively). Both bax and caspase-8 were upregulated as early as 6 h post CLP and progressively decreased (p = 0.001, p = 0.004 respectively). In contrast, the expression of the anti-apoptotic bcl-2 was upregulated progressively during the sepsis syndrome (p = 0.03). In intestine, sepsis induced a fourfold upregulation of the cytoprotective bcl-2 (p = 0.0001), accompanied by a remarkable increase in bax (p = 0.002) and caspase-8 (p = 0.0001) expression and a decrease in cytochrome-c expression (p = 0.02). The time distribution of the apoptosis regulators followed the same pattern as in gastric tissue, showing an upregulation of the proapoptotic bax and cytochrome c (p = 0.04) during the early phases and a progressively increased expression of bcl-2 during the late phases (p = 0.0001). Bax expression in gastric epithelium of subjects with septic syndrome was detrimental to survival (p = 0.0001), whereas the expression of the cytoprotective bcl-2 in intestinal epithelium appeared to favor a good prognosis (p = 0.0001).

Conclusions: Sepsis results in alterations of apoptosis regulators in gastrointestinal cells. Alterations of bax and bcl-2 expression in gastric and intestinal epithelial cells may predict the outcome in septic rats.