Sepsis: prognostic role of apoptosis regulators in gastrointestinal cells.

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.

Somatostatin versus octreotide in the treatment of patients with gastrointestinal and pancreatic fistulas.

BACKGROUND AND PURPOSE: Gastrointestinal and pancreatic fistulas are characterized as serious complications following abdominal surgery, with a reported incidence of up to 27% and 46%, respectively. Fistula formation results in prolonged hospitalization, increased morbidity/mortality and increased treatment costs. Conservative and surgical approaches are both employed in the management of these fistulas. The purpose of the present study was to assess, evaluate and compare the potential clinical benefit and cost effectiveness of pharmacotherapy (somatostatin versus its analogue octreotide) versus conventional therapy. PATIENTS AND METHODS: Fifty-one patients with gastrointestinal or pancreatic fistulas were randomized to three treatment groups: 19 patients received 6000 IU/day of somatostatin intravenously, 17 received 100 microg of octreotide three times daily subcutaneously and 15 patients received only standard medical treatment. RESULTS: The fistula closure rate was 84% in the somatostatin group, 65% in the octreotide group and 27% in the control group. These differences were of statistical significance (P=0.007). Overall mortality rate was less than 5% and statistically significant differences in mortality among the three groups could not be established. Overall, treatment with somatostatin and octreotide was more cost effective than conventional therapy (control group), and somatostatin was more cost effective than octreotide. The average hospital stay was 21.6 days, 27.0 and 31.5 days for the somatostatin, octreotide and control groups, respectively. CONCLUSIONS: Data suggest that pharmacotherapy reduces the costs involved in fistula management (by reducing hospitalization) and also offers increased spontaneous closure rate. Further prospective studies focusing on the above parameters are needed to demonstrate the clinicoeconomic benefits.

Deferoxamine administration in septic animals: improved survival and altered apoptotic gene expression.

BACKGROUND: Oxidative damage is one of the major factors that lead to cell damage, organ dysfunction and death in sepsis. Thus, an attractive candidate for the pharmacologic treatment of the septic syndrome is desferoxamine (DFX), an antioxidant iron chelator used for the removal of iron and a potential free radical scavenger. OBJECTIVE: The impact of DFX administration on the survival of septic animals. The effect on cell integrity and cycle of vital organs. METHODS: Sepsis was induced in 40 rats using the cecal ligation and puncture method (CLP) and 20 rats randomly received twice subcutaneously DFX (total dose: 40 mg/kg). Rats were monitored for 36 h and all vital organs were harvested for pathology examination and immunohistochemical detection of Bax, Bcl-2, cytochrome c and caspase-8 apoptosis regulating proteins. RESULTS: Mean survival in the DFX group was 34.2 h (median 36.0, S.D. 4.4) and 30.2 h (median 36.0, S.D. 9.1) in the control group (p=0.04), while 36 h after follow up 85% of the DFX-treated rats and 55% of placebo rats were alive (p=0.04). Expression of pro-apoptotic bax protein was significantly increased in the heart, liver and kidney of animals in the DFX group compared to the control group. CONCLUSIONS: Treatment with the polymeric iron chelator DFX significantly increases survival of septic subjects and alters the expression of bax, an apoptosis regulating protein in certain organs (heart, liver and kidney).