Regulation of peritoneal and systemic neutrophil-derived tumor necrosis factor-α release in patients with severe peritonitis: Role of tumor necrosis factor-α converting enzyme cleavage*

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Objective:Polymorphonuclear neutrophil (PMN) influx and peritoneal tumor necrosis factor (TNF)-α production are key host defense mechanisms during peritonitis. The aim of this study was to explore the potential interactions between TNF-α production and TNF-α converting enzyme (TACE) expression by PMN in the blood and peritoneum of patients with severe peritonitis.Design:A prospective study.Setting:A surgical adult intensive care unit in a university hospital.Patients:A total of 29 consecutive immunocompetent patients with severe sepsis within 48 hrs of onset were enrolled and underwent laparotomy for a diffuse secondary peritonitis. Thirteen volunteers served as controls.Measurements:Blood and peritoneal fluid recovered during laparotomy were analyzed and compared for 1) soluble TNF-α, soluble L-selectin, and type I and II TNF-α receptor levels; 2) PMN membrane TNF-α, membrane L-selectin, and TACE expression (flow cytometry); and 3) TNF-α production by cultured PMN. Correlations between these forms of PMN-derived TNF-α and the severity of the peritonitis and patient’s outcome were investigated.Main Results:Elevated soluble TNF-α levels in both plasma and peritoneal fluid from the patients were found, together with decreased expression of membrane TNF-α and TACE up-regulation at the PMN surface. Soluble L-selectin and type I and II TNF receptors were highly released, suggesting also the role of TACE. In contrast, the capacity of both blood and peritoneal PMN to synthesize TNF-α in vitro, in optimal conditions of stimulation (lipopolysaccharide + interferon-γ), was impaired as compared with controls’ blood PMN. Regulation of PMN-derived TNF-α was similar in the two compartments, but responses were more pronounced in the peritoneum. TACE up-regulation at the surface of blood-derived PMN correlated with the Sequential Organ Failure Assessment score and vital outcome.Conclusion:These human data demonstrate that mTACE is up-regulated at the PMN surface during severe peritonitis. This finding could be related to a paracrine regulatory loop involving some TACE substrates such as TNF-α, L-selectin, and TNF receptors.

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