Regulation of peritoneal and systemic neutrophil-derived tumor necrosis factor-alpha release in patients with severe peritonitis: role of tumor necrosis factor-alpha converting enzyme cleavage.
OBJECTIVE
Polymorphonuclear neutrophil (PMN) influx and peritoneal tumor necrosis factor (TNF)-alpha production are key host defense mechanisms during peritonitis. The aim of this study was to explore the potential interactions between TNF-alpha production and TNF-alpha converting enzyme (TACE) expression by PMN in the blood and peritoneum of patients with severe peritonitis.


METHODS
A prospective study.


METHODS
A surgical adult intensive care unit in a university hospital.


METHODS
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.


METHODS
Blood and peritoneal fluid recovered during laparotomy were analyzed and compared for 1) soluble TNF-alpha, soluble L-selectin, and type I and II TNF-alpha receptor levels; 2) PMN membrane TNF-alpha, membrane L-selectin, and TACE expression (flow cytometry); and 3) TNF-alpha production by cultured PMN. Correlations between these forms of PMN-derived TNF-alpha and the severity of the peritonitis and patient's outcome were investigated.


RESULTS
Elevated soluble TNF-alpha levels in both plasma and peritoneal fluid from the patients were found, together with decreased expression of membrane TNF-alpha 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-alpha in vitro, in optimal conditions of stimulation (lipopolysaccharide + interferon-gamma), was impaired as compared with controls' blood PMN. Regulation of PMN-derived TNF-alpha 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.


CONCLUSIONS
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-alpha, L-selectin, and TNF receptors.
Kermarrec
Nathalie
N
Department of Surgical Intensive Care Unit and Anesthesiology, Hôpital Bichat Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France.
Selloum
Saphia
S
Plantefeve
Gaetan
G
Chosidow
Denis
D
Paoletti
Xavier
X
Lopez
Anne
A
Mantz
Jean
J
Desmonts
Jean-Marie
JM
Gougerot-Pocidalo
Marie-Anne
MA
Chollet-Martin
Sylvie
S
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015415:Biomarkers; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D010537:Peritoneum / Q000378:metabolism; D010538:Peritonitis / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
D015415:Biomarkers; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human