Glucocorticoid regulation of hepatic TNF production following cecal ligation and puncture sepsis.
Tumor necrosis factor-alpha (TNF) is a critical early mediator in the genesis of a systemic inflammatory response during a septic insult. Many of the harmful effects evident during sepsis are ascribed to excessive endogenous TNF production. Because the liver is an important source of circulating TNF during endotoxicosis, and because glucocorticoids are believed to have a regulatory role in suppressing endogenous TNF production, we evaluated the effect of adrenalectomy on the hepatic production of TNF in an isolated perfused liver model after cecal ligation and puncture (CLP) sepsis. Fasted, male Holtzman rats (n = 4/group) underwent CLP alone, adrenalectomy (ADREX) alone, or CLP plus ADREX (CLP/ADREX). Two hours after the operation, the rat livers were explanted and perfused in an isolated recirculating model. Serum TNF levels were greater in CLP/ADREX rats than in both other groups. TNF production in the perfused liver was greater in the CLP/ADREX rats when compared with either CLP alone or ADREX alone. A separate mortality study was performed (N = 35) that demonstrated a CLP induced mortality of 45%, and a CLP/ADREX mortality of 100%. Thus, adrenalectomy increased circulating TNF and hepatic TNF production as well as mortality in CLP sepsis. These findings suggest an important role for endogenous glucocorticoids in modulating hepatic TNF production during CLP-induced sepsis.
Zawacki
J K
JK
Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA.
Hunt
J L
JL
Gamelli
R L
RL
Filkins
J P
JP
D000315:Adrenalectomy; D000818:Animals; D005938:Glucocorticoids / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha