Pretreatment with tumor necrosis factor-alpha attenuates arterial hypotension and mortality induced by endotoxin in pigs.
OBJECTIVE
Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that seen during severe sepsis. The objective of this study was to determine whether small doses of TNF-alpha might decrease the disposition for the development of shock induced by a subsequent infusion of endotoxin and to determine whether the mechanism of this protective effect of TNF-alpha pretreatment could be associated with up-regulation of the anti-inflammatory cytokine interleukin (IL)-10.


METHODS
Prospective, randomized, experimental study.


METHODS
Investigative intensive care unit at an academic medical center.


METHODS
A total of 14 female Yorkshire pigs, weighing 20-25 kg.


METHODS
We studied two groups of animals-pigs treated with 500 ng/kg recombinant porcine TNF-alpha (n = 7) and pigs given diluent alone (n = 7). At 24 hrs after treatment, both groups of pigs were subjected to a 24-hr continuous infusion of lipopolysaccharide (LPS) at a rate of 80 ng/kg/min.


RESULTS
The mortality rate was determined in both groups. Hemodynamic indices, oxygen transport variables, total and differential white cell counts, and serum concentrations of TNF and IL-10 were determined at frequent intervals before and after TNF-alpha administration and during the LPS infusion. Additionally, peripheral blood mononuclear cells were collected for determination of messenger ribonucleic acid expression of IL-10 by reverse transcription-polymerase chain reaction. The administration of TNF-alpha at the dose used in this study did not have any profound effect. No pig treated with TNF-alpha died in response to the LPS infusion. In contrast, three of seven control pigs died during the LPS infusion. Lipopolysaccharide-induced arterial hypotension and arterial hypoxemia were attenuated in the TNF-alpha-treated group. Both groups had significant increases in serum concentrations of TNF-alpha in response to LPS, with no significant difference in peak serum TNF-alpha between groups. Neither serum concentrations of IL-10 nor expression of IL-10 messenger ribonucleic acid in circulating mononuclear cells differed between groups.


CONCLUSIONS
The administration of TNF-alpha attenuated the severity of hyperdynamic shock induced by a subsequent infusion of endotoxin. This effect could not be associated with increased expression or elaboration of the anti-inflammatory cytokine IL-10.
Murphey
E D
ED
Department of Anesthesiology, The University of Texas Medical Branch and Shriners Burns Hospital, Galveston, USA. edm@vetmed.wsu.edu
Traber
D L
DL
D000818:Animals; D005260:Female; D006439:Hemodynamics; D007022:Hypotension / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D016753:Interleukin-10 / Q000096:biosynthesis; D011897:Random Allocation; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015996:Survival Rate; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10