TNF binding protein prevents hyperlactatemia and inactivation of PDH complex in skeletal muscle during sepsis.
BACKGROUND
Hyperlactatemia is a metabolic complication of hypermetabolic, hyperdynamic sepsis. An important mechanism responsible for elevating plasma lactate concentrations in sepsis is altered regulation of the pyruvate dehydrogenase complex (PDH) in skeletal muscle. We investigated the ability of a specific tumor necrosis factor binding protein, TNFbp, to modulate lactate concentrations and skeletal muscle PDH activity in a rodent model of chronic abdominal sepsis.


METHODS
We examined the regulation of lactate metabolism in four groups of animals: Control, Control + TNFbp, Septic, and Septic + TNFbp. Chronic (5 days) sepsis was induced by the creation of a stable intraabdominal abscess using a sterile fecal-agar pellet inoculated with E. coli plus B. Fragilis as the foreign body nidus. TNFbp (1 mg/kg/day) was injected subcutaneously daily.


RESULTS
Sepsis increased plasma and skeletal muscle lactate concentrations 2-fold compared with control. In septic rats treated with TNFbp, plasma and skeletal muscle lactate concentrations were significantly decreased compared with untreated septic rats. In skeletal muscle, sepsis resulted in a 70% decrease in the proportion of the PDH in the active form compared with controls. The sepsis-induced inhibition in the PDH complex activity was prevented by TNFbp. PDH kinase was enhanced 1.8-fold in sepsis, and the increase in PDH kinase activity was prevented by treatment with TNFbp. TNFbp treatment did not have any effects on plasma lactate or the proportion of active skeletal muscle PDH activity in control animals.


CONCLUSIONS
TNFbp prevents the sepsis-induced hyperlactatemia and derangements in skeletal muscle lactate concentrations and PDH activity. These observations suggest that TNF is an important mediator responsible for lactate dyshomeostasis during sepsis.
Vary
T C
TC
Department of Surgery, Milton S. Hershey Medical Center, Hershey, Pennsylvania, 17033, USA.
Hazen
S A
SA
Maish
G
G
Cooney
R N
RN
D000005:Abdomen / Q000382:microbiology; D000818:Animals; D001424:Bacterial Infections / Q000097:blood / Q000378:metabolism*; D001442:Bacteroides Infections / Q000097:blood / Q000378:metabolism; D001441:Bacteroides fragilis; D004789:Enzyme Activation / Q000502:physiology; D004927:Escherichia coli Infections / Q000097:blood / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors
D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D019344:Lactic Acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases