Monocyte deactivation in severe human sepsis or following cardiopulmonary bypass.
We investigated the specificity for gram-negative stimuli as well as the contribution of signal transduction pathways for leukocyte hyporesponsiveness in sepsis or following cardiopulmonary bypass (CPB). Whole blood of nine patients undergoing CPB and 25 patients with severe sepsis was stimulated ex vivo with LPS (E. coli O111:B4) or with Staphylococcus aureus Cowan strain I (SAC-I) lysate in the absence or presence of inhibitors of protein kinase C (PKC), protein-tyrosine kinase (PTK), or protein-tyrosine phosphatase (PTP). Both toxins stimulated a TNF-alpha response through PTK signaling. Although suppression of the cytokine response was similar for LPS and SAC-I after CPB, it was significantly more pronounced for SAC-I in sepsis. Inhibition of PTP failed to increase TNF-alpha upon LPS, whereas a moderate increase was observed with SAC-I. Impaired TNF-alpha responses occur in sepsis and after CPB. Although this has primarily been reported for gram-negative stimuli, our data suggest that this is even more pronounced for gram-positive stimuli in severe sepsis. Although PTK was the predominant signaling pathway, inhibition of PTP only partially restored the TNF-alpha response to SAC-I. Our results suggest that cellular mechanisms underlying monocyte deactivation are different in sepsis or following CPB and are discriminate for gram-positive and gram-negative toxins.
Wilhelm
Wolfram
W
Department of Anesthesiology and Intensive Care Medicine, University of Saarland, Homburg/Saar, Germany. wolfram.wilhelm@t-online.de
Grundmann
Ulrich
U
Rensing
Hauke
H
Werth
Marco
M
Langemeyer
Jan
J
Stracke
Christian
C
Dhingra
Dania
D
Bauer
Michael
M
D000328:Adult; D000368:Aged; D001772:Blood Cell Count; D002315:Cardiopulmonary Bypass; D002395:Catecholamines / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000382:microbiology / Q000473:pathology / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018805:Sepsis / Q000097:blood* / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction; D015996:Survival Rate; D014638:Vanadates / Q000494:pharmacology
D002395:Catecholamines; D016207:Cytokines; D008070:Lipopolysaccharides; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases