The Effect of Cardiopulmonary Bypass on the Monocytes’ Tolerance

Tolerance is a phenomenon first discovered in septic patients and resulting in a second status of immune paralysis and a high susceptibility for secondary infections. Tolerance is induced by endotoxin (LPS) stimulation of Toll-like receptor 4 (TLR4) but can also be triggered by endogenous TLR4 ligands like the S100 proteins S100A8/A9 in sterile inflammation. We investigated the effect of mechanical stress of cardiopulmonary bypass on human monocytes by examining inflammatory cytokines and reactivity of patients’ monocytes on inflammatory stimulation in vitro.

We enrolled prospectively 35 patients (mean age 68.5, 15 females) who underwent on-pump cardiac surgery. Exclusion criteria were current infectious, oncologic, immunologic, or neurologic diseases. Blood samples were taken 1 day before surgery, after switching off the cardiopulmonary bypass, at first and sixth postoperative days. Monocytes (isolated or in whole blood samples) were stimulated with LPS. Expression and secretion of cytokines and S100 proteins into cell culture supernatants or in serum was determined by qRT-PCR and immunoassays. In addition, surface molecule expression and leucocyte activation were analyzed by FACS. Intracellular translocation of transcription factor NF-kB was quantified by imaging flow cytometry.

Serum concentrations of S100A8/A9 and IL-10 increased directly after cardiopulmonary bypass. mRNA expression of these factors in monocytes was increased, too. After cardiac surgery monocytes showed a decreased inflammatory response to LPS stimulation. Inflammatory markers such as HLA-DR, CD86, and CD14 were significantly less inducible. Nuclear translocation of NF-kB after LPS stimulation was significantly reduced with a maximum at day 1 and a slow recovery 6 days after surgery. TNF-α release of isolated and cultivated monocytes into culture supernatants was significantly reduced as well.

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