Journal of Clinical Immunology, Vol. 18, No. 6, 1998 Minimally Invasive Surgery Induces Endotoxin-Tolerance in the Absence of Detectable Endotoxemia LUCIENNE C. J. M. LEMAIRE, 1,2,5 TOM VAN DER POLL, 2 J. JAN B. VAN LANSCHOT, 1 ERIK ENDERT, 3 WIM A. BUURMAN, 4 SANDER J. H. VAN DEVENTER, 2 and DIRK J. GOUMA 1 Accepted: July 24, 1998 Lipopolysaccharide (LPS) tolerance is characterized by an impaired proinflammatory cytokine production upon restimu- lation of mononuclear cells with LPS. LPS is considered the primary activator for this phenomenon. In response to major injury and extensive abdominal surgery, an immune reaction comparable to LPS tolerance has been described. Therefore, it was investigated whether primary stimuli other than LPS could induce cytokine downregulation. In eight patients who under- went a laparoscopic cholecystectomy, blood was obtained before and after induction of anaesthesia and 2, 6, and 24 hr postoperatively. Ex vivo stimulation of whole blood resulted in a transient reduction (nadir 2 hr postoperatively) of tumor necrosis factor-a, interleukin (IL)-lB, and interferon-y release, while IL-1 receptor antagonist production increased. Stress hormones, LPS-binding protein, and bactericidal/permeability- increasing protein do not seem to be involved. This study shows that minimally invasive surgery, in the absence of endotoxemia, can induce LPS desensitization. These data suggest that prior endotoxemia is not essential for the devel- opment of LPS tolerance. 1 Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2 Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3 Department of Clinical Chemistry & Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 4 Department of Surgery, University Hospital Maastricht, University of Limburg, Limburg, The Netherlands. 5 To whom correspondence should be addressed at Department of Surgery, Academic Medical Center, room G4-134, 1105 AZ Amster- dam, The Netherlands. venous injection of LPS in humans (8), a LPS refractory state develops. This phenomenon, designated LPS toler- ance, is associated with downregulation of the produc- tion of tumor necrosis factor-a (TNF-a), interleukin (IL)-lB, IL-6, and IL-10 (1-5, 8) but with an enhanced synthesis of IL-1 receptor antagonist (IL-1RA) (2, 4, 5, 8) upon ex vivo restimulation of mononuclear cells with LPS. Therefore LPS tolerance can be interpreted as an adapted immune response, rather than a state of general hyporesponsiveness, to a second challenge with LPS. LPS is considered the primary activator of LPS toler- ance. In response to major injury (9, 10) and extensive abdominal surgery (11-13), an immune reaction compa- rable to LPS tolerance has been described. In these conditions, however, LPS either has been detected (13) or can be expected to be found in the circulation. The objective of this study was to investigate whether sur- gery, not associated with endotoxemia, could induce LPS tolerance upon ex vivo stimulation of whole blood. METHODS Patients Patients were eligible for the study if they (a) under- went an elective laparoscopic cholecystectomy for symp- tomatic gallbladder stones in the absence of acute cho- lecystitis, common bile duct stones, cholangitis, and/or jaundice, (b) were not immunosuppressed (e.g., use of corticosteroids), (c) did not undergo surgery in the month preceding the operation, and (d) did not have an infection for which antibiotics were indicated in the month pre- ceding the operation. The study was approved by the institutional scientific and ethics committees. Written informed consent was obtained from all patients. 414 0271-9142/98/1100-0414$15.00/0 © 1998 Plenum Publishing Corporation KEY WORDS: Lipopolysaccharide (LPS); LPS tolerance; minimally invasive surgery, cytokines. INTRODUCTION Endotoxin (lipopolysaccharide; LPS) is the toxic constit- uent of the outer membrane of Gram-negative bacteria. During Gram-negative sepsis (1-7), or following intra-