Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges. This was a randomized, double-blind, placebo-controlled study with single ascending low doses of LPS (0.5, 1 and 2 ng/kg body weight) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS: placebo 6:2). The in vivo inflammatory response was assessed by measurement of cytokines and CRP. Ex vivo LPS challenges were performed (at -2, 6, 12, 24, 48 and 72 hours relative to in vivo LPS administration) to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release (TNF-alpha, IL-1 beta, IL-6, IL-8). LPS administration dose-dependently increased body temperature (+1.5 degrees C for 2 ng/kg LPS), heart rate (+28 bpm for 2 ng/kg LPS), CRP and circulating cytokines which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (0.5 ng/kg, contrast for timeframe 0-6 hours: TNF-alpha+413%, IL-6+288%, IL-8+254%; all p <= 0.0001). In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release (IL-1 beta, IL-6 and TNF-alpha), with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. We demonstrated that an in vivo LPS challenge, with LPS doses as low as 0.5 ng/kg, elicits a cytokine response that is clearly distinctive from baseline cytokine levels. This study expanded the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring pharmacological or nutritional immune-modulating effect

Characterization of immune cell, endothelial, and renal responses upon experimental human endotoxemia

Introduction: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low-to moderate dose (0.5, 1 or 2 ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. Methods: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2 ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS: placebo 6: 2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. Results: Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P-Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2 ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. Discussion: We demonstrated that administration of a single LPS dose of 2 ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the human endotoxemia model in future clinical pharmacology studie