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

J Pharmacol Toxicol Methods. Jan-Feb 2018;89:39-46. doi: 10.1016/j.vascn.2017.10.004. Epub 2017 Oct 19.

Abstract

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 2ng/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 2ng/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 2ng/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 2ng/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 studies.

Keywords: Acute kidney injury; Cell adhesion molecules; Cytokines; Endothelial activation; Endotoxin; Human endotoxemia model; LPS; Lipopolysaccharide.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / physiopathology*
  • Administration, Intravenous
  • Adult
  • Biomarkers / blood
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Endothelial Cells / drug effects
  • Endotoxemia / chemically induced
  • Endotoxemia / immunology
  • Endotoxemia / physiopathology*
  • Escherichia coli
  • Healthy Volunteers
  • Humans
  • Kidney Tubules / drug effects
  • Kidney Tubules / physiopathology*
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / toxicity*
  • Male
  • Microvessels / physiopathology*
  • Young Adult

Substances

  • Biomarkers
  • Lipopolysaccharides