Lipopolysaccharide challenge: immunological effects and safety in humans

Abstract

Lipopolysaccharide (LPS) is a constituent of the outer membranes of Gram-negative bacteria and an important microbial trigger that stimulates innate immunity. It is ubiquitous; it can be inoculated from the environment via inhalation of dust. The resultant inflammatory responses are essential to early host defense but may also contribute to later and/or chronic organ injury. LPS challenge either intravenously or by inhalation has been widely used for the evaluation of anti-inflammatory reagents as well as to address basic scientific questions. The acute inhalation of LPS is used as a model of acute bronchitis in human volunteers. LPS inhalation is considered a well-established method that is safe and tolerable and aids in the improved characterization of anti-inflammatory drugs in proof-of-concept studies. This article reviews immunogenicity and safety data pertaining to LPS administration, with a particular focus on LPS inhalation, which may facilitate the optimization of its use in human research.

Keywords:

• local reactions
• LPS challenge
• LPS inhalation
• safety
• side effects
• systemic reactions

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Lipopolysaccharide (LPS) inhalation represents a significant occupational and environmental hazard with greatly varying inhaled concentrations, which can lead to the development of chronic respiratory diseases.

• For inhaled LPS challenges, sterile LPS prepared from Escherichia coli 026:B6 administered via a flow-controlled nebulizer system provides a standardized and repeatable method.

• Inhalation of LPS leads to an acute pro-inflammatory response, involving increases in neutrophils, macrophages and certain chemokines/cytokines in the sputum and bronchoalveolar lavage fluid. It also causes flu-like symptoms like chills and fever in healthy volunteers.

• Effects of the inhaled LPS challenge on lung function vary, from no effect on forced expiratory volume in 1 s (FEV1) to a 25% decrease in FEV1 in sensitive subjects. Whereas there seems to be a high inter-individual variation, effects always resolved within 24 h.

• Reviewing the literature, we could define a lower threshold for an effective LPS dose at 5 µg, with safe and tolerable doses of up to 100 µg in humans.

• Although no severe side effects have been reported to date, it is mandatory to monitor volunteers after LPS inhalation, including repeated hourly assessments of symptoms and vital signs, including body temperature, blood pressure and FEV1 for at least 8 h.

Notes