Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers

Abstract

Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 10 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.Results: LPS elicited a visible response and returned to baseline at 48 hours.Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1β, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.

Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers

“…In line with this, glucocorticoids may impair the capacity of neutrophils to extravasate into inflamed tissue, 7 but in the present study the recruitment of neutrophils was unaffected (Figure 4a). Neutrophils, as we have already shown during the earlier characterization of the intradermal LPS model, are the first cells to arrive in response to LPS, 5,6 and it is known that neutrophils play a central role in orchestrating the acute immune response. 17 The fact that we did not observe a reduction in neutrophil infiltration but did observe a reduction of all other immune cell subsets gave rise to our hypothesis that corticosteroid pretreatment did not affect the capacity of stromal cells and local immune cells to initiate neutrophil attraction but did lead to a reduced capacity of arriving neutrophils to further drive the acute immune response.…”

“…Secondly, exposure to systemic LPS leads to a prolonged state of immunological hyporesponsiveness to LPS due to innate memory which hampers the possibility of rechallenging the same individual 3,4 . We and others have published a local inflammatory challenge with intradermal LPS 5,6 . In our comprehensive characterization we showed that intradermal administration of 5 ng of LPS induces a transient local inflammatory response, characterized by an increase in local perfusion, heat, erythema, immune cell attraction, and cytokine production 6 .…”

“…5,6 In our comprehensive characterization we showed that intradermal administration of 5 ng of LPS induces a transient local inflammatory response, characterized by an increase in local perfusion, heat, erythema, immune cell attraction, and cytokine production. 6 As a next step, we conducted a study evaluating the effects of corticosteroid treatment on the LPS-driven inflammatory response of the skin in heathy volunteers to validate our previously established intradermal LPS model. Corticosteroids were selected as these drugs have been used for more than 70 years as topical or oral treatment for inflammatory skin diseases.…”

Examining the associations between testosterone and biomarkers as men age

“…For example, obesity is hypothesized to reduce TT and SHBG concentrations via several proposed mechanisms, including inflammation. Therefore, an interventional study could be conducted using an intradermal lipopolysaccharide (LPS) challenge, with a similar study design to Buters et al, (2022), which would induce inflammation. TT and SHBG concentrations could be tested at various timepoints after administration, and perhaps compared with a placebo intradermal challenge.…”

A multimodal, comprehensive characterization of a cutaneous wound model in healthy volunteers

“…Skin erythema was quantified using multispectral imaging (Antera 3D®, Miravex), as described in detail before. 22,23,25 The multispectral camera creates a closed chamber of 25 cm 2 for image capture with standardized lighting and distance. A region of interest of 4 mm in diameter was defined and kept analogous with all analysed images.…”