A unified model for the human response to lipopolysaccharide-induced inflammation

TL;DR

This paper presents a comprehensive mathematical model simulating the human body's multi-scale response to lipopolysaccharide-induced inflammation, integrating immune, hormonal, and physiological responses over time.

Contribution

It introduces a unified differential equation-based model that captures the systemic response to endotoxin, including circadian effects and various administration protocols, which was not previously available.

Findings

LPS administration timing affects hormonal response intensity.

Most effects resolve within 24-48 hours, but some persist over 10 days.

Increased dosage amplifies systemic responses and risks.

Abstract

This study develops a unified model predicting the whole-body response to endotoxin. We simulate dynamics using differential equations examining the response to a lipopolysaccharide (LPS) injection. The model tracks pro- and anti-inflammatory cytokines (TNF-$\alpha$, IL-6, IL-10), concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol in the hypothalamic-pituitary-adrenal (HPA) axis. Daily hormonal variations are integrated into the model by including circadian oscillations when tracking CRH. Additionally, the model tracks heart rate, blood pressure, body temperature, and pain perception. Studied quantities function on timescales ranging from minutes to days. To understand how endotoxin impacts the body over this vast span of timescales, we examine the response to variations in LPS administration methods (single dose, repeated dose, and continuous dose) as well as the timing of the administration and the amount of endotoxin released into the system. We calibrate the model to literature data for a 2 ng/kg LPS bolus injection. Results show that LPS administration during early morning or late evening generates a more pronounced hormonal response. Most of the LPS effects are eliminated from the body 24 hours after administration, the main impact of inflammation remains in the system for 48 hours, and repeated dose simulations show that residual effects remain more than 10 days after the initial injection. We also show that if the LPS administration method or total dosage is increased, the system response is amplified, posing a greater risk of hypotension and pyrexia.