title: A computational model of unresolved allergic inflammation in chronic asthma.
abstract: We have previously developed an agent-based computational model to demonstrate the feasibility of a novel hypothesis we term the inflammatory twitch. This hypothesis potentially explains the dynamics of the normal response to allergic inflammation in the lung (Pothen JJ, Poynter ME, Bates JH. J Immunol 190: 3510-3516, 2013) on the basis that antigenic stimulation sets in motion both the onset of inflammation and its subsequent resolution. The result is a self-limited inflammatory event that is similar in a formal sense to a skeletal muscle twitch. We hypothesize here that the chronic airway inflammation characteristic of asthma may represent the failure of the inflammatory twitch to resolve back to baseline. Our model provides a platform with which to perform virtual experiments aimed at investigating possible mechanisms leading to accentuation and/or prolongation of the inflammatory twitch. We used our model to determine how the inflammatory twitch is modified by knocking out certain cell types, interfering with cell activity, and altering cell lifetimes. Increasing the duration of activation of proinflammatory cells (considered to be chiefly neutrophils and eosinophils) markedly accentuated and prolonged the inflammatory twitch. This aberrant twitch behavior was largely abrogated by knocking out T-helper cells (simulating the effect of corticosteroids). The aberrant inflammatory twitch was also normalized by reducing the lifetime of the proinflammatory cells, suggesting that increasing apoptosis of these cells may be a therapeutic target in asthma.
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Pothen
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont jason.h.bates@med.uvm.edu.
authors.forename: Jason H T
authors.initials: JH
authors.lastname: Bates
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D003198:Computer Simulation; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018448:Models, Immunological; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
keywords: agent-based computational model; chronic inflammation