Chemical-induced airway hyperreactivity in mice: evaluation and mechanisms

Abstract

Asthma is a chronic airway disease, characterized by reversible airway obstruction following exposure to the causative agent, non-specific airway hyperreactivity (AHR) and airway inflammation, ultimately leading to airway remodelling. Initially, asthma has been considered an allergic, T-helper 2 lymphocyte-driven, eosinophilic airway inflammatory disease. Yet, other subtypes with distinct pathophysiological mechanisms can be defined based on etiology and pattern of airway inflammation. Occupational asthma (OA), the most common work-related lung disease in industrial countries, can be caused by low molecular compounds, such as reactive chemicals. In contrast to ‘classic’ allergic asthma, induced by complete allergens, part of the pathophysiology of chemical-induced OA remains unknown. The aim of this doctoral thesis was to study the underlying mechanisms of chemical-induced asthma, using a C57Bl/6 mouse model, in which toluene-2,4-diisocyanate, a known chemical sensitizer, serves as a prototypical occupational asthmogen. In this model mice are dermally sensitized, followed by a single intranasal airway challenge, resulting in AHR to methacholine 24 h after the challenge, without the influx of inflammatory cells in the airways. As such, our model mimics chemically-induced paucigranulocytic OA, a clinically relevant asthmatic phenotype. Via gene-deficient mice and pharmacological interventions we were able to demonstrate that the pathophysiology of chemical-induced asthma relies on a complex interplay between neurological pathways (TRPA1 and TRPV1), innate immune players (mast cells) and adaptive immune players (IL-13 and lymphocytes).status: publishe