| Popis: |
Asthma is a complex obstructive airway disease characterised by airway hyper-reactivity to innocuous allergens. It may be categorised as either classical eosinophilic, T helper 2 type of disease or as one driven by neutrophils that may be associated with T helper 17 cells and that is corticosteroid resistant. While the pathogenesis of the disease is not fully understood, there is increasing evidence for the role of environmentally-derived pathogen-associated molecular patterns (PAMPs) including fungal β-(1,3)-glucans and bacterial lipopolysaccharide (LPS) in inducing and exacerbating airway inflammation. We investigated the effects of these components, either alone or in combination, in several models of pulmonary inflammation and discovered that they modified airway responses in vivo. Notably, a combination of PAMPs drove a profound neutrophilia that was associated with synergistic CCL5 production. Moreover, in allergic models using house dust mite, sensitisation with these agonists resulted in corticosteroid resistant airway hyper-responsiveness. Interestingly, we found severe asthmatics with corticosteroid resistant neutrophilia to have upregulated CCL5 mRNA levels when compared to moderate asthmatics or controls. Interactions of environmental PAMPs from multiple sources could present a key determinant in the development and pathogenesis of corticosteroid resistant asthma. |
