Chronic inflammation and asthma

Abstract

Allergic asthma is a complex and chronic inflammatory disorder which is associated with airway hyper-responsiveness and tissue remodelling of the airway structure. Although originally thought to be a Th2-driven inflammatory response to inhaled innocuous allergen, the immune response in asthma is now considered highly heterogeneous. There are now various in vivo systems which have been designed to examine the pathways leading to the development of this chronic immune response and reflect, in part this heterogeneity. Furthermore, the emergence of endogenous immunoregulatory pathways and active pro-resolving mediators hold great potential for future therapeutic intervention. In this review, the key cellular and molecular mediators relating to chronic allergic airway disease are discussed, as well as emerging players in the regulation of chronic allergic inflammation.

Fig. 1

Gene environment interactions in asthma. Asthma is an inflammatory disorder of profound heterogeneity with strong genetic and environmental components. Local airway susceptibility factors together with allergen-specific immune polarisation interact both in the induction and subsequent expression of the disease phenotype. Key: EpC, epithelial cell.

Fig. 2

Immune cells and the inflammatory cascade in asthma. Initial exposure(s) to allergen leads to the activation of allergen-specific Th2 cells and IgE synthesis (sensitisation). Subsequent allergen exposures cause inflammatory-cell recruitment, activation and mediator release. IgE-sensitised mast cells expressing the high affinity IgE receptor (FcɛRI) degranulate, releasing both pre-formed and newly synthesized mediators including histamine, leukotrienes and cytokines, which promote vascular permeability, smooth muscle contraction and mucus production. Chemokines released by inflammatory and resident cells direct recruitment of inflammatory cells characterised eosinophils and Th2 cells. Eosinophils release an array of pro-inflammatory mediators, including leukotrienes and basic proteins and mediators such as, IL-5. Key: APC, antigen-presenting cell; ASM, airway smooth muscle; EpC, epithelial cell; GM-CSF, granulocyte monocyte colony stimulating factor; MHC, major histocompatibility; TCR, T cell receptor; TSLP, thymic stromal lymphopoietin.

Fig. 3

Th2 effector cells and asthma pathogenesis. Th2 cells have a central role in orchestrating the allergen-induced inflammatory response. Th2 derived IL-4 and IL-13 stimulate B cells to synthesise IgE whilst IL-5 is necessary for eosinophilic inflammation. Th2 cytokines are also involved in mast cell proliferation and allergic airway remodelling. Key: Eϕ, eosinophil; EpC, epithelial cell; EMTU, epithelial to mesenchymal tropic unit; ASM, airway smooth muscle; AHR, airway hyperreactivity.

Fig. 4

Airway remodelling in asthma. Activation of airway epithelium by aeroallergens and pollutants leads to downstream effects including inflammation, dysregulated repair, activated EMTU and tissue remodelling. Key: ASM, airway smooth muscle; ECM, extracellular matrix; EMTU, epithelial to mesenchymal trophic unit; Epc, EpC, epithelial cell; TGF-β, transforming growth factor-β.