Short reviewsThe allergic cascade: Review of the most important molecules in the asthmatic lung
Introduction
The prevalence of asthma in children has dramatically increased in the last decades all over the world [1]. According to the World Health Organization (WHO), 300 million people suffer from asthma and 255,000 died of asthma in 2005. The exact cause of asthma remains uncertain. Several factors will influence the disease, for example genetic factors (e.g. a history of asthma in the family, atopy), environmental factors (e.g. air pollution, occupational exposure, viral infections, allergen exposure) and life style factors (e.g. smoking habits, food). In susceptible individuals, asthma causes recurrent episodes of wheezing, breathlessness, chest tightness and cough [2]. Crucial in the development of airway inflammation in allergic asthma is the allergic cascade. Inhaled allergens that escape the mucociliary clearance are taken up and processed by antigen presenting cells (APCs), which are distributed throughout the respiratory tract, from the nasal mucosa to the lung pleura. These APCs then migrate to the draining lymph nodes where the processed allergen is presented to allergen-specific T and B cells [3]. Interactions between those cells elicit responses that are characterized and influenced by secreted cytokines and the presence or absence of cell-bound costimulatory molecules. Activation of T helper (Th) cells by APCs leads to the production of cytokines that regulate the isotype switch of B cells in their production of immunoglobulin (Ig) E [4]. Once synthesized, IgE antibodies circulate in the blood before binding to the high-affinity IgE receptor FcɛRI that is present on mast cells in tissue or on peripheral blood basophils. After re-exposure, allergens cross-link to mast cell-bound specific IgE, thus causing the activation of membrane and cytosolic pathways, which subsequently trigger the release of preformed mediators, such as histamine, the synthesis of prostaglandins (PGs) and leukotrienes (LTs), and the transcription of cytokines by mast cells [5]. These mediators cause the so-called early-phase asthmatic reaction (EAR), which is characterized by constriction of airway smooth muscle (ASM) cells, vascular leakage, mucus production, enhanced airway hyperresponsiveness (AHR) and recruitment of inflammatory cells [6]. This EAR is immediate, lasting 30–60 min and 4–6 h later followed by the late-phase asthmatic reaction (LAR) [7]. The late-phase is characterized by excessive inflammation of the airways, resulting in structural changes, including airway wall thickening, subepithelial fibrosis, goblet cell hyperplasia, myofibroblast hyperplasia, ASM cell hyperplasia and hypertrophy, and epithelial hypertrophy [8], [9]. This is collectively known as airway remodeling.
Research has focused on mechanisms of airway inflammation, regulation of these processes, and translation of these events into altered lung function. The use of animal models, in vitro tests, human allergen challenge studies, and biopsy and lavage studies that generate human samples for ex vivo analysis, continues to expand our understanding of the role of various mediators, inflammatory molecules, and cellular and physiologic changes associated with allergic disorders [10]. Recent research focuses specifically on early markers for respiratory diseases using preferably non-invasive techniques such as exhaled breath condensate (EBC).
Molecular changes that occur in asthmatic lungs will be focussed on in this review. Special attention will be paid to cytokines and chemokines that are involved in asthma against the background of molecules that play an important role in normal lung physiology. A summary of the mediators discussed can be found in Table 1. These mediators offer the possibility to be used as diagnostic biomarkers. Potential markers measured in EBC are summarized in Table 2.
Section snippets
Induction of the allergic reaction
During the induction phase, allergens enter the airways, are processed by APCs, and are brought to the lymph nodes. Here, they are presented to T and B cells. Activation of Th cells leads to the production of various cytokines, such as interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, IL-18, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, TNF-β and granulocyte macrophage colony stimulating factor (GM-CSF). Of these, IL-4, IL-5, IL-9 and IL-13 are the most important in
Mast cells
The most crucial cell type in the EAR are mast cells [18]. Mast cells are involved in the pathophysiology of asthma through their capacity to secrete a wide variety of mediators after activation by allergens. Re-exposure to a previously met allergen leads to its binding on IgE antibodies that are attached to mast cell FcɛRI receptors. This causes cross-linking of FcɛRI receptors, whereupon mast cells degranulate and synthesize pro-inflammatory molecules [19], [20]. Mediators produced by mast
Late-phase asthmatic reaction
The late-phase of the asthmatic reaction is characterized by excessive inflammation of the airways resulting in structural changes induced by various mediators derived from inflammatory cells, like eosinophils, neutrophils, T cells, macrophages, dendritic cells (DCs), endothelial cells, airway smooth muscle cells (ASM) and bronchial epithelial cells (BECs) [8]. The role of several chemokines is thereby firmly established [41], [42], [43].
Airway remodeling
Ongoing inflammation may result in structural remodeling: wall thickening, subepithelial fibrosis, metaplasia, hypertrophy and hyperplasia of airway cells, cartilage breakdown, and angiogenesis [90], [110], [111]. Progress is being made in understanding the mechanisms of remodeling in which many asthma-related molecules are potently involved. Below, the most prominent mediators of airway remodeling are summarized.
Conclusion
All processes that occur in the asthmatic lung are mediated by a broad network of various molecules. In this review, mediators secreted by the different cell types that play a role in the allergic cascade are discussed. Moreover, the effects of the most important mediators of airway remodeling are summarized. However, further research is still needed for a better understanding of the complex interactions between molecules and cells involved in the processes leading to asthma.
Acknowledgements
K. Bloemen and S. Verstraelen received a PhD-grant from VITO.
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2021, Life SciencesCitation Excerpt :Similarly, elevated exhaled CO concentration and reduction in peak expiratory flow rate in patients infected with influenza are considered as some of the key markers in the development of viral-induced asthma exacerbation [25]. Classically, allergen-specific T-helper type 2 (TH2) cells that are present in the airways of almost all asthmatic patients are largely known to be associated with the developmental features of asthma [26]. Activation of such cell types results in the production of major cytokines such as, IL-4, IL-5, IL-9 and IL-13 that are essentially involved in the pathogenesis of the disease [27].
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These authors contributed equally to this review.