Asthma : Pathogenesis

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Asthma

"Pathogenesis"

Pathogenesis
The pathogenesis of asthma is complex and not fully understood. It involves a number of cells, mediators, nerves and

Different types of asthmatic reactions following challenge with allergen. M, midnight; N, noon.

vascular leakage that can be activated by several different mechanisms, of which exposure to allergens is among the most significant (Next Fig.). The varying clinical severity and chronicity of asthma is dependent on an interplay between airway inflammation and airway wall remodelling. The inflammatory component is driven by Th2-type T lymphocytes which facilitate IgE synthesis through production of IL-4 and eosinophilic inflammation through IL-5 (Next Fig.). However, as the disease becomes more severe and chronic and loses its sensitivity to corticosteroids, there is greater evidence of a Th1 response with release of mediators such as TNF-α and associated tissue damage, mucous metaplasia and aberrant epithelial and mesenchymal repair.

Inflammation
Several key cells are involved in the inflammatory response that characterizes all types of asthma.
- Mast cells. These are increased in the epithelium, smooth muscle and mucous glands in asthma and release powerful preformed and newly generated mediators that act on smooth muscle, small blood vessels, mucussecreting cells and sensory nerves, such as histamine, tryptase, PGD2 and LTC4, and its metabolites LTD4 and LTE4 (previously known as slow reacting substance of anaphylaxis, SRS-A), which cause the immediate asthmatic reaction. Mast cells are inhibited by such drugs as sodium cromoglicate and β2-agonists which might contribute to their therapeutic efficacy in preventing acute bronchoconstriction triggered by indirect challenges. Mast cells also release an array of cytokines, chemokines and growth factors that contribute to the late asthmatic response and more chronic aspects of asthma.
- Eosinophils. These cells are found in large numbers in the bronchial wall and secretions of asthmatics. They are attracted to the airways by the eosinophilopoietic cytokines IL-3, IL-5 and GM-CSF as well as by chemokines which act on type 3 C-C chemokine receptors (CCR-3) (i.e. eotaxin, RANTES, MCP-1, MCP-3 and MCP-4). These mediators also prime eosinophils for enhanced mediator secretion. When activated, they release LTC4, and basic proteins such as major basic protein (MBP), eosinophil cationic protein (ECP) and peroxidase (EPX) that are toxic to epithelial cells. Both the number and activation of eosinophils are rapidly decreased by corticosteroids. Sputum eosinophilia is of diagnostic help as well as providing a biomarker of response to controller therapy.
- Dendritic cells and lymphocytes. These cells are abundant in the mucous membranes of the airways and the alveoli. Dendritic cells have a role in the initial uptake and presentation of allergens to lymphocytes. T helper lymphocytes (CD4+) show evidence of activation (Next Fig.) and the release of their cytokines plays a key part in the migration and activation of mast cells (IL-3, IL-4, IL-9 and IL-13) and eosinophils (IL-3, IL-5, GM-CSF). In addition, production of IL-4 and IL- 13 helps maintain the proallergic Th2 phenotype, favouring switching of antibody production by B lymphocytes to IgE. In mild/moderate asthma there occurs a selective upregulation of Th2 T cells with reduced evidence of the Th1 phenotype (producing gamma-interferon, TNF-α and IL-2), although additional Th1 prominence may accompany more severe disease. This polarization is mediated by dendritic cells and

Inflammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unit. Epithelial damage alters the set point for communication between bronchial epithelium and underlying mesenchymal cells, leading to myofibroblast activation, an increase in mesenchymal volume, and induction of structural changes throughout airway wall. Adapted from Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults.

involves a combination of antigen presentation, costimulation and exposure to polarizing cytokines. The activity of both macrophages and lymphocytes is influenced by corticosteroids but not β2-adrenoceptor agonists.

Remodelling
A characteristic feature of chronic asthma is an alteration of structure and functions of the formed elements of the airways. Together, these structural changes interact with inflammatory cells and mediators to cause the characteristic features of the disease. Deposition of matrix proteins, swelling and cellular infiltration cause an expansion of the submucosa beneath the epithelium so that for a given degree of smooth muscle shortening there is excess airway narrowing. Swelling outside the smooth muscle layer spreads the retractile forces exerted by the surrounding alveoli over a greater surface area so that the airways close more easily. Several factors contribute to these changes.
- The epithelium. In asthma the epithelium of the conducting airways is stressed and damaged with loss of ciliated columnar cells on to the lumen. Metaplasia occurs with a resultant increase in the number and activity of mucus-secreting goblet cells. The epithelium is a major source of mediators, cytokines and growth factors that serve to enhance inflammation and promote tissue remodelling (previous Fig.). Damage and activation of the epithelium make it more vulnerable to infection by common respiratory viruses, e.g. rhinovirus, coronavirus, and to the effects of air pollutants. Increased production of nitric oxide (NO), due to the increased expression of inducible NO synthase, is a feature of epithelial damage and activation and the measurement of exhaled NO is proving useful as a non-invasive test of continuing inflammation.
- Epithelial basement membrane. A pathognomonic feature of asthma is the deposition of repair collagens (types I, III and V) and proteoglycans in the lamina reticularis beneath the basement membrane. This, along with the deposition of other matrix proteins such as laminin, tenascin and fibronectin, causes the appearance of a thickened basement membrane observed by light microscopy in asthma. This collagen deposition reflects activation of an underlying sheath of fibroblasts that transform into contractile myofibroblasts which also have an increased capacity to secrete matrix. Aberrant signalling between the epithelium and underlying myofibroblasts is thought to be the principal cause of airway wall remodelling, since the cells are prolific producers of a range of tissue growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF) -α and -β, connective tissue-derived growth factor (CTGF), platelet-derived growth factor (PDGF), endothelin (ET), insulin-like growth factors (IGF), nerve growth factors and vascular endothelial growth factors ( previous Fig.). The same interaction between epithelium and mesenchymal tissues is central to branching morphogenesis in the developing fetal lung. It has been suggested that these mechanisms are reactivated in asthma, but instead of causing airway growth and branching, they lead to thickening of the airway wall (remodelling, Previous Fig.). Increased deposition of collagens, proteoglycans and matrix proteins creates a microenvironment conducive to ongoing inflammation since these complex molecules also possess cell-signalling functions, which aid cell movement, prolong inflammatory cell survival and prime them for mediator secretion.
- Smooth muscle. A prominent feature of asthma is hyperplasia of the helical bands of airway smooth muscle. In addition to increasing in amount, the smooth muscle alters in function to contract more easily and stay contracted because of a change in actin–myosin cross-link cycling. These changes allow the asthmatic airways to contract too much and too easily at the least provocation. Asthmatic smooth muscle also secretes a wide range of cytokines, chemokines and growth factors that help sustain the chronic inflammatory response. ADAM33, the newly described asthma gene, may be involved in driving increased airway smooth muscle and other features of remodelling through increased availability of growth factors.
- Nerves. Neural reflexes, both central and peripheral, contribute to the irritability of asthmatic airways. Central reflexes involve stimulation of nerve endings in the epithelium and submucosa with transmission of impulses via the spinal cord and brain back down to the airways where release of acetylcholine from nerve endings stimulates M3 receptors on smooth muscle causing contraction. Local neural reflexes involve antidromic neurotransmission and the release of a variety of neuropeptides. Some of these are smooth muscle contractants (substance P, neurokinin A), some are vasoconstrictors (e.g. calcitonin gene-related peptide, CGRP) and some vasodilators (e.g. neuropeptide Y, vasoactive intestinal polypeptide). The polymorphism in the neuropeptide S receptor (GPR 154) is associated with asthma susceptibility. Bradykinin generated by tissue and serum proteolytic enzymes (including mast cell tryptase and tissue kallikrein) is also a potent stimulus of local neural reflexes involving (nonmyelinated) nerve fibres.