Asthma is a heterogenous, chronic inflammatory disorder of the airways. It is characterised by a range of recurring symptoms, bronchial hyperresponsiveness, airflow obstruction, and inflammation. Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second, and peak expiratory flow rate. There are many variables of asthma that determine the severity and how responsive you are to treatment. There are four different ranks of asthma, determined by severity and frequency of asthma symptoms ranging from mild to severe. These include mild intermittent, mild persistent, moderate persistent and severe persistent. Furthermore, asthma may also be classified as atopic (extrinsic), or non-atopic based on whether asthma is triggered by allergens or not. Atopic meaning allergen induced. Although there are different phenotypes of this disease, airway inflammation is a consistent component whether the disease is persistent, intermittent, exercise induced, drug induced or severe.
There are many cells and cellular components that play a role in this disorder. These include eosinophils, T lymphocytes, mast cells, epithelial cells, macrophages and neutrophils. Other components from the immune system may include cytokines, chemokines, histamine and leukotrienes. Inflammation in some individuals, causes recurring episodes of chest tightness, breathlessness, wheezing and coughing. Nights, early mornings, cold weather or exercise may also cause episodes. These episodes may reverse spontaneously or treatment may be needed. Inflammation caused by a variety of different stimuli is associated with increased bronchial hyperresponsiveness. Reversibility of airflow limitation may be incomplete in some patients with asthma.
Airway changes typically include an increase in eosinophils and thickening of the lamina reticularis. Smooth muscle in the airway may chronically increase in size along with an increase in the numbers of mucous glands.
A variety of changes in the airway causes airflow limitation. These include bronchoconstriction, airway edema, airway hyperresponsiveness and airway remodeling.
Bronchoconstriction is the quick contraction of the bronchial smooth muscle in response to irritants or allergens. The release of IgE-dependent mediators from mast cells that include histamine, leukotrienes, tryptase, and prostaglandins directly contract airway smooth muscle resulting in allergen-induced bronchoconstriction. Aspirin and other nonsteroidal anti-inflammatory drugs can also cause acute airflow obstruction in some patients, as well as other factors including exercise, cold air, and irritants.
Airway edema occurs when the disease becomes more persistent and inflammation more progressive, causing mucus hypersecretion and the formation of inspissated mucus plugs, as well as structural changes including hypertrophy and hyperplasia of the airway smooth muscle further limiting airflow. These may not respond to usual treatment.
Airway hyperresponsiveness. Airway hyperresponsiveness is an exaggerated bronchoconstrictor. The degree to which airway hyperresponsiveness can be defined by contractile responses to challenges with methacholine correlates with the clinical severity of asthma. Airway hyperresponsiveness is influenced by inflammation, dysfunctional neuroregulation, and structural changes. The degree of airway hyperresponsiveness is determined by inflammation.
Airway hyperresponsiveness treatment that is directed at inflammation improves asthma control.
Airway remodeling involves an activation of many structural cells and refers to structural changes in airways of patients with asthma. Structural changes include loss of epithelial integrity, thickening of basement membrane, subepithelial fibrosis, goblet cell and submucosal gland enlargement, increased smooth muscle mass, angiogenesis, decreased cartilage integrity, and increased airway vascularity. Chronic inflammation that involves activation of inflammatory cells including CD4+ T cells, neutrophils, eosinophils, and mast cells is believed to have a role in this process.
These are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy.
Stimulation of T cells and epithelial cells causes the activation and recruitment of other effector leukocytes to the airway, and mediators produced by these cells result in chronic inflammation, tissue damage, and remodeling. Mast cells are the central effector cell in allergic disease and are present in increased numbers in the airways of patients with asthma. Binding of allergen to IgE on the cell surface induces a signal transduction cascade that results in the release of mediators. The release of histamine and prostaglandin D2 (PGD2) results in bronchoconstriction.
Mast cells are also the primary producers of cysteinyl leukotrienes, lipid mediators derived from arachadonic acid. Leukotrienes bind to their G protein-coupled receptors on the cell surfaces of structural airway cells. There they produce smooth muscle contraction, increase vascular permeability of small blood vessels, enhance secretion of mucus, and recruit leukocytes to the airway. Cysteinyl leukotrienes play an important role in asthma, and their inhibition with leukotriene antagonists is effective in the treatment of patients with asthma. Mast cells also release inflammatory cytokines, chemokines, and proteases that contribute to airway inflammation. These mediators stimulate an inflammatory response in the epithelium, directly damage the airway, and recruit more leukocytes to the airway.
Most patients with asthma have an increased number of eosinophils present in the airways. Factors released from airway epithelial cells, mast cells and Th2 cells promote the growth and survival of eosinophils. Th2 cytokine IL-5 is crucial for the survival of eosinophil, just as GM-CSF, which is obtained from mast cells and epithelium. The role of eosinophils in asthma may vary with different phenotypes. Severe asthmatic patients are noted to have elevated numbers of eosinophils.
Chemokines, particularly CCL5 and CCL11, recruit eosinophils to the airway. Eosinophils express a variety of proinflammatory cytokines, Th2 cytokines, and chemokines that can activate mast cells and stimulate the epithelium. In addition, eosinophils can present antigen to T cells and release growth factors such as TGF-?—highlighting the importance of eosinophils in multiple facets of asthmatic inflammation. Phagocytes are also present in asthmatic airways, though their role is not well-defined. They may be more prevalent in certain phenotypes than in others.29,30Macrophages are present in high numbers in the airways and synthesize many inflammatory cytokines and chemokines.29 Neutrophils may occur in increased numbers in the airways of patients with severe asthma, particularly in smokers.30Their pathogenic role remains to be determined, but it may account for a lack of glucocorticoid effects in some patients.30
T cells are now recognized to play important effector roles in patients with asthma.31 Interleukin 13 produced from Th2 cells has been the focus of much research as a therapeutic target. It induces airway hyperresponsiveness and has numerous effects on structure, such as subepithelial fibrosis, airway smooth muscle proliferation, and goblet cell hyperplasia.32 Interleukin 13 induces inflammation by acting primarily on the airway epithelium, and it increases eosinophil numbers by up-regulating multiple chemokines, including CCL11.32Induction of chemokines may also be important in lung fibrosis, as suggested by mouse studies demonstrating that the blockade of CCL2, CCL3, and CCL6 abrogates lung remodeling.10
Furthermore, IL-13 has been proposed to be associated with glucocorticoid resistance, with the level of IL-13 being elevated in patients with glucocorticoid-insensitive asthma.32 Glucocorticoids regulate the level of many cytokines and chemokines at transcriptional and posttranscriptional levels, and research has shown that IL-13 can directly affect the phosphorylation of the glucocorticoid receptor to alter its function.32-35 Thus, IL-13 provides an attractive therapeutic target that might be beneficial to consider in many asthma phenotypes, including steroid-insensitive asthma.
In asthmatic airways, several inflammatory cells are activated, including mast cells and dendritic cells, and there is infiltration of activated lymphocytes and eosinophils. The predominant lymphocytes in allergic asthma are helper T cells (Th2) and in non-allergic asthma innate lymphoid cells. In severe asthma, Th17 cells may also be involved and linked to neutrophilic inflammation. Structural cells, especially airway epithelial cells and airway smooth muscle cells, can also release inflammatory mediators to drive inflammation. Many mediators have been implicated in asthma, including lipid mediators, such as cysteinyl leukotrienes, prostaglandin D2, cytokines, particularly T2 cytokines, interleukins 4, 5 and 13, and chemokines that attract inflammatory cells such as Th2 cells and eosinophils into the airways. Chronic inflammation can lead to structural changes, with friability of airway epithelial cells, increased bulk of airway smooth muscle, fibrosis under the epithelium, airway smooth muscle hyperplasia and hypertrophy, increased blood vessels and mucus hyperplasia. Superimposed on the chronic persistent inflammation are acute increases linked to exacerbations and loss of asthma control.
Immunoglobulin E IgE is an antibody that is responsible for activation of allergic reactions and is important to the pathogenesis of allergic diseases and the development and persistence of inflammation. IgE attaches to cell surfaces via a specific high-affinity receptor. The mast cell has large numbers of IgE receptors; these, when activated by interaction with antigen, release a wide variety of mediators to initiate acute bronchospasm and also to release pro-inflammatory cytokines to perpetuate underlying airway inflammation (Boyce 2003; Sporik et al. 1995). Other cells, basophils, dendritic cells, and lymphocytes also have high-affinity IgE receptors. The development of monoclonal antibodies against IgE has shown that the reduction of IgE is effective in asthma treatment.
