Asthma - a chronic inflammatory disorder of the airways.
Asthma
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an increase in existing bronchial
hyperresponsiveness to a variety of stimuli.
Asthma is characterized by spastic contraction of the smooth muscle in the bronchioles, which causes extremely difficult breathing. Asthma is about 70 percent is caused by allergic hypersensitivity, especially sensitivity to plant pollens.
Asthma is a common increasing and relapsing disease that is associated with genetic and environmental factors such as respiratory viruses and allergens.
The pathology of asthma is characterised by various changes in the airways including mucus plugging, shedding of epithelial cells, thickening of the basement membrane, engorgement of the vessels, and angiogenesis, inflammatory cell infiltration, and smooth muscle hypertrophy and hyperplasia. The pathogenesis of asthma can be broadly subdivided into inflammatory and remodelling components.
The inflammatory features of asthma consist of a dense inflammatory infiltrate in which eosinophils, mast cells, and CD41 helper T lymphocytes predominate. Neutrophilic infiltration also arises during asthma exacerbations and in the late response to allergen challenge. Dendritic cells seem to be the key cells for antigen presentation in asthma. Antigens then cause cross-linking of IgE and as a consequence mast cells are activated and degranulate. Mast cells are important in the acute airway responses to allergens and may also contribute to remodelling in chronic asthma. Interest in the mast cell will probably increase with the recent report that the presence of mast cells in the smooth muscle layer in bronchial biopsies helps to differentiate asthma from eosinophilic bronchitis, suggesting that interactions between mast cells and smooth muscle are important in asthma pathogenesis. Such an observation is consistent with results of studies of sensitised human airway smooth muscle in vitro where the degree of contraction to antigen is related to the number of mast cells present.
A defining characteristic of asthma is the presence of many activated eosinophils, which are thought to contribute to airway epithelial damage by release of products such as eosinophil major basic protein. However, the central role for eosinophils as effector cells in asthma has been challenged. Administration of antibodies against interleukin 5 to patients with asthma greatly reduces systemic and sputum eosinophilia, but has a negligible effect on airflow and airway hyper-responsiveness. Similarly, administration of interleukin 12, which drives differentiation of T cells to a Th1 rather than a Th2 phenotype, reduced eosinophil numbers, but not airway responsiveness in patients with asthma. Furthermore, a study[56] in MBP-1 knockout mice suggested that this protein does not contribute to airway hyper-responsiveness.
The role of T lymphocytes is less controversial. T lymphocytes seem to be essential cells in the orchestration of the airway inflammation that characterises asthma. T-helper lymphocytes differentiate into two main phenotypes, Th1 and Th2, which produce distinct profiles of cytokines and chemokines. Th1 cells produce interferon g whereas Th2 cells produce interleukin 4, 5, and 13. Th2 cells are potent stimulators of IgE production from B lymphocytes. Results of studies in mice have suggested that Th2 cytokines have key roles, and results of bronchoscopic lavage studies in human beings have shown increased concentrations of these cytokines. Asthma ...
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The role of T lymphocytes is less controversial. T lymphocytes seem to be essential cells in the orchestration of the airway inflammation that characterises asthma. T-helper lymphocytes differentiate into two main phenotypes, Th1 and Th2, which produce distinct profiles of cytokines and chemokines. Th1 cells produce interferon g whereas Th2 cells produce interleukin 4, 5, and 13. Th2 cells are potent stimulators of IgE production from B lymphocytes. Results of studies in mice have suggested that Th2 cytokines have key roles, and results of bronchoscopic lavage studies in human beings have shown increased concentrations of these cytokines. Asthma is probably not due to Th2 driven inflammation alone however, and studies in mice suggest that Th1 cells also contribute.
Inflammatory cells are recruited into the airways by chemokines, which exert some degree of selectivity in the cells they attract. Eosinophil chemotractants include eotaxin, interleukin 5, RANTES (ie, regulated by activation, normal T-cell expressed and secreted), and monocyte chemotractant proteins 3 and 4, whereas neutrophils are recruited mainly by interleukin 8. These chemokines are produced by inflammatory and structural cells such as airway smooth muscle cells and airway epithelium. Inflammatory cells bind to adhesion molecules on bronchial vessel endothelium and subsequently undergo a process of transmigration into the airway interstitium. Adhesion molecules that are important in this process include ICAM-1, VCAM-1, and E-selectin. Airway cells also release survival factors, such as granulocyte macrophage colony stimulating factor (GM-CSF), which extend the life of inflammatory cells at the site of inflammation.
Acute inflammatory diseases usually resolve with repair processes restoring normal structure and function. In chronic asthma, this process becomes disturbed and ineffective repair leads to remodelling involving several structures. Epithelial damage and loss of its protective barrier function exposes the deeper airway structures to environmental insults, and both inflammatory and structural cells produce several growth factors that lead to angiogenesis, proliferation of smooth muscle in the airway, thickening of basement membranes, and fibrosis. The increase in the mass of smooth muscles in the airway increases bronchial responsiveness by increasing force in response to bronchoconstrictor stimuli and by reduction of the airway's diameter. Smooth muscle in the airways of patients with asthma proliferates excessively in vitro.Important cytokines and enzymes during the remodelling process include transforming growth factor b, epidermal growth factor, and matrix metalloproteinases.
Asthma causes significant morbidity and mortality. The changes occurring in the airways consist of a chronic eosinophilic and lymphocytic inflammation, together with epithelial and structural remodeling and proliferation, and altered matrix proteins, which underlie airway wall narrowing and bronchial hyperresponsiveness (BHR). Several inflammatory mediators released from inflammatory cells such as histamine and cysteinyl-leukotrienes induce bronchoconstriction, mucus production, plasma exudation, and BHR. Increased expression of T-helper 2 (Th2)-derived cytokines such as interleukin-4 and 5 (IL-4,5) have been observed in the airway mucosa, and these may cause IgE production and terminal differentiation of eosinophils. Chemoattractant cytokines (chemokines) such as eotaxin may be responsible for the chemoattraction of eosinophils to the airways. The initiating events are unclear but may be genetically determined and may be linked to the development of a Th2-skewed allergen-specific immunological memory. The use of molecular biology techniques on tissues obtained from asthmatics is increasing our understanding of the pathophysiology of asthma. With the application of functional genomics and the ability to transfer or delete genes, important pathyways underlying the cause if asthma will be unraveled.
It is important to discuss neuronal mechanisms of asthma development. Cholinergic mechanisms are the predominant bronchoconstrictor neural pathway in human airways. There is increased airway tone and vagal nerve activity in patients with asthma compared with healthy individuals. Studies with anticholinergic agents have taught us that cholinergic mechanisms are very important in beta-blocker-induced bronchospasm and in the bronchoconstriction induced by emotions and suggestions. Other stimuli such as SO2, bradykinin, irritant gases and ozone induce some vagal reflexes, but the importance of the cholinergic system in allergen- and exercise-induced asthma is unclear. There has been much investigation, mainly in animal models, examining the importance of the three different types of muscarinic receptor (M1, M2, M3). Dysfunction of the M2 receptor has been proposed as a mechanism leading to excessive bronchoconstriction and mucus secretion in asthma. Dysfunction of the M2 receptor in guinea pigs can be induced by exposure to various stimuli such as allergen, viral infection, ozone, eosinophil products such as major basic protein (MBP) and eosinophil peroxidase (EPO), and other factors such as transforming growth factor (TGF)b1, tumour necrosis factor (TNF)a and interleukin (IL)-1b.
Another important system, which is the only neural bronchodilator mechanism in human airways, is the inhibitory NANC (i-NANC) system. Over the past 20 years, several putative neurotransmitters of this system have been proposed including purines, vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). In vivo and in vitro studies have shown that there is no defect of the i-NANC system either in mild or severe asthma. Some studies have suggested that the amount of VIP is reduced in more severe asthma, but others have not reproduced this. Lucchini et al. have shown that there are more VIP immunoreactive nerves around the ubmucosal glands in chronic bronchitis, but again it is a rather limited effect.
Asthma has long been recognised as a major problem in Australia. In the late 1980s, health professionals, consumers and governments shared a common concern about rising morbidity and mortality attributable to this illness. Although inhaled corticosteroids had been available for the treatment of asthma since the early 1970s, it was not until around the late 1980s that compelling evidence of their effectiveness in the long-term treatment of asthma became available. Also at this time, consensus developed around the value of a systematic approach to asthma management and Australian respiratory physicians led the world in publishing a national asthma management plan. Over two million Australians have asthma: 14% - 16% of children and 10% - 12% of adults. 20% - 30% of all Australians will have had wheezing in the last year. There was an increase in the proportion of children with asthma in the 1980s and early 1990s. More boys than girls have asthma, but in adults it is more common in women than in men. There are similar rates of asthma in major cities, inner regional areas and outer regional and remote areas.
It is clear that the prevalence of asthma and allergic disease has been increasing in developed countries for the last thirty to fifty years, though this has been most apparent since the 1960's. Asthma mortality data offer the longest continuous series, but interpretation is made difficult by the changes in diagnostic classifications (ICD) over time. For Australia, in persons aged 5-34 years, mortality rose from approximately 0.25-0.5 per 100000 person- years prior to 1950 in a linear fashion up to 1.2 per 100000 in 1955, fell briefly, rose to 2 per 100000 in the late 1960's, fell through the 1970's to 1 per 100000, reached a second peak in the 1985 of 1.5 per 100000 and has fallen below 1 per 100000 since then. In age-period-cohort Poisson regressions, there were linear increases in mortality with each 5 year birth cohort since approximately 1930. The only period showing an increase was in the 1960s, with a steady decrease in adjusted mortality into the 1990s, interpreted as due to increased use of inhaled corticosteroids.
For reported asthma, the sexes were almost equally affected (51% male). There had been a marked increase in reported long-term asthma at all ages since the 1977-78 Survey, most noticeably in those under 15 years of age, where the prevalence had risen from 4% to 14%. An examination of birthplaces noted the (age-sex adjusted) prevalence of asthma was highest in those born in Australia and New Zealand, next for those from the UK and Ireland, less for those born in Southeast Asia, Africa and Southern Europe, and least for those born in Western Europe.
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1. www.British Medical Bulletin, Vol 48, Issue 1 10-22, Copyright (c) 1992 by Oxford University Press.
