Asthma is a chronic condition of airway obstruction in which patients experience wheezing, coughing, shortness of breath, and chest tightness in an episodic fashion. This obstruction is reversible upon treatment. The true cause of asthma remains unknown; however, the asthmatic airway is known for its hyperresponsiveness to various stimuli — including physical, chemical and pharmacologic triggers. In the past, asthma was believed to be a disease of the smooth muscle in the lung, and treatment focused on bronchodilators to relax the muscles. More recent investigation has revealed asthma to be an inflammatory process, with treatment focusing on the chronic use of anti-inflammatory agents.
Many physiologic changes are present in the airways of asthmatic patients. Structural changes evident throughout the lung include airway wall thickening, collagen deposition, subepithelial fibrosis and an increase in goblet cells that produce and secrete mucus. The airway wall epithelial cell lining is disrupted with desquamation of cells, airway wall thickening, and edema. Hypertrophy and hyperplasia of smooth muscle is evident. Inflammatory cells and mediators of inflammation are present within the bronchial lumen and the tissue.
Inflammatory cells are triggered to produce mediators of asthma that result in inflammation and symptoms. Mast cells are an example of inflammatory cells found throughout the lungs and when stimulated, produce various mediators. The degranulation of mast cells results in the release of histamine, leukotrienes (C4, D4, and E4), prosta-glandins, and platelet-activating factor, all of which are responsible for initial bronchoconstriction and inflammation. Chemotactic factors that attract other inflammatory cells to the region are also produced.
Other inflammatory cells responsible for asthma symptoms include lymphocytes, eosinophils, neutrophils, and macrophages. These cells all produce various cytokines and other mediators such as leukotrienes, prostaglandins, interferon, granulocyte-macrophage colony stimulating factor (GM-CSF), platelet-activating factor, and major basic protein. All these mediators work to produce the inflammatory process resulting in symptoms of asthma.
Important in the process of inflammation is the presence of adhesion molecules necessary in the migration of inflammatory cells to the site of action. These molecules are present on the surface of endothelial and inflammatory cells, and are responsible for cell recruitment and retainment in the lung tissue. Adhesion molecules identified as important in the pathogenesis of asthma include those from the immunoglobulin supergene family, namely, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). Other adhesion molecules important to the process include integrins, selectins, vascular adressins, cadherins, and carbohydrate ligands.
Epithelial cells lining the airway produce cytokines and other inflammatory mediators such as interleukins, tumor necrosis factor alpha, and GM-CSF. These cells also produce various enzymes including cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS). COX is responsible for the production of prostaglandins and thromboxane from arachidonic acid, while iNOS aids in the production of nitric oxide, which is found in exhaled air of asthmatics. Epithelial cells are also responsible for direct airway inflammation and bronchoconstriction associated with asthma by producing the bronchoconstrictor endothelin.
With the approval of leukotriene modifying agents, leukotrienes have received attention as mediators of asthma’s inflammatory process. Leukotrienes are produced from membrane phospholipids in inflammatory cells. The cysteinyl leukotrienes important in asthma include LTC4, LTD4, and LTE4. Previously these were referred to collectively as the slow-reacting substance of anaphylaxis (SRS-A). It is these cysteinyl leukotrienes that are responsible for effects such as bronchoconstriction, increased mucus secretion, decreased mucus clearance, eosinophil infiltration and activation.
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