Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning. The hallmarks of asthma are intermittent, reversible airway obstruction; chronic bronchial inflammation with eosinophils; bronchial smooth muscle cell hypertrophy and hyperreactivity; and increased mucus secretion. Sometimes trivial stimuli are sufficient to trigger attacks in patients, because of airway hyper-reactivity. Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells. Of note, asthma has increased in incidence significantly in the Western world over the past 4 decades. One explanation for this troubling trend is the hygiene hypothesis, according to which a lack of exposure to infectious organisms (and possibly nonpathogenic microorganisms as well) in early childhood results in defects in immune tolerance and subsequent hyperreactivity to immune stimuli later in life.
Major factors contributing to the development of asthma include genetic predisposition to type I hypersensitivity (atopy), acute and chronic airway inflammation, and bronchial hyperresponsiveness to a variety of stimuli.
Asthma may be subclassified as atopic (evidence of allergen sensitization) or nonatopic. In both types, episodes of bronchospasm may be triggered by diverse exposures, such as respiratory infections (especially viral), airborne irritants (e.g., smoke, fumes), cold air, stress, and exercise. There also are varying patterns of inflammation—eosinophilic (most common), neutrophilic, mixed inflammatory, and pauci-granulocytic—that are associated with differing etiologies, immunopathologies, and responses to treatment.
The classic atopic form is associated with excessive type 2 helper T (TH2) cell activation. Cytokines produced by TH2 cells account for most of the features of atopic asthma— IL-4 and IL-13 stimulate IgE production, IL-5 activates eosinophils, and IL-13 also stimulates mucus production. IgE coats submucosal mast cells, which on exposure to allergen release their granule contents and secrete cytokines and other mediators. Mast cell–derived mediators produce two waves of reaction: an early (immediate) phase and a late phase (
Fig. 13.10
The early-phase reaction is dominated by bronchoconstriction, increased mucus production, and vasodilation. Bronchoconstriction is triggered by mediators released from mast cells, including histamine, prostaglandin D2, and leukotrienes LTC4, D4, and E4, and also by reflex neural pathways.
The late-phase reaction is inflammatory in nature. Inflammatory mediators stimulate epithelial cells to produce chemokines (including eotaxin, a potent chemoattractant and activator of eosinophils) that promote the recruitment of TH2 cells, eosinophils, and other leukocytes, thus amplifying an inflammatory reaction that is initiated by resident immune cells.
• Repeated bouts of inflammation lead to structural changes in the bronchial wall that are collectively referred to as airway remodeling. These changes include hypertrophy of bronchial smooth muscle and mucus glands and increased vascularity and deposition of sub-epithelial collagen, which may occur as early as several years before initiation of symptoms.
Asthma tends to “run” in families, but the role of genetics in asthma is complex. Genome-wide association studies have identified a number of genetic variants associated with asthma risk, some in genes enocding factors like the IL-4 receptor that are clearly involved in asthma pathogenesis. However, the precise contribution of asthma-associated genetic variants to the development of disease remains to be determined.