Pathogenesis

The key initiating event in the pathogenesis of asthma is currently felt to be inflammation of the conducting airways. T lymphocyte activation is suggested by increased surface expression of CD25, CD45, HLA-DR and VLA-1 on lymphocytes from bronchoalveolar lavage (BAL) and bronchial biopsy specimens of asthmatic subjects. Moreover, expression of interleukin-4 (IL-4) and IL-5 but not interferon y (IFNy), in a pattern consistent with a Th2 response, has been shown in asthmatic subjects; this expression is greater in symptomatic subjects, increased after allergen challenge, positively correlated with asthma symptoms, and negatively correlated to FEVt (forced expiratory volume in 1 second). Early activation of pulmonary mast cells is suggested by elevations of both histamine and tryptase in BAL samples immediately following allergen challenge. IgE-dependent activation of mast cells results in the generation of sulfidopeptide leukotrienes that contribute to mucus hypersecretion, increased microvascular permeability and smooth muscle contraction. The participation of tryptase in neuropeptide metabolism may further contribute to neuronally mediated increases in airway smooth muscle tone. The late inflammatory response is associated with a marked influx of eosinophils and basophils into the asthmatic airway. Eosinophil degranulation is suggested by increases in major basic protein, eosinophil peroxidase, and eosinophil cationic protein in asthmatic airways. These highly toxic substances may promote BHR through direct damage to airway epithelium, resulting in exposure of mast cells and nerve endings. Activation of basophils recruited to these sites of inflammation result in both the generation of mediators of bronchoconstriction and mucus hypersecretion and the elaboration of proinflammatory cytokines such as IL-4 and IL-13. Selective and coordinated recruitment of these various effector cell types may be achieved through the upregulation of specific members of the integrin and selectin super-families of cellular adhesion molecules and the elaboration of specific cellular chemoattractants (Figure 1).

The pathology of asthma reflects these basic principles of allergic inflammation. Those airways most affected in asthmatics are the large and medium conducting airways. Classic changes seen on biopsy of severe asthmatic subjects, as well as postmortem examination of subjects suffering fatal asthma, include vascular congestion, mucosal edema with exudation of fluid and proteins from the microvascu-lature, and infiltration of inflammatory cells into interstitial tissue. Mucus hypersecretion with disruption of pulmonary epithelial cells results in luminal obstruction. Chronic inflammation may also result in airway remodeling with thickening and fibrosis in the region of the basement membrane. Curschman spirals (expectorated casts of inflamed airways), Creola bodies (compact clusters of sloughed epithelial cells), and Charcot-Leyden crystals (condensed eosinophil granular proteins) are considered classic findings in severe asthma. Squamous metaplasia may occur as a response to epithelial disruption. The functional

Genetic factors -Environmental factors

Genetic factors -Environmental factors

B cell activation

T cell activation

Eosinophil recruitment

Mast cell/ basophil priming

B cell activation

T cell activation

Eosinophil recruitment

Adhesion molecule upregulation

Airway inflammation

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

Get My Free Ebook


Post a comment