Asthma: Encyclopedia II - Asthma - Pathophysiology

Asthma - Pathophysiology

Asthma - Bronchoconstriction

In essence, asthma is the result of an abnormal immune response in the bronchial airways.^[5] The airways of asthmatics are “hypersensitive” to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an “asthma attack”). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

There are seven categories of stimuli:

• allergens, typically inhaled, which include waste from common household insects, such as the house dust mite and cockroach, grass pollen, mould spores and pet epithelial cells;
• medications, including aspirin^[6] and β-adrenergic antagonists (beta blockers);
• air pollution, such as ozone, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas;
• various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH₂Cl), dichloramine (NHCl₂) and trichloramine (NCl₃)—in the air around them, which are known to induce asthma;^[7]
• early childhood infections, especially viral respiratory infections;
• exercise, the effects of which differ somewhat from those of the other triggers; and
• emotional stress, which is poorly understood as a trigger.

Asthma - Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then “present” pieces of the allergen to other immune system cells. In most people, these other immune cells (T_H0 cells) “check” and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (T_H2), for reasons that are not well understood. The resultant T_H2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies “recognize” it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.

Asthma - The immune response

When an inhaled antigen becomes trapped in the airways, it is enzymatically degraded into shorter peptides by APCs such as dendritic cells. APCs express the peptides derived from the antigen on the cell surface, in what is known as the binding groove of the class II major histocompatiblity complex (MHC) molecule. Now located on the cell surface, the antigen-MHC complex is presented to T cells, which express a receptor that is specific to the MHC II peptide.^[5]

Presented with the antigen-MHC II complex, T helper 0 (T_H0) cells become activated and start to differentiate into either T helper type 1 (T_H1) or type 2 (T_H2) cells. The selective differentiation of T_H0 cells has profound consequences for the immune system: T_H1 cell production leads to cell-mediated immunity, while the production of predominantly T_H2 cells provides humoral immunity. The resulting balance of T_H1 or T_H2 cells is a crucial variable in the development of asthma; the dominance of the T_H2 cell type appears to be necessary for the development of asthma. In one study, mice that lacked the ability to create T_H1 cells displayed an asthma-like phenotype.^[8] The variables that decide the fate of T_H1 vs. T_H2 cells are not well understood, but depend on many factors, including childhood exposure to infectious agents and the cytokines elicited by those agents.

One cytokine secreted by T_H2 cells—IL-4—combined with the action of other cytokines induces synthesis by antigen-stimulated B cells of IgE, an allergen-specific antibody. IgE binds allergens and then receptors on mast cells, basophils, and eosinophils in the airway epithelium. Subsequent exposure of the same antigen to these cells in the airway epithelium initiates the acute-phase reaction of asthma. Stimulated mast cells in the airway release preformed granules of mediators such as histamine, eicosanoids, and cytokines. These molecules are responsible for the symptoms of asthma. They affect the mucosa of the airways, increasing mucosal edema, and mucus production, smooth muscle constriction, and recruit other immune cells, thereby exacerbating the reaction.

The late phase of an asthmatic reaction is characterized by an influx of inflammatory and immune cells during the first several hours after antigen exposure. These cells—particularly eosinophils—secrete a series of cytokines, leukotrienes, and polypeptides, which contribute to hyperresponsiveness, mucus secretion, bronchoconstriction, and sustained inflammation.

Asthma - Pathogenesis

The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

One theory of pathogenesis is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria and other antigens soon after birth, “switching on” the T_H1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient—as it may be in modern, clean environments—then T_H2 cells predominate, and asthma and other allergic diseases may develop. This “hygiene hypothesis” may explain the increase in asthma in affluent populations. The T_H2 lymphocytes and eosinophil cells that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. In the developed world, these parasites are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.

Another theory is based on the correlation of air pollution and the incidence of asthma. Although it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proved that air pollution is responsible for the development of asthma. In Western Europe, most atmospheric pollutants have fallen significantly over the last 40 years, while the prevalence of asthma has risen.

Adapted from the Wikipedia article "Pathophysiology", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki