Focus in Pathophysiology of Asthma

Asthma is an airway disorder that causes respiratory hypersensitivity, inflammation, and intermittent obstruction. Asthma commonly causes constriction of the smooth muscles in the airway, wheezing, and dyspnea. Asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment.

Asthma is a common chronic disease worldwide and affects 22 million persons in the United States. Asthma is the most common chronic disease in childhood, affecting an estimated 6 million children, and it is a common cause of hospitalization for children in the United States. Despite recent advances in the understanding of the pathophysiology, assessment, and treatment of asthma, the condition continues to have significant medical and economic impacts worldwide.

They defined asthma as follows: 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 associated increase in the existing bronchial responsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma.

Pathophysiology of Asthma

Asthma is a condition characterized by paroxysmal narrowing of the bronchial airways due to inflammation of the bronchi and contraction of the bronchial smooth muscle. The inflammatory component is central to the pathogenesis of symptoms: dyspnea, cough, and wheezing.

The pathophysiology of asthma is complex and involves the following components:

• Airway inflammation
• Intermittent airflow obstruction
• Bronchial hyperresponsiveness

Interactions between environmental and genetic factors result in airway inflammation, which limits airflow and leads to functional and structural changes in the airways in the form of bronchospasm, mucosal edema, and mucus plugs. Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of breathing.

• Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intraalveolar pressure due to hyperinflation all lead to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxia also contributes to this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion mismatch.
• In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the early stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes a decrease in PaCO₂. An increase in alveolar ventilation in the early stages of an acute exacerbation prevents hypercarbia. With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis.
• Chronic inflammation of the airways is associated with increased BHR, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease.

The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling are present

• Some of the principal cells identified in airway inflammation include mast cells, eosinophils, epithelial cells, macrophages, and activated T lymphocytes. T lymphocytes play an important role in the regulation of airway inflammation through the release of numerous cytokines. Other constituent airway cells, such as fibroblasts, endothelial cells, and epithelial cells, contribute to the chronicity of the disease. Other factors, such as adhesion molecules (eg, selectins, integrins), are critical in directing the inflammatory changes in the airway. Finally, cell-derived mediators influence smooth muscle tone and produce structural changes and remodeling of the airway.
• The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the clinical severity of asthma
• Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling. Acute bronchoconstriction is the consequence of immunoglobulin E–dependent mediator release upon exposure to aeroallergens and is the primary component of the early asthmatic response. Airway edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic response. Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take weeks to resolve. Airway remodeling is associated with structural changes due to long-standing inflammation and may profoundly affect the extent of reversibility of airway obstruction.
• Aspirin, a cyclooxygenase inhibitor, produces severe bronchospasm in sensitive individuals. Leukotriene inhibitors reverse this sensitivity, providing further evidence that leukotrienes are important mediators of asthma.
• A balance between the adrenergic and cholinergic systems controls bronchomotor tone. Beta-agonist stimulation induces bronchodilation, and beta-blockers cause bronchoconstriction. More specific beta2-agonists have been developed to avoid the tachycardia associated with nonspecific beta-agonist agents. Cholinergic stimulation may cause bronchoconstriction. Anticholinergic agents (eg, ipratropium) produce bronchodilation.
• The airway narrowing in acute asthma manifests itself most commonly in adults as wheezing; in children, nocturnal cough is a very common presentation. The initial component is generally rapidly reversible bronchospasm of the smooth muscles that develops into more refractory inflammation of the airways characterized by bronchial edema, tenacious viscid secretions, mucous plugging, and atelectasis. Common causes of acute asthma include viral upper respiratory infections; exposure to allergens (eg, dustmites, animal dander); smoke inhalation; and cold, dry weather. A strong association had been thought to exist in women between the perimenstrual phase of their cycle and asthma symptoms, but the latest data suggest a more complex association between female sex hormones and asthma.

Another important mechanism underlying acute asthma involves antigen-antibody interactions, which activate membrane phospholipase and result in production of arachidonic acid. Arachidonic acid is metabolized by cyclooxygenase to vasoactive prostaglandins (eg, thromboxanes, prostacyclins) or leukotrienes and their precursors. Several are potent smooth muscle contractors that produce airway hyperresponsiveness and inflammation. The pharmacologic inhibition of leukotriene synthesis and/or action has a beneficial effect on induced and spontaneous asthma, demonstrating that leukotrienes can be important mediators of acute asthma and reactive airway disease (RAD).

The 2007 Expert Panel Report 3 noted several key new differences in the pathophysiology of asthma, as follows:

• The critical role of inflammation has been further substantiated, but evidence is emerging for considerable variability in the pattern of inflammation, thus indicating phenotypic differences that may influence treatment responses.
• Of the environmental factors, allergic reactions remain important. Evidence also suggests a key and expanding role for viral respiratory infections in these processes.
• The onset of asthma for most patients begins early in life, with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma.
• Current asthma treatment with anti-inflammatory therapy does not appear to prevent progression of the underlying disease severity.

New insights in the pathogenesis of asthma suggest the role of lymphocytes. Airway inflammation in asthma may represent a loss of normal balance between two “opposing” populations of Th lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2 and IFN-α, which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation.

• The current “hygiene hypothesis” of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in Westernized countries. This hypothesis is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation). Following birth, environmental stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance.
• Evidence suggests that the prevalence of asthma is reduced in association with certain infections (Mycobacterium tuberculosis, measles, or hepatitis A); country living, exposure to other children (eg, presence of older siblings and early enrollment in childcare); and less frequent use of antibiotics. Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern.
• Under these conditions, the genetic background of the child, with a cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating IgE, and sensitization occurs. A reciprocal interaction is apparent between the two subpopulations, in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternately, the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished has been suggested in recent studies.
• In preschool children with asthma, 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued.
• Evidence suggests that rhinovirus is a significant risk factor for the development of wheeze in preschool children and a frequent trigger of wheezing illnesses in children with asthma. In addition, some studies highlight the importance of genotypes.
• Attempts to identify clinical subtypes of asthma using cluster analysis resulted in the identification of 5 phenotypes of asthma that differ in multiple ways, including age of onset, gender, body weight, degree of flow limitation, and frequency of exacerbatio

Exercise-Induced Asthma

• The pathogenesis of exercise-induced bronchospasm is controversial. The disease may be mediated by water loss from the airway, heat loss from the airway, or a combination of both. The upper airway is designed to keep inspired air at 100% humidity and body temperature at 37°C (98.6°F). The nose is unable to condition the increased amount of air required for exercise, particularly in athletes who breathe through their mouths. The abnormal heat and water fluxes in the bronchial tree result in bronchoconstriction, occurring within minutes of completing exercise. Results from bronchoalveolar lavage studies have not demonstrated an increase in inflammatory mediators. These patients generally develop a refractory period, during which a second exercise challenge does not cause a significant degree of bronchoconstriction.
• Functional Anatomy. The problem in EIA occurs distal to the glottis, in the lower airway. Bronchoconstriction is involved that is distinguishable from laryngospasm, which can occur in other exercise-related conditions. One such example is the condition known as vocal cord dysfunction in which there is paradoxical narrowing of the vocal cords during inspiration, resulting in stridor that is often misconstrued as audible wheezing. Normally, the vocal cords open with inspiration. (See also the eMedicine article Vocal Cord Dysfunction.)
• Sport-Specific Biomechanics. EIA usually affects individuals who participate in sports that include an aerobic component. The condition can be seen in any sport, but EIA is much less common in predominantly anaerobic activities. This is likely due to the role of consistent and repetitive air movement through the airways (seen in aerobic sports), which affect airway humidity and temperature. EIA triggers an unknown biochemical and neurochemical pathway, resulting in the bronchospasm, which manifests as the symptoms of the disease.
• Although the exact mechanism of EIA is unknown, there are 2 predominant theories as to how the symptom complex is triggered. One is the airway humidity theory, which suggests that air movement through the airway results in relative drying of the airway. This, in turn, is believed to trigger a cascade of events that results in airway edema secondary to hyperemia and increased perfusion in an attempt to combat the drying. The result is bronchospasm.
• The other theory is based on airway cooling and assumes that the air movement in the bronchial tree results in a decreased temperature of the bronchi, which may also trigger a hyperemic response in an effort to heat the airway. Again, the result is a spasm in the bronchi.
• Many authors think that there may be a combination of the above 2 theories that takes place, but the biochemical or physical pathways that mediate these responses are unclear. Evidence may even exist to support the idea that the resulting cascades are not the inflammatory pathways to which we attribute allergic asthma.
• Likewise, certain sports and their environments predispose individuals with asthma to experience EIA. Sports played in cold and dry environments usually result in more symptom manifestation for athletes with this condition. On the other hand, when the environment is warm and humid, the incidence and severity of EIA decrease.

Pregnancy

• Pregnancy has a significant effect on the respiratory physiology of a woman. While the respiratory rate and vital capacity does not change in pregnancy, there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual capacity and residual volume of air as a consequence of the elevated diaphragm. In addition, airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of progesterone. 
• The result of all of these physiologic changes is a hyperventilatory picture as a normal state of affairs in the later half of pregnancy. This results in the picture of a chronic respiratory alkalosis during pregnancy with a decreased pCO₂, decreased bicarbonate, and increased pH. A normal pCO₂ in a pregnant patient may signal impending respiratory failure. The increased minute ventilation and improved pulmonary function in pregnancy promote more efficient gas exchange from the maternal lungs to the blood. Therefore, changes in respiratory status occur more rapidly in pregnancy than in the nonpregnant patient. Asthma is characterized by inflammation of the airways, with an abnormal accumulation of eosinophils, lymphocytes, mast cells, macrophages, dendritic cells, and myofibroblasts. This leads to a reduction in airway diameter caused by smooth muscle contraction, vascular congestion, bronchial wall edema, and thick secretions.

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