The 2007 Expert Panel Report 3 (EPR-3) of the National Asthma Education and Prevention Program (NAEPP) noted several key changes in the understanding of the pathophysiology of asthma: 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 The pathophysiology of asthma is complex and involves the following components: Airway inflammation Intermittent airflow obstruction Bronchial hyperresponsiveness Airway inflammation 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. See the image below. Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma symptoms. 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. A study by Balzar et al reported changes in airway resident mast cell populations from a large group of subjects with asthma and normal control subjects. A greater proportion of chymase-positive mast cells in the airways and increased prostaglandin D2 levels were identified as important predictors of severe asthma as compared with other steroid-treated subjects with asthma. Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, 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. 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. A study by Gauvreau et al found that IL-13 has a role in allergen-induced airway responses. 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. However, unequivocal support for the "hypgiene hypothesis" has not been demonstrated. Airflow obstruction 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. 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. Bronchial hyperresponsiveness 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 intra-alveolar 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 due to retention of carbon dioxide as alveolar ventilation decreases. Source
