Airway Inflammation in Asthma


Pathway Description

Asthma is a complex, chronic inflammatory lung disease that is characterized by epithelial shedding, airway smooth muscle hypertrophy and hyperplasia, overproduction of mucus, and airway inflammation. Its clinical phenotypes have in common the propensity to develop acute episodes of airway obstruction and wheezing. Current treatment options are not very effective, and sometimes impractical due to side effects. The pathophysiology of asthma has been attributed to an inflammatory process that occurs predominantly in the large airways by the accumulation of eosinophils and CD4+ lymphocytes in the submucosa, mucous-gland hyperplasia, thickening of the sub epithelial collagen layer, submucosal matrix deposition, mast-cell degranulation, and hypertrophy and hyperplasia of the airway smooth muscle.The epithelial cell is a focal point in the pathogenesis of viral respiratory infections because it serves as the host cell for viral replication, and it can also initiate innate immune responses. Chronic inflammation in asthma usually includes an increase in the number of activated T-Cells, predominantly TH2 cells. TH2 cells secrete cytokines (Interleukin-4, 5, 6, 9, and 13) that promote allergic inflammation and stimulate B-Cells to produce IgE and other antibodies. IL-5 stimulates the release of eosinophils into the circulation and prolongs their survival. Interaction of the airway with allergesn increases the local concentration of IL-5, which correlates directly with the degree of airway eosinophilia. The eosinophil is a rich source of leukotrienes, particularly the cysteinyl leukotriene C4, which contracts airway smooth muscle, increases vascular permeability, and may recruit more eosinophils to the airway. In contrast, TH1 cells, another class of CD4 T-Cells, produce IFN-γ and IL-2, which initiate the killing of viruses and other intracellular organisms by activating macrophages and cytotoxic T-Cells. These two subgroups of TH cells arise in response to different immunogenic stimuli and cytokines, and they constitute an immunoregulatory loop: cytokines from TH1 cells inhibit TH2 cells, and vice versa. These factors, together with chronic structural changes to the airway and increased production of mucus by goblet cells, increase the risk of intermittent episodes of acute obstruction of airflow through the small airways of the lung in response to irritants, allergens and acute viral infections.

Some cytokines initiate inflammatory responses by activating transcription factors that bind to the promoter region of genes. Transcription factors involved in asthmatic inflammation include NF-κB, Activator Protein-1, NFAT, CREB, and various members of the family of STAT factors. These transcription factors act on genes that encode inflammatory cytokines, chemokines, adhesion molecules, and other proteins that induce and perpetuate inflammation. Corticosteroids modulate immunoinflammatory responses in asthma by inhibiting these transcription factors.

IL-4 is critical for the synthesis of IgE by B-lymphocytes and is also involved in eosinophil recruitment to the airways. A unique function of IL-4 is to promote differentiation of TH2 cells and it therefore acts at a proximal and critical site in the allergic response, making IL-4 an attractive target for inhibition. Anti-IL-5 antibody is very effective at inhibiting peripheral blood and airway eosinophils but is not effective in symptomatic asthma. Inhibitory cytokines, such as IL-10, IFNs, and IL-12 are less promising because systemic delivery produces intolerable side effects. The most widely used therapies for the control of asthma symptoms are the corticosteroids and the β2-agonists. Inhaled corticosteroids inhibit inflammatory cell activation, whereas β2-agonists are effective bronchodilators. (Upgraded 01/2020)