Airway Inflammation in Asthma
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Airway Inflammation in Asthma

Asthma is a highly prevalent disease that involves a complex interplay of environmental factors, airflow obstruction, bronchial hyperresponsiveness, and inflammation. The dominant feature that leads to clinical symptoms is smooth muscle contraction and inflammation, which results in narrowing of the airway and obstruction.Numerous triggers can induce bronchoconstriction, including allergic responses, respiratory infections, exercise, irritants, and nonsteroidal anti-inflammatory drugs in select patients1,2. Persistent inflammation in the airway may lead to structural changes, such as mucus hypersecretion, smooth muscle hyperplasia, subepithelial fibrosis, blood vessel proliferation, and infiltration of inflammatory cells (Ref.1) 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 (Ref.2).

The inflammatory response in the airways of patients with asthma involves an orchestrated interplay of the respiratory epithelium, innate immune system, and adaptive immunity that initiates and drives a chronic inflammatory response. Central to this process is an interaction between genes and environment, resulting in an abnormal immune response to allergens and other environmental triggers in genetically susceptible individuals (Ref. 3). 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, which predominantly secrete TH2 (T Helper2) cells. TH2 cells secrete cytokines(Interleukin-4, 5, 6, 9, and 13) that promote allergic inflammation and stimulate B-Cells to produce IgE (Immunoglobulin) and other antibodies. IL-5 stimulates the release of eosinophils into the circulation and prolongs their survival. Interaction of the airway with allergen increases the local concentration of IL-5, which correlates directly with the degree of airway eosinophilia (Ref.4). 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-Gamma (Interferon-Gamma) 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 (Ref.5). 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 (such as tobacco, smoke and air pollution), 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-KappaB (nuclear factor-kappaB), Activator Protein-1, NFAT (Nuclear Factor of Activated T-Cells), CREB (cyclic AMP Response-Element Binding Protein), and various members of the family of STAT (Signal Transduction- Activated Transcription) 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 (Ref.4).

Asthma is a complex collection of clinical phenotypes that have in common the propensity to develop acute episodes of airway obstruction and wheezing and, unfortunately, current treatment options are not very effective, impractical due to significant side effects. The first possibility is either to prevent viral infections or use antiviral medicines to treat infections at the onset of the illness. Another potential therapeutic approach to respiratory viral infections in asthma is to inhibit pro-inflammatory immune responses induced by the virus, either by targeting specific signaling pathways or pro-inflammatory cytokines or mediators. Several drugs that modulate cytokines have now been developed for the treatment of asthma and other allergic diseases (Ref.6). 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 Beta2-agonists. Inhaled corticosteroidsinhibit inflammatory cell activation, whereas Beta2-agonists are effective bronchodilators (Ref.7).