RNA Interference as a Therapeutic Agent for Asthma Asthma Pathophysiology
 
Asthma is most commonly identified as an immunological disease. Its pathophysiology is characterized by four major signs: reversible airway obstruction, chronic airway inflammation, airway hyperreactivity, and airway remodeling.5 Asthma begins with airway hyperreactivity, an exaggerated response to a environmental trigger, like allergen, cold air, exercise, or emotional stress. This immunological phenomenon is termed “Type I hypersensitivity,” and is mediated through IgE antibodies. The acute response of asthma starts with inhalation of allergen, which eventually bind to IgE antibodies on the surface of submucosal mast cells. The IgE’s subsequently cross-link on the surface of mast cells via Fc epsilon RI (receptor) which in turn trigger activation of these cells.6 Mast cells secrete local inflammatory mediators that increase vascular leakiness, bronchial constriction and mucus secretion causing airway obstruction. This occurs within seconds. This makes breathing more difficult. The chronic part of the response involves the recruitment of inflammatory cells, i.e. Th2 and mast cells from the circulation. Chronic airway inflammation mainly involves Th2 cells secreting cytokines (notably IL-4 and IL-13) that affect airway epithelial cells. Specifically, these cytokines induce goblet cell proliferation, which further increases mucus production. Furthermore, certain chemokine receptors like CCR3 are upregulated on epithelial cell surfaces. In addition, these receptors’ ligands, like RANTES and eotaxin 1 are also upregulated to recruit more Th2 and eosinophils to the inflammatory region in the lungs. In the longer term, a second event in the chronic inflammatory response is seen in airway remodeling. The Th2 cytokines and chemokines affect smooth muscle cells and lung fibroblasts by essentially causing hypertrophy of airway smooth muscle and mucous glands, and eventually subepithelial fibrosis. Of interest is the fact that after the initial allergen encounter, asthma can be triggered by hyperresponsiveness to a different stimulus like cigarette smoke. A virus infection can also cause a Th2 cytokine mediated response. Conclusion%20%26%20References.htmlConclusion%20%26%20References.htmlshapeimage_4_link_0shapeimage_4_link_1
The etiology of asthma involves a fine balance between the Th1 (cell-mediated) and the Th2 (humoral) responses of the immune system. Usually in asthma, a Th2-mediated response dominates, resulting in eosinophil and Th2 cell recruitment to the injury site. The factors that affect this balance are both genetic and environmental in origin. Environmental causes include allergen inhalation, i.e. cockroach droppings, pollen, etc. One may have a genetic predisposition to allergic hypersensitivity, known as atopy. Genomic screening has elucidated loci of susceptibility for asthma. The susceptibility chromosomal gene loci that have been identified include: • 5q31-32: IL-4, IL-5, IL-13, TGF-β1 • 6p21-22: TNF-α • 11q13: Fc Epsilon RI • 12q: IFN-γ, nitric oxide synthetase, glutathione-S-transferase, selectin P ligand, mast cell growth factor The mRNA transcripts of these and other genes may be targets for RNAi therapy. Janeway, Charles A. et al. Immunobiology. 6th Edition. New York: Garland Science, 2005.