Area Broca

ABSTRACT

Nearly 12% of children and 6% of adults in Canada have been diagnosed with asthma. Although in most patients symptoms are controlled by inhaled steroids, a subpopulation (~ 10%) characterized by excessive airway neutrophilia, is refractory to treatment; these patients exhibit severe disease, and account for more than 50% of asthma health care costs. These numbers underscore the need to better understand the biology of severe asthma and identify pro-asthma mediators released by cells, such as neutrophils, that are unresponsive to common steroid therapy. This review focuses on a unique protein complex consisting of S100A8 and S100A9. These subunits belong to the large [Ca.sup.2+]-binding S100 protein family and are some of the most abundant proteins in neutrophils and macrophages. S100A8/A9 is a damage-associated molecular pattern (DAMP) protein complex released in abundance in rheumatoid arthritis, inflammatory bowel disease, and cancer, but there are no definitive studies on its role in inflammation and obstructive airways disease. Two receptors for S100A8/A9, the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptor4 (TLR4), are expressed in lung. TLR4 is linked with innate immunity that programs local airway inflammation, and RAGE participates in mediating fibroproliferative remodeling in idiopathic pulmonary fibrosis. S100A8/A9 can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. We hypothesize that this capacity suggests S100A8/A9 could underpin chronic airway inflammation and airway remodeling in asthma by inducing effector responses of resident and infiltrating airway cells. This review highlights some key issues related to this hypothesis and provides a template for future research.

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