The long-term goal of this project is to understand how the immune response contributes to COPD. In that context, we submit that the innate immune system of the airways can provide critical signals for host defenses under normal conditions but can also trigger excessive mucous cell metaplasia under other conditions. Indeed, studies of genetically susceptible mice indicate that respiratory paramyxoviruses can trigger a permanent switch to excessive mucous cell metaplasia driven by natural killer T cell (NKT cell) activation and consequent macrophage production of IL-13. Moreover, if mice with an activated NKT cell-macrophage pathway are then exposed to a normally innocuous level of cigarette smoke, they develop a striking increase in small airway mucus production to the point of respiratory death. The nature the response to viral infection or virus-smoke interaction appears to be distinct from the traditional view of NKT cell pressure on macrophages or the development of alternative macrophage activation developed in studies of the response to microbial infection or allergens. However, a similar immune pathway may be active in COPD patients as well as amplification of the terminal ste in the pathway (i.e., mucous cell metaplasia) perhaps by IL-13 production and/or responsiveness in airway epithelial cells. Our new observations prompt us to propose how the immune response may be triggered and maintained to drive the COPD phenotype. We specifically hypothesize that mucous cell metaplasia depends on NKT cell activation and consequent macrophage production of IL-13. This pathway overlaps with the one in allergic asthma, but exhibits distinct features. Furthermore, we suggest that this pathway synergizes with the response to cigarette smoking and thereby produces more severe mucous cell metaplasia and mucus obstruction. We further propose that this disease trait is a critical but treatable feature of COPD and may be associated with distinct biomarkers of bronchitic airway disease versus emphysema or allergic asthma. Accordingly, we have the following specific aims: (1) define the role of the NKT cell-macrophage activation pathway leading to IL-13 production and mucous cell metaplasia in COPD patients;(2) define the role of the innate immune program of airway epithelial cells in COPD patients, focusing on auto-amplification of IL-13 action at the level of the epithelium and (3) define the immune mechanism for increased susceptibility to cigarette smoke induction on goblet cell metaplasia and airway hyperreactivity in a mouse model, focusing on the molecular mechanism for NKT cell activation, macrophage activation towards IL-13 production, and epithelial programming towards IL-13 and mucin gene expression. Together, the studies aim to establish a new immune pathway that may normally defend against respiratory infection but may be skewed to drive the development of mucous cell metaplasia in COPD.
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