This R01 award will provide the necessary resources to examine the role of the complement system on airway obstruction during inflammatory diseases such as asthma. Increasing numbers of studies on human asthma and rodent models of allergic airway inflammation have focused on the function of the airway epithelial cell in obstructive airway disease. Airway epithelial cells are thought to contribute to the pathology in asthma through their production of mucus. Under normal conditions, mucus is an important component of host defense in the airway, but during severe episodes of asthma, mucus hypersecretion represents an important cause of airway obstruction. Mucus is comprised of mucin glycoproteins which are produced by specialized airway epithelial cells called goblet cells. Although studies have identified inflammatory mediators which will promote goblet cell development and mucus plugging of the airway, the direct effect of complement system activation and release of the complement anaphylatoxins C3a and C5a to mucin expression by goblet cells has not been elucidated. Cell culture techniques have recently been developed which permit investigation in vitro of airway epithelial cell function in parallel with in vivo models. Here we demonstrate a novel role for C3a and its receptor (C3aR) in the production of mucins by airway epithelial goblet cells and describe regulatory mechanisms involving T lymphocytes and production of IL-13 as well as airway epithelial production of chemokines and recruitment of leukocytes. Given the problems with mucus plugging in asthma, this proposal will delineate the complement-mediated mechanisms that regulate goblet cell development, mucus production, and airway obstruction in asthma.
|Lim, Hoyong; Kim, Young Uk; Drouin, Scott M et al. (2012) Negative regulation of pulmonary Th17 responses by C3a anaphylatoxin during allergic inflammation in mice. PLoS One 7:e52666|