Chronic lung disease in humans is typically associated with epithelial remodeling that includes changes in secretory cell function. These changes to airways lead to increased susceptibility to environmental agents (such as pollutants and microorganisms). These environmental agents have the potential to induce disease exacerbations (injury and inflammation) that lead to accelerated decreases in lung function and in some cases death. We have been interested in understanding how the function of secretory cells, particularly bronchiolar Clara cells, contributes to normal lung function and how epithelial remodeling in chronic lung disease compromises these functions. We generated a mouse model of secretory cell dysfunction through targeted introduction of a null allele for the abundant Clara cell secretory product CCSP (See Stripp et al., 1996 in References). Using this model we have shown that secretory cell dysfunction increases the sensitivity of the conducting airway epithelium to injury by inhaled oxidant gases such as ozone and elevated levels of oxygen (See Plopper et al., 2006, in references). We have also shown that CCSP deficiency leads to immunoregulatory defects in airways of mice that increase their susceptibility to inflammation induced by bacteria (see Reynolds et al., 2007 in References).