NKCC1 is an electrolyte transporter localized to the basolateral membrane of airway epithelial cells that mediates electroneutral transport of chloride into the cell. The apical expulsion of CI- provides a driving force for the formation of airway surface liquid. Along with its high level of expression on airway epithelial cells, NKCC1 is widely expressed throughout the lung in airway smooth muscle cells as well as both resident and recruited immune cells. Less is known about its function in these non-epithelial cells where it has traditionally been considered to act simply as a regulator of cell volume. However, recent evidence suggests that NKCC1 might contribute to fundamental cellular functions including cell division, cell migration and optimal activity of a number of intracellular signaling pathways. The apparent importance of NKCC1 in this wide range of critical functions suggests that alterations in its expression level or activity might have direct consequences in the pathogenesis and pathophysiology of airway diseases. This view is supported by recent gene expression analyses from individuals with asthma revealing dramatic increases in the expression of NKCC1 in the asthmatic airway and by airway epithelial cells. This observation also suggests a molecular basis for previous reports showing that furosemide, an inhibitor of NKCC1, might be useful in the treatment of asthma. To further define the role of NKCC1 in airway disease we have recently examined the development of allergic airway disease in mice lacking NKCC1. We found that the loss of NKCC1 significantly attenuated inflammatory cell infiltration and airway reactivity. Based on these findings indicating a non-redundant role for NKCC1 in allergic airway disease, we propose to test the hypothesis that NKCC1 contributes to airway inflammation by: 1. modifying secretory functions of the airway epithelia; 2. increasing airway smooth muscle reactivity; and 3. by optimizing the migration and activation of inflammatory cells.
