The airways are equipped with a number of innate defence mechanisms that protect them against pathogens and other harmful particles that are inhaled, and many of these mechanisms are sensitive to ambient pH. Given the pH sensitivity of these defensive processes, we may expect that lung diseases will be associated with changes in luminal pH (pH_Lumen). Although measurements of the pH of the fluid bathing the airway lumen are difficult to make, there is evidence that it does change during lung disease, particularly that associated with inflammation, for example cystic fibrosis. The role that alterations in pH_Lumen may have in contributing to the pathogenesis of these pulmonary diseases is not yet known, but it is possible that the disease process may be ameliorated by restoring pH_Lumen to normal. We are a long way from being able to manipulate airway luminal pH, however, since the mechanisms by which it is controlled are not understood, and indeed the normal range of luminal pH is still under debate as a result of the difficulties in measuring this parameter. We have therefore studied some of the mechanisms that may be involved in regulating airway pH_Lumen. We and others have shown that stimulation of submucosal glands in intact, isolated airways that contain both glandular and surface epithelia results in HCO₃^– secretion, and this secretion of HCO₃^– by airway submucosal glands is essential for normal liquid and mucus secretion (3). We may therefore expect that the pH of ASL is likely to be relatively alkaline, particularly during periods of glandular secretion. However, numerous measurements of ASL pH, both in vitro (e.g. 7) and in vivo (6), have shown that ASL is acidic relative to plasma. This led us to hypothesise that the surface epithelium may acidify the HCO₃^– -rich glandular secretions, whilst others have suggested that proximal regions of the glands carry out this acidification (8). We isolated distal bronchi from porcine lungs, perfused them with a lightly buffered solution and demonstrated that they are capable of both acidifying and alkalinising their lumen (5). The alkalinisation was stimulated by the gland secretagogue acetylcholine and was inhibited by removal of bath HCO₃^–, the Na⁺/H⁺ exchange blocker dimethylamiloride and the anion channel blocker NPPB. It thus matched the properties previously described for ACh-evoked submucosal gland HCO₃^– secretion from these tissues (4). The bronchi also secreted acid equivalents into the lumen, and this was inhibited 65% by the H⁺-ATPase blocker, bafilomycin A₁. Immunohistochemistry confirmed the presence of H⁺-ATPase in the surface epithelium, and removal of this epithelium reduced luminal acidification suggesting that the surface epithelium can acidify the airway lumen. Other studies of surface epithelia have revealed activities of the non-gastric form of the K⁺/H⁺ -ATPase (1) and a zinc-sensitive proton conductance (2), both of which may also be involved in luminal acidification. It thus seems possible that the surface epithelium may indeed acidify the airway lumen, and that the glandular and surface epithelia together determine the pH_Lumen in glandular airways. However, others have demonstrated that Calu-3 cells, thought to be representative of submucosal gland serous cells, also acidify their luminal surface through activity of a K⁺/H⁺ -ATPase (9). It is possible, therefore, that both glandular and surface regions of airway epithelia can acidify the luminal surface. The mechanisms by which they regulate pH_Lumen, however, are as yet unknown. 1. Coakley, R. D., B. R. Grubb, A. M. Paradiso, J. T. Gatzy, L. G. Johnson, S. M. Kreda, W. K. O’Neal, and R. C. Boucher. Proceedings of the National Academy of Science of the United States of America 100: 16083-16088, 2003. 2. Fischer, H., J. H. Widdicombe, and B. Illek. American Journal of Physiology 282: C736-C743, 2002 3. Inglis, S. K., M. R. Corboz, and S. T. Ballard. American Journal of Physiology 274: L762-L766, 1998. 4. Inglis, S. K., and S. M. Wilson. Pediatric Pulmonology In press, 2005. 5. Inglis, S. K., S. M. Wilson, and R. E. Olver. American Journal of Physiology 284: L855-L862, 2003. 6. Ireson, N. J., J. S. Tait, G. A. MacGregor, and E. H. Baker. Clinical Science 100: 327-333, 2001. 7. Jayaraman, S., Y. Song, and A. S. Verkman. American Journal of Physiology 281: C1508-C1511, 2001. 8. Joo, N. S., Y. Saenz, M. E. Krouse, and J. J. Wine. Journal of Biological Chemistry 277: 28167-28175, 2002. 9. Krouse, M. E., J. F. Talbott, M. M. Lee, N. S. Joo, and J. J. Wine. American Journal of Physiology 287: L1274-L1283, 2005.