This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0458OCv1 41/6/639    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Althaus, M. Articles by Morty, R. E. PubMed PubMed Citation Articles by Althaus, M. Articles by Morty, R. E.

Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels

¹ Department of Internal Medicine, and ² Institute of Animal Physiology, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany; and ³ Department of Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy

Correspondence and requests for reprints should be addressed to Rory E. Morty, Ph.D., Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Room 6-11), D-35392 Giessen, Germany. E-mail: rory.morty{at}innere.med.uni-giessen.de

Carbon monoxide (CO) is currently being evaluated as a therapeutic modality in the treatment of patients with acute lung injury and acute respiratory distress syndrome. No study has assessed the effects of CO on transepithelial ion transport and alveolar fluid reabsorption, two key aspects of alveolocapillary barrier function that are perturbed in acute lung injury/acute respiratory distress syndrome. Both CO gas (250 ppm) and CO donated by the CO donor, CO-releasing molecule (CORM)-3 (100 µM in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked ²²Na⁺ clearance from the alveolar compartment, and blocked alveolar fluid reabsorption after fluid challenge. Apical application of two CO donors, CORM-3 or CORM-A1 (100 µM), irreversibly inhibited amiloride-sensitive short-circuit currents in H441 human bronchiolar epithelial cells and primary rat alveolar type II cells by up to 40%. Using a nystatin permabilization approach, the CO effect was localized to amiloride-sensitive channels on the apical surface. This effect was abolished by hemoglobin, a scavenger of CO, and was not observed when inactive forms of CO donors were employed. The effects of CO were not blocked by 8-bromoguanosine-3',5'-cyclic guanosine monophosphate, soluble guanylate cyclase inhibitors (methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), or inhibitors of trafficking events (phalloidin oleate, MG-132, and brefeldin A), but the amiloride affinity of H441 cells was reduced after CO exposure. These data indicate that CO rapidly inhibits sodium absorption across the airway epithelium by cyclic guanosine monophosphate– and trafficking-independent mechanisms, which may rely on critical histidine residues in amiloride-sensitive channels or associated regulatory proteins on the apical surface of lung epithelial cells.

Key Words: carbon monoxide • carbon monoxide–releasing molecule • acute respiratory distress syndrome • epithelial Na⁺ channel • sodium/potassium–exchanging ATPase

CLINICAL RELEVANCE Delivery of controlled amounts of carbon monoxide (CO) is currently being explored as a novel therapy in patients with acute lung injury, where alveolocapillary barrier function is disrupted. This study describes the deleterious effects of CO on pulmonary transepithelial sodium transport and alveolar fluid clearance. These observations warrant consideration when employing CO in patients with compromised alveolocapillary barrier function.