title: Carbon monoxide rapidly impairs alveolar fluid clearance by inhibiting epithelial sodium channels.
abstract: 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 microM in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked (22)Na(+) 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 microM), 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.
authors.affiliation: Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Room 6-11), D-35392 Giessen, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Althaus
authors.forename: Martin
authors.initials: M
authors.lastname: Fronius
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Buchäckert
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Clauss
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000378:metabolism; D000584:Amiloride / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001826:Body Fluids / Q000187:drug effects / Q000378:metabolism; D001880:Boranes / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002254:Carbonates / Q000494:pharmacology; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D001880:Boranes; D002254:Carbonates; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D009942:Organometallic Compounds; C503854:sodium boranocarbonate; C476530:tricarbonylchloro(glycinato)ruthenium(II); D006639:Histidine; D000584:Amiloride; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP