TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Althaus, Mike
A1  - Fronius, Martin
A1  - Buchaeckert, Yasmin
A1  - Vadasz, Istvan
A1  - Clauss, Wolfgang G.
A1  - Seeger, Werner
A1  - Motterlini, Roberto
A1  - Morty, Rory E.
T1  - Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels
JF  - American Journal of Respiratory Cell and Molecular Biology
N2  - 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 mu M in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked Na-22(+) 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 mu M), 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.
KW  - sodium/potassium-exchanging ATPase
KW  - Epithelial Na+ channel
KW  - acute respiratory distress syndrome
KW  - carbon monoxide
KW  - carbon monoxide-releasing molecule
SN  - 1044-1549
SS  - 1044-1549
U6  - https://doi.org/10.1165/rcmb.2008-0458OC
DO  - https://doi.org/10.1165/rcmb.2008-0458OC
PM  - 19251942
VL  - 41
IS  - 6
SP  - 639
EP  - 650
S1  - 12
PB  - American Thoracic Society
ER  -