ACUTE ALCOHOL EXPOSURE AFFECTS CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR (CFTR) CHLORIDE CHANNEL ACTIVITY. CAN COFFEE BE A SOLUTION?
Document Type
Presentation
Start Date
22-10-2010 9:45 AM
End Date
22-10-2010 10:00 AM
Description
Alcohol abuse has been associated with an increased susceptibility to pulmonary infections. The pathophysiological mechanisms underscoring such a clinical observation are incompletely understood. Cystic fibrosis transmembrane regulator (CFTR), a cAMP-activated chloride channel is mutated in Cystic fibrosis (CF) patients who suffer with severe lung infections. Decreased CFTR chloride ion secretions in airways are known to lead to compromised mucociliary clearance and lung infections. Further, paracrine adenosine signaling establishes effective CFTR function and mucociliary clearance. Here, we tested our hypothesis that alcohol compromises adenosine-mediated CFTR chloride channel functions promoting lung infections.
Method: Human airway epithelial Calu-3 cells were cultured at an air-liquid interface for 2 weeks and were exposed to basolateral alcohol for 24 hours. Ussing chamber electrophysiological assays were performed to measure the effects of alcohol exposure on adenosine-stimulated transepithelial ion transport.
Results: Alcohol exposure decreased adenosine-stimulated chloride ion transport in a dose-dependent manner. Adenosine-stimulated chloride ion transport was blocked by CFTR inhibitor-172 and was completely absent in CF airway epithelial cells. Adenosine signaling in Calu-3 cells is largely through its A2b receptor whose expression was not affected by alcohol. However, alcohol suppressed adenosine-stimulated intracellular cAMP production that is required to open CFTR channel. Further, alcohol suppressed chloride ion secretion was restored by prolonging the half-life of cAMP by non-specific phosphodiesterase inhibitor IBMX. Conclusion: alcohol exposure caused CF-like compromise in airway CFTR chloride transport that might compromise mucociliary clearance and promote infections. Phosphodiesterase inhibitors in coffee like theophyllline and caffeine could be a viable prophylactic strategy to restore alcohol suppressed CFTR function.
Recommended Citation
Raju, Vamsee; Kolls, Jay K.; Bagby, Gregory J.; Nelson, Steve; and Wang, Guoshun, "ACUTE ALCOHOL EXPOSURE AFFECTS CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR (CFTR) CHLORIDE CHANNEL ACTIVITY. CAN COFFEE BE A SOLUTION?" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 6.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/presentation1/6
ACUTE ALCOHOL EXPOSURE AFFECTS CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR (CFTR) CHLORIDE CHANNEL ACTIVITY. CAN COFFEE BE A SOLUTION?
Alcohol abuse has been associated with an increased susceptibility to pulmonary infections. The pathophysiological mechanisms underscoring such a clinical observation are incompletely understood. Cystic fibrosis transmembrane regulator (CFTR), a cAMP-activated chloride channel is mutated in Cystic fibrosis (CF) patients who suffer with severe lung infections. Decreased CFTR chloride ion secretions in airways are known to lead to compromised mucociliary clearance and lung infections. Further, paracrine adenosine signaling establishes effective CFTR function and mucociliary clearance. Here, we tested our hypothesis that alcohol compromises adenosine-mediated CFTR chloride channel functions promoting lung infections.
Method: Human airway epithelial Calu-3 cells were cultured at an air-liquid interface for 2 weeks and were exposed to basolateral alcohol for 24 hours. Ussing chamber electrophysiological assays were performed to measure the effects of alcohol exposure on adenosine-stimulated transepithelial ion transport.
Results: Alcohol exposure decreased adenosine-stimulated chloride ion transport in a dose-dependent manner. Adenosine-stimulated chloride ion transport was blocked by CFTR inhibitor-172 and was completely absent in CF airway epithelial cells. Adenosine signaling in Calu-3 cells is largely through its A2b receptor whose expression was not affected by alcohol. However, alcohol suppressed adenosine-stimulated intracellular cAMP production that is required to open CFTR channel. Further, alcohol suppressed chloride ion secretion was restored by prolonging the half-life of cAMP by non-specific phosphodiesterase inhibitor IBMX. Conclusion: alcohol exposure caused CF-like compromise in airway CFTR chloride transport that might compromise mucociliary clearance and promote infections. Phosphodiesterase inhibitors in coffee like theophyllline and caffeine could be a viable prophylactic strategy to restore alcohol suppressed CFTR function.