@article{3057184,
    title = "High CO2 levels impair alveolar epithelial function independently of pH",
    author = "Briva, A. and Vadász, I. and Lecuona, E. and Welch, L.C. and Chen, J. and Dada, L.A. and Trejo, H.E. and Dumasius, V. and Azzam, Z.S. and Myrianthefs, P.M. and Batlle, D. and Gruenbaum, Y. and Sznajder, J.I.",
    journal = "PLOS ONE",
    year = "2007",
    volume = "2",
    number = "11",
    doi = "10.1371/journal.pone.0001238",
    keywords = "adenosine triphosphatase (potassium sodium);  carbon dioxide;  cell surface protein;  eosin;  hematoxylin;  protein kinase C zeta;  adenosine triphosphatase (potassium sodium);  carbon monoxide, acute respiratory failure;  animal cell;  article;  artificial ventilation;  basolateral membrane;  biotinylation;  cell fractionation;  cell membrane;  cell metabolism;  cell pH;  controlled study;  endocytosis;  enzyme activation;  enzyme activity;  enzyme inhibition;  enzyme phosphorylation;  enzyme regulation;  epithelium cell;  fluorescence microscopy;  histochemistry;  homeostasis;  human;  human cell;  hypercapnia;  immunoprecipitation;  isolated lung;  lung alveolus cell type 2;  lung alveolus epithelium;  lung fluid;  lung gas exchange;  lung perfusion;  male;  mammal cell;  nonhuman;  plant cell;  polyacrylamide gel electrophoresis;  rat;  signal transduction;  Western blotting;  animal;  body fluid;  chemistry;  cytology;  enzymology;  lung alveolus;  metabolism;  pH;  phosphorylation;  physiology;  Sprague Dawley rat, Mammalia;  Rattus, Animals;  Body Fluids;  Carbon Monoxide;  Epithelial Cells;  Hydrogen-Ion Concentration;  Male;  Phosphorylation;  Pulmonary Alveoli;  Rats;  Rats, Sprague-Dawley;  Sodium-Potassium-Exchanging ATPase",
    abstract = "Background. In patients with acute respiratory failure, gas exchange is impaired due to the accumulation of fluid in the lung airspaces. This life-threatening syndrome is treated with mechanical ventilation, which is adjusted to maintain gas exchange, but can be associated with the accumulation of carbon dioxide in the lung. Carbon dioxide (CO2) is a by-product of cellular energy utilization and its elimination is affected via alveolar epithelial cells. Signaling pathways sensitive to changes in CO2 levels were described in plants and neuronal mammalian cells. However, it has not been fully elucidated whether non-neuronal cells sense and respond to CO2. The Na,K-ATPase consumes ∼40% of the cellular metabolism to maintain cell homeostasis. Our study examines the effects of increased pCO2 on the epithelial Na,K-ATPase a major contributor to alveolar fluid reabsorption which is a marker of alveolar epithelial function. Principal Findings. We found that short-term increases in pCO2 impaired alveolar fluid reabsorption in rats. Also, we provide evidence that non-excitable, alveolar epithelial cells sense and respond to high levels of CO2, independently of extracellular and intracellular pH, by inhibiting Na,K-ATPase function, via activation of PKCζ which phosphorylates the Na,K-ATPase, causing it to endocytose from the plasma membrane into intracellular pools. Conclusions. Our data suggest that alveolar epithelial cells, through which CO2 is eliminated in mammals, are highly sensitive to hypercapnia. Elevated CO2 levels impair alveolar epithelial function, independently of pH, which is relevant in patients with lung diseases and altered alveolar gas exchange. © 2007 Briva et al."
}