High CO2 levels impair alveolar epithelial function independently of pH

Arturo Briva, István Vadász, Emilia Lecuona, Lynn C. Welch, Jiwang Chen, Laura A. Dada, Humberto E. Trejo, Vidas Dumasius, Zaher S. Azzam, Pavlos M. Myrianthefs, Daniel Batlle, Yosef Gruenbaum, Jacob I. Sznajder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


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.

Original languageEnglish (US)
Article numbere1238
JournalPloS one
Issue number11
StatePublished - Nov 28 2007

ASJC Scopus subject areas

  • General


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