High CO2 levels impair alveolar epithelial function independently of pH.
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 approximately 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.


RESULTS
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 PKCzeta 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.
Briva
Arturo
A
Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Vadász
István
I
Lecuona
Emilia
E
Welch
Lynn C
LC
Chen
Jiwang
J
Dada
Laura A
LA
Trejo
Humberto E
HE
Dumasius
Vidas
V
Azzam
Zaher S
ZS
Myrianthefs
Pavlos M
PM
Batlle
Daniel
D
Gruenbaum
Yosef
Y
Sznajder
Jacob I
JI
D000818:Animals; D001826:Body Fluids; D002248:Carbon Monoxide / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D008297:Male; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism
D002248:Carbon Monoxide; D000254:Sodium-Potassium-Exchanging ATPase