High CO2 Levels Impair Alveolar Epithelial Function Independently of pH

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

doi:10.1371/journal.pone.0001238

Cited by 110 publications

(145 citation statements)

References 46 publications

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“…36). The signaling pathways sensitive to changes in CO 2 levels in mammalian non-neuronal cells are incompletely understood (37,38), but in plants and neuronal mammalian cells, many reports have identified conserved signaling pathways (39 -41).…”

Section: Discussionmentioning

confidence: 99%

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Vohwinkel

Lecuona

Sun

et al. 2011

Journal of Biological Chemistry

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153

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Background: Cells are exposed to elevated levels of CO 2 (hypercapnia) in many diseases. Results: Hypercapnia decreased cell proliferation, which was prevented with ␣-ketoglutarate, IDH2 overexpression, and microRNA-183 inhibition. Conclusion: Hypercapnia causes mitochondrial dysfunction by up-regulation of microRNA-183, which decreases the levels of IDH2. Significance: Hypercapnia causes mitochondrial dysfunction, which is relevant for patients with lung diseases.

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Section: Discussionmentioning

confidence: 99%

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Vohwinkel

Lecuona

Sun

et al. 2011

Journal of Biological Chemistry

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153

151

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“…and then injected with insulin. The isolated lung preparation has been previously described (Briva et al, 2007;Myrianthefs et al, 2005;Rutschman et al, 1993;Saldias et al, 2001). Briefly, the lungs and heart were removed en bloc.…”

Section: Isolated Perfused Rat Lung Modelmentioning

confidence: 99%

Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt

Comellas

Kelly

Trejo

et al. 2010

Journal of Cell Science

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Stimulation of Na+/K+-ATPase translocation to the cell surface increases active Na+ transport, which is the driving force of alveolar fluid reabsorption, a process necessary to keep the lungs free of edema and to allow normal gas exchange. Here, we provide evidence that insulin increases alveolar fluid reabsorption and Na+/K+-ATPase activity by increasing its translocation to the plasma membrane in alveolar epithelial cells. Insulin-induced Akt activation is necessary and sufficient to promote Na+/K+-ATPase translocation to the plasma membrane. Phosphorylation of AS160 by Akt is also required in this process, whereas inactivation of the Rab GTPase-activating protein domain of AS160 promotes partial Na+/K+-ATPase translocation in the absence of insulin. We found that Rab10 functions as a downstream target of AS160 in insulin-induced Na+/K+-ATPase translocation. Collectively, these results suggest that Akt plays a major role in Na+/K+-ATPase intracellular translocation and thus in alveolar fluid reabsorption.

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“…However, more recent studies have suggested that high pCO 2 can cause oxidative stress in the lung, and injury (3). More recently it has been reported that in rat lungs and human epithelial cells, high pCO 2 decreased alveolar fluid clearance independently of pH and ROS (4,5). In some reports it has been shown that CO 2 uptake involves the aquaporin and RH1 channels (6,7).…”

mentioning

confidence: 99%

Elevated CO ₂ levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans

Sharabi

Hurwitz

Simon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Hypercapnia (high CO2 levels) occurs in a number of lung diseases and it is associated with worse outcomes in patients with chronic obstructive lung disease (COPD). However, it is largely unknown how hypercapnia is sensed and responds in nonneuronal cells. Here, we used C. elegans to study the response to nonanesthetic CO 2 levels and show that levels exceeding 9% induce aberrant motility that is accompanied by age-dependent deterioration of body muscle organization, slowed development, reduced fertility and increased life span. These effects occur independently of the IGF-R, dietary restriction, egg laying or mitochondrial-induced aging pathways. Transcriptional profiling analysis shows specific and dynamic changes in gene expression after 1, 6, or 72 h of exposure to 19% CO 2 including increased transcription of several 7-transmembrane domain and innate immunity genes and a reduction in transcription of many of the MSP genes. Together, these results suggest specific physiological and molecular responses to hypercapnia, which appear to be independent of early heat shock and HIF mediated pathways.aging ͉ gene expression ͉ hypercapnia ͉ muscle deterioration ͉ physiology T he internal environment of a living organism self-regulates CO 2 /H ϩ . In mammals the lungs are the organs that dispose of excess CO 2 produced in the different tissues by adjusting the ventilatory pattern. Hypercapnia occurs in a number of lung disease states and usually reflects hypoventilation inadequate gas exchange. Some investigators have proposed that high CO 2 levels had beneficial effects in models of acute lung injury and proposed the term ''permissive hypercapnia'' and even ''therapeutic hypercapnia'' (1, 2). However, more recent studies have suggested that high pCO 2 can cause oxidative stress in the lung, and injury (3). More recently it has been reported that in rat lungs and human epithelial cells, high pCO 2 decreased alveolar fluid clearance independently of pH and ROS (4, 5). In some reports it has been shown that CO 2 uptake involves the aquaporin and RH1 channels (6, 7). In red blood cells, the RH1 complex also functions as an ammonium transporter (8). The sensing of CO 2 levels in the brain involves CO 2 /H ϩ chemoreceptors. CO 2 chemoreceptors were also identified in the central and peripheral nervous system and pulmonary vascular tissues (9, 10). However, very little is known about what senses the CO 2 levels and how these tissues respond to hypercapnia. The effect of low pH (acidosis) in kidney and lung cells can be altogether separated from that of high CO 2 /HCO 3 Ϫ (4, 11). The genetically tractable model organism, C. elegans, is a very powerful system in which to investigate cellular sensing and response to CO 2 . Despite being an invertebrate, C. elegans has differentiated tissues including hypodermis, epidermis, muscle, nervous system and others. Also demonstrated is the importance of evolutionary conserved genes in studying diseases and specific biological processes including hypoxia, longevity, and others.Recent ...

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High CO2 Levels Impair Alveolar Epithelial Function Independently of pH

Cited by 110 publications

References 46 publications

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt

Elevated CO ₂ levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans

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High CO2 Levels Impair Alveolar Epithelial Function Independently of pH

Cited by 110 publications

References 46 publications

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Insulin regulates alveolar epithelial function by inducing Na+/K+-ATPase translocation to the plasma membrane in a process mediated by the action of Akt

Elevated CO 2 levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans

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Elevated CO ₂ levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans