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HYPERCAPNIA IMPAIRS ALVEOLAR FLUID CLEARANCE VIA PROTEIN KINASE CASCADE SIGNALING FREE TO VIEW

Istvan Vadasz, MD*; Laura A. Dada, PhD; Emilia Lecuona, PhD; Arturo Briva, MD; Lynn C. Welch, BS; Jiwang Chen, PhD; JacobI. Sznajder, MD
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Northwestern University, Feinberg School of Medicine, Division of Pulmonary, Chicago, IL



Chest. 2006;130(4_MeetingAbstracts):85S-d-86S. doi:10.1378/chest.130.4_MeetingAbstracts.85S-d
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Abstract

PURPOSE: Hypercapnia occurs in a significant number of patients with COPD and ARDS, in part as a consequence of the “permissive hypercapnia” ventilation strategy. We observed that hypercapnia impairs alveolar fluid clearance by decreasing Na,K-ATPase function in alveolar epithelial cells, however the mechanism by which elevated levels of CO2 lead to decreased fluid clearance and inhibition of Na,K-ATPase function has not been elucidated.

METHODS: Alveolar fluid clearance was assessed in an isolated rat lung model. Na,K-ATPase activity and protein abundance in alveolar type II cell cultures were evaluated. Activity of protein kinases was assessed by immuno-blotting with specific phospho-antibodies and in vitro kinase assay.

RESULTS: Elevated levels of CO2 (60 to 120 mmHg) led to sequential activation of AMP-activated protein kinase (AMPK), protein kinase C-ζ (PKC-ζ) and c-Jun N-terminal kinase (JNK) within minutes of exposure in rat alveolar type II cells, while alveolar fluid clearance, Na,K-ATPase activity and membrane protein abundance were significantly decreased. These effects were prevented by pharmacological inhibition or overexpression of dominant negative AMPK, PKC-ζ or JNK.

CONCLUSION: We provide the first evidence that hypercapnia impairs alveolar fluid clearance via activation of a protein kinase signaling cascade in the alveolar epithelium, thus leading to the downregulation of the Na,K-ATPase.

CLINICAL IMPLICATIONS: Hypercapnia has deleterious effects on the alveolar epithelium, which may have significant implications in COPD and ARDS patients.

DISCLOSURE: Istvan Vadasz, None.

Monday, October 23, 2006

10:30 AM - 12:00 PM


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