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417 EFFECTS OF CHRONIC ETHANOL ON NITRIC OXIDE PRODUCTION IN PORCINE PULMONARY ARTERY ENDOTHELIAL CELLS
  1. J. A. Polikandriots,
  2. H. L. Rupnow,
  3. C. M. Hart
  1. Atlanta, GA.

Abstract

Purpose Chronic ethanol (EtOH) ingestion increases the incidence and severity of the acute respiratory distress syndrome (ARDS), a pulmonary disorder characterized by disruption of the alveolar-capillary barrier. Nitric oxide (NO) has been implicated in regulation of endothelial barrier function. Because previous reports have demonstrated that exposure to EtOH for periods up to 6 hours increases endothelial NO production, we sought to determine if more chronic EtOH exposure could directly modulate endothelial nitric oxide synthase (eNOS) activity and endothelial NO production, thereby contributing to altered lung responses during chronic EtOH ingestion.

Methods To test this hypothesis, porcine pulmonary artery endothelial cells (PAEC) were treated with 0.1% (w/v) EtOH for 72 hours in sealed chambers to prevent evaporation.

Results EtOH caused dose-dependent increases in NO production and increased eNOS expression, effects that were attenuated by wortmannin, a specific PI-3 kinase inhibitor. EtOH also increased heat shock protein 90 (hsp90)-eNOS interaction, and geldanamycin, an hsp90 inhibitor, attenuated ETOH-stimulated eNOS-hsp90 interaction as well as NO production. In contrast to acute EtOH stimulation, chronic EtOH treatment did not stimulate Akt activation or phosphorylation of eNOS ser1177.

Conclusions These results indicate that chronic EtOH exposure increases endothelial NO production via PI-3 kinase-mediated increases in eNOS expression and enhanced binding of hsp90 to eNOS. This study highlights potential differences in the mechanisms regulating endothelial NO production during acute and chronic EtOH exposure.

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