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The peroxisome proliferator‐activated gamma (PPARγ) ligand, rosiglitazone, attenuates lung barrier dysfunction following chronic alcohol ingestion
Author(s) -
Wagner Matthew Christian,
Hart C. Michael,
Brown LouAnn S.,
Kleinhenz Dean Jason
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.964.2
Subject(s) - rosiglitazone , oxidative stress , bronchoalveolar lavage , peroxisome proliferator activated receptor , lung , endocrinology , nadph oxidase , chemistry , malondialdehyde , medicine , pharmacology , receptor
Chronic alcohol consumption increases the incidence of the Acute Respiratory Distress Syndrome in part through alcohol‐induced, NADPH oxidase‐mediated increases in oxidative stress in the lung. We hypothesized that rosiglitazone, a PPAR‐γ ligand that attenuates NADPH oxidase expression, would attenuate alcohol‐induced oxidative stress and alveolar capillary barrier dysfunction in the lung. To explore this hypothesis, C57Bl/6 mice consumed standard chow ± ethanol (EtOH, 20% w/v) in drinking water for 12 weeks. After 11 weeks, selected mice were gavaged daily with rosiglitazone (10 mg/kg) for 1 week. Mice were then treated ± lipopolysaccahride (LPS, 2mg/kg IP) 6 h prior to sacrifice. LPS treatment stimulated lung barrier dysfunction evidenced by increases in bronchoalveolar lavage (BAL) protein levels. Chronic EtOH ingestion enhanced LPS‐mediated increases in BAL protein, whereas rosiglitazone attenuated BAL protein levels in EtOH and EtOH + LPS‐treated mice. In vitro studies employing HUVEC monolayers on transwell filters confirmed that EtOH (0.1% for 72 h)‐induced endothelial barrier dysfunction was attenuated by rosiglitazone. These findings indicate that PPARγ may represent a novel therapeutic target that can reduce the barrier disruptive effects of alcohol on the lung despite continued EtOH ingestion. This work is supported by grants from NIAAA and the VA Research Service.