Rosiglitazone attenuates alcohol‐induced alveolar macrophage oxidative stress and dysfunction

Objective Alcohol abuse causes oxidative stress, alveolar macrophage (AM) dysfunction and increases risk of Acute Respiratory Distress Syndrome (ARDS) and respiratory infections. We hypothesized that rosiglitazone (RSG), a PPARγ ligand that reduces NADPH oxidase (Nox) expression, would attenuate alcohol‐induced oxidative stress and rescue AM function. Methods AMs were isolated from bronchoalveolar lavage fluid from male C57Bl/6J mice fed standard chow ± ethanol (EtOH, 20% w/v) in drinking water (12 wks). During week 12, mice were gavaged ± RSG (10 mg/kg/day). MH‐S cells, a mouse AM cell line, were treated with 0.08% EtOH (3d) ± 10 ìM RSG (1d or 3d). PPARγ, Nox subunits and TGFβ 1 expression were assessed by qRT‐PCR and Western blots. Reactive oxygen species were analyzed by DCFH‐DA and Amplex Red. S. aureus phagocytosis was evaluated by confocal microscopy. Results EtOH: 1) reduced AM PPARγ levels, 2) increased Nox1, Nox2, Nox4, p22phox, p47phox p67phox, and TGFβ 1 expression, 3) increased AM oxidative stress, and 4) impaired AM phagocytosis. RSG attenuated these EtOH‐induced derangements. Conclusions Targeting PPARγ provides a novel therapeutic approach in alcohol‐induced oxidant stress in the lung. Research Funding Source : NIAAA 5T32AA013528‐08 (SMY), 1P50AA135757 (LAB & CMH) and Atlanta VAMC Merit Review Funding (CMH).