Rosiglitazone improves alveolar macrophage mitochondrial derangements induced by chronic alcohol consumption and infection with Klebsiella pneumoniae.

Abstract

Abstract Objective: People with alcohol use disorders (AUDs) are 2–4 times more likely to develop lung infections, sepsis, and acute respiratory distress syndrome. Chronic alcohol misuse blunts alveolar macrophage (AM) immunity, in part, due to decreased peroxisome proliferator-activated receptor (PPAR)γ which increases cellular oxidative stress. Mitochondrial (MT) oxidative stress may impair AM phagocytosis; thus, we posited that chronic alcohol plus acute Klebsiella pneumoniae(Kp) dysregulates MT and treatment with rosiglitazone (RSG), a PPARγ ligand, reverses these effects to improve AM phagocytosis of Kp. Methods: AMs were isolated from 8–10-month-old male C57BL/6J mice fed ± ethanol (EtOH, 20% wt/vol in drinking water) for 12 wks ± intratracheal 2 × 10 4CFU of Kpin saline vehicle for the last 24 h of water or EtOH ± RSG (10 mg/kg/d in methylcellulose vehicle) via oral gavage 4 h prior to sacrifice (n=5/group). MT O 2•−and H 2O 2were assessed by fluorescence microscopy. mRNA and protein levels of PPARγ and MT dynamics mediators, transcription factor A mitochondrial (TFAM), dynamin-related protein 1 (DRP1), and mitofusin-2 (MFN2) were measured by qRT-PCR and cytoimmunostaining. Kpclearance by AMs was determined by plating lysed AMs on MacConkey agar. Results: EtOH feeding to mice increased MT oxidative stress; decreased PPARγ, TFAM, and MFN2 levels; and increased DRP1 levels in AMs. Kpexacerbated EtOH’s MT derangements by ~51–63% and impaired Kpclearance in AMs by 57.3 ± 11.2%. RSG treatment in vivoreversed EtOH- and Kp-induced MT derangements in AMs and restored AM clearance of Kp. Conclusion: RSG may provide a novel therapeutic strategy for mitigating AM MT derangements and immune dysfunction in AUD individuals infected with Kp. NIAAA R01-AA026086