Valproic Acid Decreases Ozone‐induced Lung Injury and Oxidative Stress in Mice
Authors: Lee Jordan M. , Sunil Vasanthi R. , Vayas Kinal , Murray Alexa , Venosa Alessandro , Cervelli Jessica , Laskin Jeffrey D. , Laskin Debra L. 
Published: June 2021

Ozone is an air pollutant which causes lung injury and oxidative stress. Macrophages accumulate in the lung in response to ozone‐induced injury and are sequentially activated towards an M1 pro‐inflammatory and an M2 anti‐inflammatory/repair phenotype. M1 macrophages contribute to toxicity by releasing proinflammatory cytokines and cytotoxic reactive oxygen and nitrogen intermediates. This promotes oxidative stress, lipid peroxidation, and lung injury. We hypothesized that valproic acid (VPA), a histone deacetylase (HDAC) inhibitor with anti‐inflammatory and antioxidant activity, would decrease ozone‐induced pulmonary toxicity. To test this hypothesis, female C57B16/J mice (18–22 g, 13–14 weeks) were exposed to air or ozone (0.8 ppm, 3 h) in a whole‐body plexiglass chamber. This was followed by i.p. injections of PBS vehicle control or VPA (300 mg/kg), 30 min and 24 h later. Animals were euthanized 48 h post‐exposure and bronchoalveolar lavage (BAL) and tissue collected. Exposure of mice to ozone increased BAL protein and IgM indicative of lung injury; BAL cells also increased after ozone exposure. While VPA reduced the effects of ozone on BAL cells, there was no effect on protein or IgM. We next analyzed the effects of VPA on the phenotype of myeloid cells responding to ozone using techniques in flow cytometry. Exposure of mice to ozone resulted in increases in CD11b+Ly6G‐monocytic and CD11b+Ly6G+ granulocytic cells in the lung. Whereas treatment of animals with VPA significantly blunted ozone‐induced increases in granulocytic cells, no major effects were observed on monocytic cells. Monocytic cells consisted of CD11b+Ly6G‐Ly6ChiF4/80+CD11c+ pro‐inflammatory and CD11b+Ly6G‐Ly6CloF4/80+CD11c+ anti‐inflammatory macrophages. VPA significantly reduced ozone‐induced increases in pro‐inflammatory macrophages with no major effect on anti‐inflammatory macrophages. Treatment of mice with VPA also reduced ozone‐induced increases in CD11b+Ly6G+Ly6C+F4/80+ monocytic myeloid‐derived suppressor cells (MDSC) and CD11b+Ly6G+Ly6C+F4/80‐granulocytic MDSC. Exposure of mice to ozone resulted in increased macrophage expression of ADP‐ribosylation factor‐like GTPase 11 (ARL11) and tumor necrosis factor α (TNFα), markers of M1 pro‐inflammatory macrophage activation; these were decreased by VPA. Macrophage expression of heme oxygenase‐1 (HO‐1), a marker of oxidative stress, and 4‐hydroxynonenal (4HNE), a lipid peroxidation end‐product, were also reduced in ozone‐exposed mice treated with VPA. These data suggest that VPA is effective in reducing ozone‐induced lung injury and oxidative stress. These findings may be useful in the development of therapeutics to treat oxidant induced lung injury.

Support or Funding Information

Supported by the American Physiological Society UGSRF Program and NIH Grants ES004738, AR055073, and ES005022.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.