title: The compromise of macrophage functions by hyperoxia is attenuated by ethacrynic acid via inhibition of NF-κB-mediated release of high-mobility group box-1.
abstract: The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions. The present study investigates whether ethacrynic acid (EA) affects hyperoxia-induced HMGB1 release from macrophages and improves their functions. Macrophage-like RAW 264.7 cells and bone marrow-derived macrophages were exposed to different concentrations of EA for 24 hours in the presence of 95% O2. EA significantly decreased the accumulation of extracellular HMGB1 in cultured media. Importantly, the phagocytic activity and migration capability of macrophages were significantly enhanced in EA-treated cells. Interestingly, hyperoxia-induced NF-κB activation was also inhibited in these cells. To determine whether NF-κB plays a role in hyperoxia-induced HMGB1 release, BAY 11-7082, an inhibitor of NF-κB activation, was used. Similar to EA, BAY 11-7082 significantly inhibited the accumulation of extracellular HMGB1 and improved hyperoxia-compromised macrophage migration and phagocytic activity. Furthermore, 24-hour hyperoxic exposure of macrophages caused hyperacetylation of HMGB1 and its subsequent cytoplasmic translocation and release, which were inhibited by EA and BAY 11-7082. Together, these results suggest that EA enhances hyperoxia-compromised macrophage functions by inhibiting HMGB1 hyperacetylation and its release from macrophages, possibly through attenuation of the NF-κB activation. Therefore, the activation of NF-κB could be one of the underlying mechanisms that mediate hyperoxia-compromised macrophage functions.
authors.affiliation: 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York.
authors.forename: Mao
authors.initials: M
authors.lastname: Wang
authors.forename: Samir
authors.initials: S
authors.lastname: Gorasiya
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.forename: Ravikumar A
authors.initials: RA
authors.lastname: Sitapara
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.forename: Lokesh
authors.initials: L
authors.lastname: Sharma
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Divya
authors.initials: D
authors.lastname: Vasudevan
authors.forename: Michelle
authors.initials: M
authors.lastname: Zur
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004976:Ethacrynic Acid / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D004976:Ethacrynic Acid
keywords: NF-κB; high-mobility group box-1; hyperoxia; macrophage; phagocytosis