title: Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury.
abstract: Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA ; The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA ; Department of Natural Science, LaGuardia Community College City University of New York, Queens, NY 11101, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Entezari
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA ; The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA ; Department of Natural Science, LaGuardia Community College City University of New York, Queens, NY 11101, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Javdan
authors.affiliation: Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA ; The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
authors.forename: Dympna M P
authors.initials: DM
authors.lastname: Morrow
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Ravikumar A
authors.initials: RA
authors.lastname: Sitapara
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Gorasiya
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Zur
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thomas
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, St. John׳s University, College of Pharmacy and Health Sciences, Queens, NY 11439, USA ; The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
authors.forename: Lin L
authors.initials: LL
authors.lastname: Mantell
mesh_terms: D000107:Acetylation; D055371:Acute Lung Injury / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007278:Injections, Spinal; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D011773:Pyruvates / Q000008:administration & dosage*
chemical_list: D000906:Antibodies; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D011773:Pyruvates; C046522:ethyl pyruvate
keywords: ALI, acute lung injury; BALF, bronchoalveolar lavage fluids; EP, ethyl pyruvate; GST, gluthatione-s-transferase; HMGB1; HMGB1, high mobility group box protein 1; Hyperacetylation; Hyperoxia; MV, mechanical ventilation; Macrophage; NLS, nuclear localization signal; PMNs, polymorphonuclear neutrophils; RA, room air; ROS, reactive oxygen species; Redox state; rHMGB1, recombinant HMGB1