title: Inhibition of the phospholipase A2 activity of peroxiredoxin 6 prevents lung damage with exposure to hyperoxia.
abstract: Lung injury associated with hyperoxia reflects in part the secondary effects of pulmonary inflammation and the associated production of reactive oxygen species due to activation of NADPH oxidase, type 2 (NOX2). Activation of NOX2 requires the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6). Therefore, we evaluated whether blocking Prdx6 PLA2 activity using the inhibitor MJ33 would be protective in a mouse model of acute lung injury resulting from hyperoxic exposure. Mice were treated with an intraperitoneal injection of MJ33 (2.5nmol/g body weight) at the start of exposure (zero time) and at 48h during continuous exposure to 100% O2 for 80h. Treatment with MJ33 reduced the number of neutrophils and the protein content in the fluid obtained by bronchoalveolar lavage, inhibited the increase in lipid peroxidation products in lung tissue, decreased the number of apoptotic cells in the lung, and decreased the perivascular edema associated with the 80h exposure to hyperoxia. Thus, blocking Prdx6 PLA2 activity by MJ33 significantly protected lungs against damage from hyperoxia, presumably by preventing the activation of NOX2 and the amplification of lung injury associated with inflammation. These findings demonstrate that MJ33, a potent inhibitor of Prdx6 PLA2 activity, can protect mouse lungs against the manifestations of acute lung injury due to oxidative stress.
authors: Institute for Environmental Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Bavneet
authors: B
authors: Benipal
authors: Institute for Environmental Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Sheldon I
authors: SI
authors: Feinstein
authors: Institute for Environmental Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Shampa
authors: S
authors: Chatterjee
authors: Institute for Environmental Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Chandra
authors: C
authors: Dodia
authors: Institute for Environmental Medicine and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: abf@mail.med.upenn.edu.
authors: Aron B
authors: AB
authors: Fisher
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005786:Gene Expression Regulation; D005994:Glycerophosphates / Q000494:pharmacology*; D018496:Hyperoxia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity; D054465:Peroxiredoxin VI / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D005994:Glycerophosphates; D008562:Membrane Glycoproteins; D064801:Phospholipase A2 Inhibitors; D017382:Reactive Oxygen Species; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D054467:Phospholipases A2; D010100:Oxygen
keywords: Acute lung injury; Inflammation; Lipid peroxidation; MJ33; Oxidative stress
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