Title: Inhibition of the phospholipase A2 activity of peroxiredoxin 6 prevents lung damage with exposure to hyperoxia.
Authors: Benipal, Bavneet; Feinstein, Sheldon I; Chatterjee, Shampa; Dodia, Chandra; Fisher, Aron B
Published In Redox Biol, (2015)
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.
PubMed ID: 25637741
MeSH Terms: Acute Lung Injury/chemically induced; Acute Lung Injury/enzymology; Acute Lung Injury/genetics; Acute Lung Injury/prevention & control*; Animals; Apoptosis/drug effects; Bronchoalveolar Lavage Fluid/chemistry; Gene Expression Regulation; Glycerophosphates/pharmacology*; Hyperoxia/chemically induced; Hyperoxia/drug therapy*; Hyperoxia/enzymology; Hyperoxia/genetics; Injections, Intraperitoneal; Lipid Peroxidation/drug effects; Lung; Male; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred C57BL; NADPH Oxidase 2; NADPH Oxidases/genetics; NADPH Oxidases/metabolism; Neutrophils/drug effects; Neutrophils/enzymology; Neutrophils/pathology; Oxidative Stress; Oxygen/toxicity; Peroxiredoxin VI/antagonists & inhibitors; Peroxiredoxin VI/genetics*; Peroxiredoxin VI/metabolism; Phospholipase A2 Inhibitors/pharmacology*; Phospholipases A2/genetics*; Phospholipases A2/metabolism; Reactive Oxygen Species/antagonists & inhibitors; Reactive Oxygen Species/metabolism; Signal Transduction