Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2).
The phospholipase A2 activity of peroxiredoxin 6 is inhibited by the transition state analog, 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33). This activity is required for the activation of NADPH oxidase, type 2. The present study evaluated the effect of MJ33 on manifestations of acute lung injury. Mice were injected intratracheally (IT) with LPS from Escherichia coli 0111:B4 (LPS, 1 or 5 mg/kg), either concurrently with LPS or 2 h later, and evaluated for lung injury 24 h later. MJ33 inhibited reactive oxygen species (ROS) generation by lungs when measured at 24 h after LPS. LPS at either a low or high dose significantly increased lung infiltration with inflammatory cells, secretion of proinflammatory cytokines (IL-6, TNF-α, and the chemokine macrophage inflammatory protein-2), expression of lung vascular cell adhesion molecule, lung permeability (protein in bronchoalveolar lavage fluid, leakage of FITC-dextran, lung wet-to-dry weight ratio), tissue lipid peroxidation (thiobarbituric acid reactive substances, 8-isoprostanes), tissue protein oxidation (protein carbonyls), and activation of NF-κB. MJ33, given either concurrently or 2 h subsequent to LPS, significantly reduced all of these measured parameters. Previous studies of toxicity showed a high margin of safety for MJ33 in the intact mouse. Thus we have identified MJ33 as a potent, nontoxic, and specific mechanism-based inhibitor of NADPH oxidase type 2-mediated ROS generation that protects mice against lung injury associated with inflammation.
Institute for Environmental Medicine, Univ. of Pennsylvania, 3620 Hamilton Walk, 1 John Morgan Bldg., Philadelphia, PA 19104. abf@mail.med.upenn.edu.
Intae
I
Lee
Chandra
C
Dodia
Shampa
S
Chatterjee
Sheldon I
SI
Feinstein
Aron B
AB
Fisher
D055371:Acute Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005994:Glycerophosphates / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000096:biosynthesis; D054465:Peroxiredoxin VI / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D018925:Chemokines; D016207:Cytokines; D005994:Glycerophosphates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D054465:Peroxiredoxin VI; D019255:NADPH Oxidases
lipid peroxidation; lung permeability; phospholipase A2; protein oxidation; reactive oxygen species; transition state inhibitor