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Therapeutic efficacy of MJ33, a novel inhibitor of phospholipase A 2 (PLA 2 ) of peroxiredoxin 6 (Prdx6), in LPS‐induced acute lung injury (ALI)
Author(s) -
Lee Intae,
Dodia Chandra,
Chatterjee Shampa,
Feinstein Sheldon I,
Fisher Aron B
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1107.11
Subject(s) - pharmacology , lung , chemistry , tbars , vascular permeability , inflammation , lipid peroxidation , phospholipase a2 , oxidative stress , immunology , medicine , biochemistry , endocrinology , enzyme
We have shown that peroxiredoxin 6 (Prdx6) on PLA 2 activity is required for activation of NOX2 and subsequent generation of ROS in normal cells and have proposed a role for it in LPS‐induced acute lung injury (ALI). We evaluated MJ33, a novel inhibitor of PLA 2 activity of Prdx6, for its therapeutic efficacy in ALI. Our recent studies of MJ33 displayed its avid lung uptake (67–86%), >;85% inhibition of phospholipase A 2 (PLA 2 ) activity, and high margin of safety in the intact mouse [toxic dose= >;25μmol/kg; PLA 2 inhibitory dose= ~0.02μmol/kg]. ROS generation by endothelial cells in vitro was increased 16–24h post LPS treatment. This increase was significantly reduced by MJ33. LPS (0111:B4 from E. coli, 1–5mg/kg) was administered intratracheally. 4nmol MJ33 in unilamellar liposomes was administered intratracheally or intravenously either concurrently or 2 h post LPS. LPS significantly increased lung infiltration with increasing in inflammatory cells, lung permeability [protein levels, lung wet to dry ratio, leakage of FITC‐dextran into the lung lavage fluid], lipid peroxidation [TBARS and 8‐isoprostanes], and protein oxidation [protein carbonylation]. MJ33 dramatically reduced all of these measured parameters. These findings show that MJ33 can suppress the manifestation of oxidant stress associated with lung inflammation and the activation of NOX2. Supported by NHLBI‐R01‐HL105509.