Abstract
1-Hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33) is a fluorinated phospholipid analog that inhibits the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6). Prdx6 PLA2 activity is required for activation of NADPH oxidase 2 and subsequent generation of reactive oxygen species (ROS). In vitro, MJ33 inhibited agonist-stimulated production of ROS by the isolated perfused mouse lung, lung microvascular endothelial cells, and polymorphonuclear leukocytes. MJ33 (0.02–0.5 µmol MJ33/kg body weight) in mixed unilamellar liposomes was administered to C57BL/6 mice by either intratracheal (i.t.) or i.v. routes. Lung MJ33 content, measured by liquid chromatography/mass spectroscopy, showed uptake of 67–87% of the injected dose for i.t. and 23–42% for i.v. administration at 4 hours postinjection. PLA2 activity of lung homogenates was markedly inhibited (>85%) at 4 hours postadministration. Both MJ33 content and PLA2 activity gradually returned to near control levels over the subsequent 24–72 hours. Mice treated with MJ33 at 12.5–25 µmol/kg did not show changes (compared with control) in clinical symptomatology, body weight, hematocrit, and histology of lung, liver, and kidney during a 30- to 50-day observation period. Thus, the toxic dose of MJ33 was >25 µmol/kg, whereas the PLA2 inhibitory dose was approximately 0.02 µmol/kg, indicating a high margin of safety. MJ33 administered to mice prior to lung isolation markedly reduced ROS production and tissue lipid and protein oxidation during ischemia followed by reperfusion. Thus, MJ33 could be useful as a therapeutic agent to prevent ROS-mediated tissue injury associated with lung inflammation or in harvested lungs prior to transplantation.
Footnotes
- Received October 12, 2012.
- Accepted March 7, 2013.
This research was supported by the National Institutes of Health [Grants R01-HL105509 (to A.B.F.) and P30-ESO13508 (to I.A.B.)].
This research was presented in part at the following meetings: Lee I, Zagorski J, Dodia C, Feinstein S, Fisher AB (2012) Safety evaluation of MJ33 as a potential in vivo inhibitor of NADPH oxidase (NOX2) activation. Experimental Biology 2012; 2012 Apr 21-25; San Diego, CA; and Fisher AB, Lee I, Dodia C, Chatterjee S, Zagorski J, Mesaros C, Blair IA, and Feinstein SI (2012) A novel and non-toxic inhibitor of the activation of NADPH oxidase (NOX2). Society for Free Radicals in Biology and Medicine 19th Annual Meeting; 2012 Nov 14-18, 2012; San Diego, CA.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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