Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.
Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action.
Kennedy
T P
TP
Division of Allergy, Critical Care and Respiratory Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Rao
N V
NV
Noah
W
W
Michael
J R
JR
Jafri
M H
MH
Gurtner
G H
GH
Hoidal
J R
JR
D000818:Animals; D002712:Chlorides; D005290:Ferric Compounds / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007052:Ibuprofen / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010477:Perfusion; D010705:Phosgene / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits
D002712:Chlorides; D005290:Ferric Compounds; D006878:Hydroxides; D007502:Iron Chelating Agents; D010705:Phosgene; D017665:Hydroxyl Radical; D011451:Prostaglandin-Endoperoxide Synthases; C024555:ferric chloride; D007052:Ibuprofen