Showing papers by "Thomas P. Kennedy published in 1990"

Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

Abstract: 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.

Role of cytochrome P-450 in reperfusion injury of the rabbit lung.

Abstract: Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P-450 enzymes are an important pulmonary source of superoxide anion (O2-.) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical (.OH) formation and propagation of lipid peroxidation, we postulated that cytochrome P-450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P-450 enzymes in a rabbit model of reperfusion lung injury. The P-450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of 125I-albumin from the vascular space into lung water and alveolar fluid. P-450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P-450 inhibitors did not block enhanced O2-. generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P-450 enzymes are not likely a major source of enhanced O2-. generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P-450 in reperfusion injury to the lung and suggest potential new therapies for the disorder.

Sulfated polysaccharides prevent human leukocyte elastase-induced acute lung injury and emphysema in hamsters.

Abstract: Studies were designed to explore the possibility that sulfated polysaccharides had the potential to prevent human leukocyte elastase (HLE)-induced lung injury. Arteparon (GAGPS), heparin, heparan sulfate, chondroitin sulfate, and dextran sulfate, but not dextran, inhibited HLE-mediated hydrolysis of succinyl-ala2-val-pNA. GAGPS, used as a paradigmatic sulfated polysaccharide, was a potent inhibitor of elastolysis in vitro. GAGPS given intratracheally prevented acute injury and emphysema in hamsters when administered up to 8 h before HLE insufflation. The results suggest that sulfated polysaccharides may be potent inhibitors of HLE-mediated lung injury.

Hydroxyl radical generating activity of hydrous but not calcined kaolin is prevented by surface modification with dipalmitoyl lecithin.

Abstract: The catalytic activity of kaolin, an aluminum silicate, for generating hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) was studied in a chemical system that measured ·OH as evolution of methane (CH4) from dimethyl sulfoxide. In the presence of a reducing agent and 10 mM H2O2, hydrous and calcined kaolin generated mean ± SE CH4 concentrations of 1634 ± 328 and 1395 ± 29 ppm, respectively. Surface modification with dipalmitoyl lecithin, the lipid of pulmonary surfactant, blocked generation of ·OH in hydrous kaolin (38 ± 38 ppm CH4) but not in calcined kaolin (875 ± 262 ppm CH4. The catalytic activity of kaolin for producing ·OH from H2O2 may be important in the pathogenesis of kaolin toxicity, and calcined kaolin may be more toxic than kydrous kaolin because the calcined form is resistant to surface modification by lipids of pulmonary surfactant.

Kaolin Generates OH and Causes Hemolysis by Acting as a Fenton Reagent

Abstract: Kaolin is one of several clays commercially exploited for its content of the nonfibrous, hydrated aluminum silicate kaolinite (Al2O3.2SiO2.2H2O). Industrial uses include the manufacture of adhesives, paper products, refractory materials, ceramics, and fillers for plastics, rubber, and paints. Inhalation of kaolin dust has been well documented to cause pneumoconiosis (Oldham, 1983; Kennedy, 1983; Sepulveda, 1983). Human (Hale,1956) and animal (Policard, 1954) studies provide evidence that kaolin itself is responsible for the lung disease rather than free silica present in the dust.