An investigation of the relationship between the generation of free radicals (both oxygen-centered and carbon-centered) and lung tissue injury is proposed. These studies are based on the hypothesis that acute inflammation of the lung caused by several toxic agents and by exposure to elevated oxygen tensions is due to increased production of reactive oxygen-centered radicals, including superoxide (0.-2), the hydroxyl radical (HO.), as well as singlet oxygen (O2). The in vitro investigations include assay of the production of reactive oxygen species in a) lung mitochondria exposed to elevated O2 levels after inhibiting the intramitochondrial superoxide dismutase with nitro-prusside, and b) lung microsomes during electron transport associated with NADPH-dependent xenobiotic metabolism. These in vitro investigations are designed to provide information about the type of oxygen-derived radicals produced by lung subcellular organelles function under oxidative stress. Other in vitro investigation will be on perfused lung subjected to treatment with leukotrienes and platelet-activating factor. In vivo investigations will include measurement of radical formation in lung tissue in several animal models of acute lung inflammation. Rats subjected to one of the following conditions: elevated normobaric oxygen tensions, hyperbaric oxygen, ozone, or NO2: phorbal ester infusion in dogs or sheep; intratracheal HCl treatment in dogs; and endotoxin infusion in sheep. The method for assaying these highly reactive radical species involves spin-trapping combined with electron paramagnetic resonance (E.P.R.) spectroscopy. This procedure has been shown in this laboratory to be useful in demonstrating the formation and identification of both carbon - and oxygen-centered radicals in biological systems in vitro and also in vivo. Preliminary data is presented demonstrating that the generation of lipid radicals is readily detected by this technique in perfused guinea pig lungs treated with the leukotriene, LTD4 and in lungs of rats exposed to CCl4 vapors. In addition, lipid oxy radicals have also been trapped in lungs of dogs treated with phorbal esters. The proposed studies will permit not only the identification of the type of radicals formed in lungs, but also determination of the relationship between the intensity of radical formation and the lung pathophysiology associated with the conditions imposed.
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