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An isolated perfused lung in situpreparation was used to study the nature of rat lung metabolism. The mammalian lung was found to metabolize reduced substrates preferentially and these were taken up in a concentration-dependent manner. The rate of lactate production accounted for approximately 50% of glucose uptake, but was nevertheless relatively minor in terms of total energy output. At a circulating lactate level of 0.4mmol there was a net release of lactate into the perfusion medium; at 2mmol and above there was a progressive increase in lactate uptake. We also demonstrate for the first time that the lung is capable of utilizing 3-hydroxybutyrate in a concentration-dependent manner. In the absence of exogenous substrate, there is a sufficient supply of endogenous substrates to maintain the mammalian lung in a viable state for up to four hours. However, unlike most other tissues, the lung contains little glycogen and triglycerides and must therefore depend on an exogenous supply of substrates over longer periods. The reliance of normally perfused lung on anaerobic metabolism may confer its protection from naturally derived products of oxidative metabolism such as oxygen-derived free radicals.