The alterations in lung glutamine (GLN) metabolism that occurs in the endotoxin-injured lung were studied in rats and subsequently correlated with flux changes that occur in patients with the adult respiratory distress syndrome (ARDS). Measurements in animals were made at various timepoints following the administration of endotoxin, while studies in surgical patients were done in a group of healthy controls, in patients with “early” sepsis who had normal chest x-ray films, and in patients with radiographic and physiologic evidence of ARDS. In healthy control rats, net amounts of GLN are released by the lungs into the systemic circulation. This release rate doubled 30 minutes after intravenous endotoxin (1,580 ± 320 nmol GLN/100 g BW/ min vs. 736 ± 179 in controls, p < 0.01) but glutamine synthetase activity was unchanged, suggesting an outpouring of cellular glutamine stores. Two hours after endotoxin treatment, this accelerated fractional release of glutamine by the lungs was no longer detected. By the 12-hour timepoint, the lungs reversed to an organ of net glutamine balance (234 ± 248 nmol/100 g BW/min, p < 0.05 vs. controls and ENDO30min) despite a more than two-fold increase in glutamine synthetase activity (p < 0.01). Simultaneously, lung weights were increased by 21% (p < 0.01) and histologic examination showed an interstitial infiltrate and pulmonary edema. Similar observations were made in humans; patients with “early” sepsis exhibited a marked increase in lung glutamine release, while patients with ARDS demonstrated glutamine balance across the lungs (4,030 ± 910 nmol GLN/kg BW/min vs. 637 ± 496 in ARDS, p < 0.05). These observations in rodents and patients suggest that the lungs release increased amounts of glutamine within minutes to hours after a septic insult; this could occur secondary to mobilization of a pre-existing pool or possibly from a “glutamine leak” out of damaged endothelium. This net release is shortlived and the apparent reversal to glutamine balance at a time when endogenous de novo glutamine biosynthesis is occurring may be caused by increased local consumption of glutamine by injured cells that require increased amounts of glutamine for repair. © 1991 by Williams & Wilkins.