Glutathione Metabolism in the Lung: Inhibition of its Synthesis Leads to Lamellar Body and Mitochondrial Defects

• Published in: Proceedings of the National Academy of Sciences - PNAS 1989-07, Vol.86 (14), p.5296-5300
• Main Authors: Mårtensson, Johannes, Jain, Ajey, Frayer, William, Meister, Alton
• Format: Article
• Language: English
• Subjects: Aminoacids, peptides. Hormones. Neuropeptides; Analytical, structural and metabolic biochemistry; Animals; Antimetabolites - pharmacology; Biological and medical sciences; Blood plasma; Buthionine Sulfoximine; Endothelial cells; Fundamental and applied biological sciences. Psychology; Glutathione - antagonists & inhibitors; Glutathione - metabolism; Heart ventricles; Kidneys; Kinetics; lamellae; Liver; Liver - drug effects; Liver - metabolism; Lung - drug effects; Lung - metabolism; Lung - ultrastructure; Lung morphology; Lungs; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Methionine Sulfoximine - analogs & derivatives; Methionine Sulfoximine - pharmacology; Mice; Microscopy, Electron; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Organoids - drug effects; Organoids - metabolism; Proteins; Swelling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.14.5296

Mice treated with buthionine sulfoximine, an inhibitor of glutathione synthesis, showed striking alterations of morphology of lung type 2 cell lamellar bodies (swelling and disintegration) and mitochondria (degeneration) and of lung capillary endothelial cells (mitochondrial swelling). These effects probably may be ascribed to glutathione deficiency; administration of glutathione monoester protects against them. Measurements of arteriovenous plasma glutathione levels across the lung indicate that the net uptake of glutathione by this organ is substantial. Thus, glutathione exported from the liver to the blood plasma is utilized by the lung which, like liver, kidney, and lymphocytes (and unlike skeletal muscle), exhibits a high overall rate of glutathione turnover. Intraperitoneal injection of glutathione into buthionine sulfoximine-treated mice leads to very high levels of plasma glutathione without significant increase in the glutathione levels of liver, lung, and lymphocytes; on the other hand, administration of glutathione monoester leads to markedly increased tissue and mitochondrial levels of glutathione. Administration of glutathione monoester (in contrast to glutathione) to control mice also increases mitochondrial glutathione levels. The findings indicate that glutathione is required for mitochondrial integrity and that it probably also functions in the processing and storage of surfactant in lamellar bodies. The morphological changes observed after treatment with buthionine sulfoximine and their prevention by glutathione monoester as well as findings on glutathione metabolism indicate that this tripeptide plays an important role in the lung. The previously observed failure of buthionine sulfoximine-treated mice to gain weight is mainly due to glutathione deficiency in the intestinal mucosa.