Serine proteinase requirement for the extra-cellular metabolism of pulmonary surfactant.
Pulmonary surfactant as lavaged from the alveoli exists in at least three structural subtypes, lamellar body-like, tubular myelin and vesicular forms that can be separated on the basis of their buoyant densities. Previous studies have suggested that surfactant is secreted in the lamellar body form and metabolized through the other subtypes in sequence. This metabolic sequence can be reproduced in vitro by cyclic expansion and contraction ('cycling') of the surface area of nascent surfactant at 38 degrees C. Cycling of nascent secretion, which is predominantly of lamellar body-like buoyant density, rapidly converted it to the buoyant density of tubular myelin and then to that of the vesicular subtype. We examined the role of proteinases in the conversion of nascent surfactant subtypes in vitro. Addition of metallo-, cysteine- and acid-proteinase inhibitors to the cycling mix did not inhibit the conversion of tubular myelin to vesicular subtype. However, a variety of serine proteinase inhibitors inhibited the formation of vesicular subtype. Their inhibitory effect was dose-related and most marked for alpha 1-antitrypsin where a concentration equal to that found in the alveolar fluid lining layer resulted in 50% inhibition of the generation of light subtype, suggesting physiological relevance. The enzyme(s) responsible for promoting the generation of light subtype was sedimentable and therefore presumably in particulate form. By differential centrifugation of lung secretions it was separable from alveolar macrophages and partially separable from surfactant itself. It has not been identified, nor has its substrate. We conclude that in vitro cycling provides a model for the study of alveolar surfactant metabolism and that the conversion of tubular myelin to vesicular forms of surfactant requires serine proteinase activity.
Gross
N J
NJ
Department of Medicine, Stritch School of Medicine, Loyola University, Chicago, IL.
Schultz
R M
RM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism*; D002499:Centrifugation, Density Gradient; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D051379:Mice; D008854:Microscopy, Electron; D011480:Protease Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000648:ultrastructure; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D011480:Protease Inhibitors; D011663:Pulmonary Surfactants; D000515:alpha 1-Antitrypsin; D012697:Serine Endopeptidases