THE ROLE OF ALPHA(1)-ANTITRYPSIN IN THE CONTROL OF EXTRACELLULAR SURFACTANT METABOLISM

Alveolar surfactant exists in several structural forms that are believ ed to be secular products of the secreted form, lamellar bodies. The c onversion of tubular myelin to the small vesicular form appears to req uire the action of a novel serine protease, surfactant convertase. As the in vitro activity of this enzyme is quite sensitive to inhibition by the serine protease inhibitor alpha(1)-antitrypsin, a normal consti tuent of the alveolar fluid lining layer, we explored the possibility that the alveolar level of alpha(1)-antitrypsin might affect the rate of subtype conversion in vivo. When the alveolar alpha(1)-antitrypsin level was augmented by tracheal instillation of exogenous alpha(1)-ant itrypsin, the newly synthesized surfactant phospholipids of spontaneou sly breathing mice accumulated in the heavy subtype, and virtually non e was found in the light subtype form up to 72 h later. An in vivo tur nover study suggested that when the alveolar alpha(1)-antitrypsin leve l was raised by the same means, the flux of surfactant through the lig ht (small vesicular) compartment was virtually shut off, despite the a vailability of abundant amounts of its precursor, heavy subtype (tubul ar myelin). Finally, mouse lungs that were lavaged to remove resident surfactant and mechanically ventilated for 1-5 h released surfactant t hat progressed through heavy and light subtype compartments as in vivo . But in mice whose lung alpha(1)-antitrypsin levels had been raised b y about 50% before ventilation, significantly less light subtype was g enerated. These results support the hypothesis that alpha(1)-antitryps in might affect the metabolism of alveolar surfactant in addition to i ts well-known role in lung defense.