Dissolution and reassembly of tubular myelin-like multilamellated structures from the lungs of patients with pulmonary alveolar proteinosis.

Tubular myelin-like multilamellated structures that accumulate in the alveoli of patients with pulmonary alveolar proteinosis are a characteristic manifestation of the disease. These multilamellated structures appear to be an abnormal form of tubular myelin consisting of phospholipid bilayers separated from each other by amorphous proteinaceous material. Treatment of tubular myelin-like multilamellated structures with 10% N-acetylcysteine in aqueous solution resulted in the dissolution and extraction of the intermembranous amorphous material. Extracts contained three major proteins with molecular weights of 36, 56, and 63 kd under reducing conditions; the 36 kd protein accounted for 76.6% of the total protein extracted. In the presence of N-acetylcysteine the 36 kd protein coexisted with a high molecular weight aggregate form (molecular weight greater than 4 X 10(6) daltons). Liposomes, prepared from lipids extracted from the insoluble phase of lavage effluents from the lungs of patients, were mixed with N-acetylcysteine-extracted proteins and then were dialyzed exhaustively against 0.9% NaCl at 37 degrees C. Examination of the precipitated material by electron microscopy revealed the presence of tubular myelin-like multilamellated structures ultrastructurally indistinguishable from those found in the alveoli of patients with pulmonary alveolar proteinosis. Tubular myelin-like multilamellated structures were also formed in large amounts when protein from the lungs of patients with pulmonary alveolar proteinosis was mixed with liposomes prepared from normal human lung surfactant. Tubular myelin-like multilamellated structures were formed with lipids from rabbit liver microsomes or brain homogenates to only a very small degree. Proteins extracted from pulmonary surfactant from the lungs of normal rabbits together with phospholipids extracted from the same source formed a few tubular myelin-like multilamellated structures in which square tubules were detected. These data demonstrate that specific proteins present in the insoluble accumulations from the lungs of patients with pulmonary alveolar proteinosis can spontaneously form tubular myelin-like multilamellated structures under in vitro conditions and in the presence of appropriate lipids.