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Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome

Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia; Institute for Environmental Medicine and Department of Physiology, and Pulmonary and Critical Care Division, Department of Medicine University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York

Correspondence and requests for reprints should be addressed to Susan Guttentag, M.D., Abramson Research Center 416G, Children's Hospital of Philadelphia, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318. E-mail: guttentag{at}email.chop.edu

Hermansky-Pudlak syndrome (HPS) in humans represents a family of disorders of lysosome-related organelle biogenesis associated with severe, progressive pulmonary disease. Human case reports and a mouse model of HPS, the pale ear/pearl mouse (ep/pe), exhibit giant lamellar bodies (GLB) in type II alveolar epithelial cells. We examined surfactant proteins and phospholipid from ep/pe mice to elucidate the process of GLB formation. The 2.8-fold enrichment of tissue phospholipids in ep/pe mice resulted from accumulation from birth through adulthood. Tissue surfactant protein (SP)-B and -C were increased in adult ep/pe mice compared with wild-type mice (WT), whereas SP-A and -D were not different. Large aggregate surfactant (LA) from adult ep/pe mice had decreased phospholipid, SP-B, and SP-C, with no differences in SP-A and -D compared with WT. Although LA from ep/pe animals exhibited an increased total protein–to–total phospholipid ratio compared with WT, surface tension was not compromised. Phospholipid secretion from isolated type II cells showed that basal and stimulated secretion from ep/pe cells were 50% of WT cells. Together, our data indicate that GLB formation is not associated with abnormal trafficking or recycling of surfactant material. Instead, impaired secretion is an important component of GLB formation in ep/pe mice.

Key Words: alveolar type II cell • Hermansky-Pudlak syndrome • lamellar body • secretion • surfactant

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