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Progressive Lung Disease and Surfactant Dysfunction with a Deletion in Surfactant Protein C Gene

2003; American Thoracic Society; Volume: 30; Issue: 6 Linguagem: Inglês

10.1165/rcmb.2003-0323oc

1535-4989

Aaron Hamvas, Lawrence M. Nogee, Frances V. White, Pamela M. Schuler, Brian P. Hackett, Charles B. Huddleston, Eric N. Mendeloff, Fong‐Fu Hsu, Susan E. Wert, Linda W. Gonzales, Michael F. Beers, Philip L. Ballard,

Congenital Diaphragmatic Hernia Studies

Mutations in the surfactant protein (SP)-C gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluorescence, proSP-C was aggregated within alveolar Type II cells in a compartment separate from SP-B. In airway surfactant, there was little or no mature SP-B or SP-C; SP-A content was increased. Minimum surface tension was increased (20 mN/m, normal < 5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy. This spontaneous deletion on one allele of the SP-C gene was associated with sporadic ILD and abnormalities in surfactant composition and function. We propose that a dominant negative effect on surfactant protein metabolism and function results from aggregation of misfolded proSP-C and subsequent cell injury and inflammation.