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A feature of emphysema is the destruction of the walls of the airspaces in the bronchioles. Ceramide is a membrane sphingolipid that induces apoptosis. In lung samples from human emphysema, ceramide levels were much higher than in lungs from patients without emphysema. Emphysema can be induced in rats or mice with the vascular endothelial growth factor receptor antagonist SU5416, and this is associated with increased levels of ceramide. Fumonisin B1 is a specific inhibitor of dihydroceramide synthase. Fumonisin B1 inhibited the production of ceramide in response to SU5416, and reduced the SU5418-induced increase in alveolar diameter and number of severely damaged distal airspaces. A synthetic short-chain ceramide, C12 ceramide instilled into the trachea of mice increased lung ceramide levels, and induced alveolar cell apoptosis and septal destruction. These results suggest that ceramide is a target in emphysema, and ways of reducing the effects of ceramide in the lung need to be investigated.

Ceramide is a key bioactive mediator that inhibits surfactant phosphatidylcholine (PtdCho) synthesis in lung epithelia. Ceramide availability is governed by sphingomyelin (SM) hydrolysis, but less is known regarding its de novo synthesis. In this study, we observed that ceramide synthesis within murine lung epithelia was associated with high-level ceramide synthase (dihydroceramide synthase) activity. Longevity assurance homolog 5 (LASS5) was the predominant ceramide synthase isoform detected in lung epithelia, whereas relatively lower level expression was detected for the other five mammalian homologs. Pulmonary LASS5 was developmentally regulated, but its expression was spatially and gender nonspecific. Exogenously expressed LASS5 in lung epithelia was membrane-associated, triggering increased ceramide synthesis, whereas knockdown studies using fumonisin B1 or LASS5 small, interfering RNA reduced ceramide synthase activity by 78% or 45%, respectively. Overexpression of LASS5 also reduced PtdCho synthesis, but maximal inhibition was achieved when LASS5 was coexpressed with a plasmid encoding a neutral sphingomyelinase involved in SM hydrolysis. These results demonstrate that LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia.