Am. J. Respir. Cell Mol. Biol., Volume 22, Number 4, April, 2000 460-468

Ceramide Path in Human Lung Cell Death

Chris Chan and Tzipora Goldkorn

Signal Transduction, Department of Medicine, University of California Davis School of Medicine, Davis, California

Lung epithelium plays a significant role in modulating the inflammatory response to lung injury. Airway epithelial cells are targeted by hydrogen peroxide (H₂O₂) and oxygen radicals, which are agents commonly produced during inflammatory processes. The mechanisms and molecular sites affected by H₂O₂ are largely unknown but may involve the induction of sphingomyelin (SM) hydrolysis to generate ceramide, which serves as a second messenger in initiating an apoptotic response. Here we show that exposure of human airway epithelial (HAE) cells to 50 to 100 µM H₂O₂ induces within 5 to 10 min a greater than 2-fold activation of neutral sphingomyelinase activity with concomitant SM hydrolysis, ceramide generation, and apoptosis. On the other hand, activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate inhibits both H₂O₂-induced ceramide production and apoptosis. The apoptotic response could be restored by the addition of 25 µM cell-permeant C6-ceramide. These findings indicate that ceramide, the product of SM hydrolysis, plays an important role in H₂O₂-induced apoptosis in HAE cells, and that PKC counteracts ceramide-mediated apoptosis in these cells. We suggest that the mediation of epithelial cell apoptosis by ceramide and its inhibition by PKC constitute a central mechanism by which inflammatory processes are modulated in the epithelium of the lung.

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