Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2004-0117OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 538-543 A more recent version of this article appeared on November 1, 2004
Submitted on April 8, 2004 Mechanistic similarities between cultured cell models of cystic fibrosis and Niemann-Pick type CNicole M White,
* To whom correspondence should be addressed. E-mail: tjk12{at}cwru.edu.
Recent data demonstrate that inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase restores normal signal transducer and activator of transcription-1 (STAT1) and inducible nitric oxide synthase expression (NOS2) regulation in CF cells through the modulation of RhoA function. These findings lead to the hypothesis that alterations in the cholesterol synthesis pathway may be an initiating factor in CF-related cell signaling regulation. A disease with a known lesion in the cholesterol synthesis pathway is Niemann-Pick type C (NPC). The hypothesis of this study is that CF cells and NPC fibroblasts share a common mechanistic lesion and should exhibit similar cell signaling alterations. NPC fibroblasts exhibit similar alterations in STAT1, RhoA, SMAD3, and NOS2 protein expression that characterize CF. Further comparison reveals NPC-like accumulation of free cholesterol in two cultured models of CF epithelial cells. These data identify novel signaling changes in NPC, demonstrate the cholesterol-synthesis pathway is a likely source of CF-related cell signaling changes, and that cultured CF cells exhibit impaired cholesterol processing.
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