The role of ceramides in cigarette smoke-induced alveolar cell death

dc.contributor.advisorPetrache, Irina
dc.contributor.authorKamocki, Krzysztof
dc.contributor.otherGunst, Susan J.
dc.contributor.otherQuilliam, Laurence
dc.contributor.otherAtkinson, Simon
dc.date.accessioned2013-05-20T15:09:06Z
dc.date.available2013-05-20T15:09:06Z
dc.date.issued2012-11
dc.degree.date2012en_US
dc.degree.disciplineDepartment of Biochemistry & Molecular Biologyen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractThe complex pathogenesis of emphysema involves disappearance of alveolar structures, in part attributed to alveolar cell apoptosis. The mechanism by which cigarette smoke (CS) induces alveolar cell apoptosis is not known. We hypothesized that ceramides are induced by CS via specific enzymatic pathways that can be manipulated to reduce lung cell apoptosis. CS increased ceramides in the whole lung and in cultured primary structural lung cells. Exposure to CS activated within minutes the acid sphingomyelinase, and within weeks the de novo- ceramide synthesis pathways. Pharmacological inhibition of acid sphingomyelinase significantly attenuated CS-induced apoptosis. To understand the mechanisms by which ceramides induce apoptosis, we investigated the cell types affected and the involvement of RTP801, a CS-induced pro-apoptotic and pro-inflammatory protein. Direct lung augmentation of ceramide caused apoptosis of both endothelial and epithelial type II cells. Ceramide upregulated RTP801 and the transgenic loss of RTP801 inhibited only epithelial, but not endothelial cell apoptosis induced by ceramide. In conclusion, CS induces acid sphingomyelinase-mediated ceramide upregulation and apoptosis in a cell-specific manner, which in epithelial cells involves induction of stress response proteins that may further amplify lung injury. Molecular targeting of amplification pathways may provide therapeutic opportunities to halt emphysema progression.en_US
dc.identifier.urihttps://hdl.handle.net/1805/3311
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1845
dc.language.isoen_USen_US
dc.subject.lcshCigarette smokeen_US
dc.subject.lcshEmphysema, Pulmonaryen_US
dc.subject.lcshApoptosisen_US
dc.subject.lcshTobacco -- Physiological effecten_US
dc.subject.lcshCeramidesen_US
dc.subject.lcshLungsen_US
dc.titleThe role of ceramides in cigarette smoke-induced alveolar cell deathen_US
dc.typeThesisen
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
KKamocki final PhD thesis.pdf
Size:
1.42 MB
Format:
Adobe Portable Document Format
Description:
KKamocki final PhD thesis
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.88 KB
Format:
Item-specific license agreed upon to submission
Description: