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dc.rights.licenseCC-BY-NC-ND
dc.contributor.advisorBeekman, J.M.
dc.contributor.authorDekkers, J.F.
dc.date.accessioned2010-07-15T17:01:07Z
dc.date.available2010-07-15
dc.date.available2010-07-15T17:01:07Z
dc.date.issued2010
dc.identifier.urihttps://studenttheses.uu.nl/handle/20.500.12932/4722
dc.description.abstractCystic fibrosis is a complex disease characterized by the presence of thick pulmonary mucus and recurrent and eventually chronic lung infections. Many studies report that CFTR-deficient cells show enhanced proinflammatory signaling and proinflammatory cytokine secretion, even in the absence of any infection. CFTR deficiency not only affects anion transport, but also many intracellular mechanisms, such as apoptosis, calcium homeostasis, GSH transport, ROS production and lipid metabolism. Many studies found that these intrinsic cellular changes result in activation of inflammatory signaling routes leading to enhanced inflammation in CF cells compared to normal cells. The most important alterations in lipid metabolism that may contribute to the proinflammatory state in CF cells are a decreased function and expression of the nuclear receptor PPAR-γ and an altered sphingolipid metabolism, in particular altered ceramide levels (summarized in figure 6). The CFTR-dependent defect in PPAR-γ function may either result from decreased PPAR-γ ligands, including 15-keto-PGE2 and DHA, or from PPAR-γ sequestration by TG2. The decreased 15-keto-PGE2 level in CFTR-deficient cells likely results from decreased levels of HPGD, the enzyme that converts PGE2 to 15-keto-PGE2. However, the specific molecular mechanisms and signaling events that connect CFTR defects with decreased PPAR-γ function still need to be defined. Two in vivo studies address opposite conclusions about ceramide levels in murine CF cells. While Teichgraber and colleagues found excessive ceramide accumulation in respiratory tract epithelium of CFTR-deficient mice, Radzoich and associates note diminished ceramide levels in CF related organs of CF mice. Ceramide accumulation was attributed to a disturbed balance of pH-sensitive acid SMase and ceramidase present in lysosomes. However, as ceramide activates production of proinflammatory mediators, rather increased ceramide levels observed by Teichgraber and colleagues than decreased ceramide levels observed by Radzoich et al. correspond with enhanced inflammation observed in CF. Ceramide accumulation in CF cells could also explain enhanced production of arachidonic acid and PGE2 via induction of PLA2 and COX-2 (Fig. 6). Activation of PPAR-γ by PPAR-γ ligands resolve abnormal lung symptoms in a murine model. Besides, normalization of ceramide levels in mice by either treatment with acid SMase inhibitors or fenretinide has beneficial effects on CF pathogenesis. These findings indicate that drugs that normalize altered lipid metabolism are promising for treating the pathofysiological lung symptoms in CF patients.
dc.description.sponsorshipUtrecht University
dc.format.extent772255 bytes
dc.format.mimetypeapplication/msword
dc.language.isoen
dc.titleHow changes in lipid metabolism contribute to enhanced inflammation in cystic fibrosis.
dc.type.contentMaster Thesis
dc.rights.accessrightsOpen Access
dc.subject.keywordsCeramide,
dc.subject.courseuuInfection and Immunity


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