RGD Reference Report - A critical role for Fas/CD-95 dependent signaling pathways in the pathogenesis of hyperoxia-induced brain injury. - Rat Genome Database

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A critical role for Fas/CD-95 dependent signaling pathways in the pathogenesis of hyperoxia-induced brain injury.

Authors: Dzietko, M  Boos, V  Sifringer, M  Polley, O  Gerstner, B  Genz, K  Endesfelder, S  Borner, C  Jacotot, E  Chauvier, D  Obladen, M  Buhrer, C  Felderhoff-Mueser, U 
Citation: Dzietko M, etal., Ann Neurol. 2008 Dec;64(6):664-73. doi: 10.1002/ana.21516.
RGD ID: 8662854
Pubmed: PMID:19107989   (View Abstract at PubMed)
DOI: DOI:10.1002/ana.21516   (Journal Full-text)

OBJECTIVE: Prematurely born infants are at risk for development of neurocognitive impairment in later life. Oxygen treatment has been recently identified as a trigger of neuronal and oligodendrocyte apoptosis in the developing rodent brain. We investigated the role of the Fas death receptor pathway in oxygen-triggered developmental brain injury. METHODS: Six-day-old Wistar rats were exposed to 80% oxygen for various periods (2, 6, 12, 24, 48, and 72 hours), and mice deficient in either Fas (B6.MRL-Tnfrsf6(lpr)) or Fas ligand (B6Smn.C3-Fasl(gld)) and control mice (C57BL/6J) were exposed to 80% oxygen for 24 hours. Polymerase chain reaction, Western blotting, and caspase activity assays of thalamus and cortex tissue were performed. RESULTS: Fas and Fas ligand messenger RNA and protein were upregulated. Furthermore, hyperoxia resulted in induction of downstream signaling events of Fas, such as Fas-associated death domain (FADD), the long and short form of FADD-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP-L, FLIP-S), and cleavage of caspase-8 and caspase-3. Injection of a selective caspase-8 inhibitor (TRP801, 1mg/kg) at the beginning of hyperoxia blocked subsequent caspase-3 cleavage in this model. B6.MRL-Tnfrsf6(lpr) mice were protected against oxygen-mediated injury, confirming Fas involvement in hyperoxia-induced cell death. Mice deficient in Fas ligand did not differ from control animals in the amount of cell death. INTERPRETATION: We conclude that neonatal hyperoxia triggers Fas receptor and its downstream signaling events in a Fas ligand-independent fashion. Lack of functional Fas receptors and selective pharmacological inhibition of caspase-8 prevents activation of caspase-3 and provides significant neuroprotection.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Brain Injuries  ISOFas (Mus musculus)8662854; 8662854associated with HyperoxiaRGD 
Brain Injuries  IMP 8662854associated with HyperoxiaRGD 
Hyperoxia  ISOCflar (Rattus norvegicus)8662854; 8662854protein:increased expression:cerebral cortex (rat)RGD 
Hyperoxia  IEP 8662854protein:increased expression:cerebral cortex (rat)RGD 
Hyperoxia  ISOFadd (Rattus norvegicus)8662854; 8662854protein:increased expression:thalamusRGD 
Hyperoxia  ISOFas (Rattus norvegicus)8662854; 8662854mRNA:increased expression:thalamus and cerebral cortex (rat)RGD 
Hyperoxia susceptibilityISOFas (Mus musculus)8662854; 8662854 RGD 
Hyperoxia  IDA 8662854protein:increased expression:thalamusRGD 
Hyperoxia  IEP 8662854mRNA:increased expression:thalamus and cerebral cortex (rat)RGD 
Hyperoxia susceptibilityIMP 8662854 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

Objects Annotated

Genes (Rattus norvegicus)
Cflar  (CASP8 and FADD-like apoptosis regulator)
Fadd  (Fas associated via death domain)
Fas  (Fas cell surface death receptor)

Genes (Mus musculus)
Cflar  (CASP8 and FADD-like apoptosis regulator)
Fadd  (Fas associated via death domain)
Fas  (Fas cell surface death receptor)

Genes (Homo sapiens)
CFLAR  (CASP8 and FADD like apoptosis regulator)
FADD  (Fas associated via death domain)
FAS  (Fas cell surface death receptor)


Additional Information