Document Detail

Accelerated apoptosis contributes to aging-related hyperinflammation in endotoxemia.
MedLine Citation:
PMID:  20428798     Owner:  NLM     Status:  MEDLINE    
Sepsis is associated with an increase in circulating levels of bacterial endotoxin. Sepsis is a particularly serious problem in the geriatric population due to the associated high mortality rate. However, it remains unknown whether this phenomenon is related to an increase in apoptosis in splenic cells. To investigate this issue, male Fischer-344 rats (young, 3 months old; aged, 24 months old) were subjected to endotoxemia by injection of LPS. Splenic samples were collected 4 h thereafter. Apoptosis was determined by cleaved caspase-3 levels and TUNEL staining. The levels of proinflammatory mediators, TNF-alpha, IL-6 and high mobility group box-1 (HMGB-1), were also measured. Our results showed that, while splenic cell apoptosis increased in the young and aged rats with endotoxemia, the aged animals had much higher levels of apoptotic cell death. The elevated expression of cell cycle inhibitory protein P21 was also observed in the aged animals after treatment with LPS. Moreover, endotoxemia significantly increased TNF-alpha, IL-6 and HMGB-1. The accelerated apoptosis in the aged animals was correlated with significantly higher levels of TNF-alpha, IL-6 and HMGB-1. It is suggested that this accelerated rate of apoptosis contributes to age-related hyperinflammation in endotoxemia. To investigate the factors involving accelerated apoptosis in aged animals, we analyzed the Fas/Fas ligand (Fas-L) pathway. Our results showed that Fas and Fas-L gene expression was markedly higher in the spleen in the aged animals after LPS. Similarly, cleaved caspase-8 expression, a downstream element of Fas and Fas-L, was also significantly higher in the aged rats after LPS. Fas-L neutralizing antibodies markedly decreased apoptosis and proinflammatory cytokines in the aged animals after endotoxemia. Thus, there is substantial evidence that the Fas/Fas-L pathway may play an important role in LPS-induced accelerated apoptosis and hyperinflammation in aged animals.
Mian Zhou; Rongqian Wu; Weifeng Dong; Jennifer Leong; Ping Wang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  International journal of molecular medicine     Volume:  25     ISSN:  1791-244X     ISO Abbreviation:  Int. J. Mol. Med.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-04-29     Completed Date:  2010-07-15     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  9810955     Medline TA:  Int J Mol Med     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  929-35     Citation Subset:  IM    
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MeSH Terms
Aging / blood,  pathology*
Antibodies, Neutralizing
Antigens, CD95 / genetics,  metabolism
Caspase 3 / metabolism
Caspase 8 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Endotoxemia / blood,  complications*,  pathology
Fas Ligand Protein / genetics,  metabolism
Gene Expression Regulation
HMGB1 Protein / blood
In Situ Nick-End Labeling
Inflammation / blood,  complications*,  pathology
Interleukin-6 / metabolism
Rats, Inbred F344
Spleen / enzymology,  pathology
Tumor Necrosis Factor-alpha / metabolism
Grant Support
R01 GM057468/GM/NIGMS NIH HHS; R01 AG028352/AG/NIA NIH HHS; R01 AG028352/AG/NIA NIH HHS; R01 AG028352-04/AG/NIA NIH HHS; R01 AG028352-04S1/AG/NIA NIH HHS; R01 GM053008/GM/NIGMS NIH HHS; R01 GM053008/GM/NIGMS NIH HHS; R01 GM053008-15/GM/NIGMS NIH HHS; R01 GM057468/GM/NIGMS NIH HHS; R01 GM057468-13/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Antibodies, Neutralizing; 0/Antigens, CD95; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Fas Ligand Protein; 0/HMGB1 Protein; 0/Interleukin-6; 0/Tnfrsf6 protein, rat; 0/Tumor Necrosis Factor-alpha; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8

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