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Suppression of PTRF Alleviates the Polymicrobial Sepsis Induced by Cecal Ligation and Puncture in Mice.
- Source :
-
Journal of Infectious Diseases . Dec2013, Vol. 208 Issue 11, p1803-1812. 10p. - Publication Year :
- 2013
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Abstract
- Background. Sepsis and sepsis-associated organ failure are devastating conditions. Understanding the detailed cellular/molecular mechanisms involved in sepsis should lead to the identification of novel therapeutic targets.Methods. Cecal ligation and puncture (CLP) was used as a polymicrobial sepsis model in vivo to determine mortality and end-organ damage. Macrophages were adopted as the cellular model in vitro for mechanistic studies.Results. PTRF+/− mice survived longer and suffered less organ damage after CLP. Reductions in nitric oxide (NO) and iNOS biosynthesis were observed in plasma, macrophages, and vital organs in the PTRF+/− mice. Using an acute sepsis model after CLP, we found that iNOS−/− mice had a comparable level of survival as the PTRF+/− mice. Similarly, polymerase I transcript release factor (PTRF) deficiency resulted in decreased iNOS and NO/ROS production in macrophages in vitro. Mechanistically, lipopolysaccharide (LPS) enhanced the co-localization and interaction between PTRF and TLR4 in lipid rafts. Deletion of PTRF blocked formation of the TLR4/Myd88 complex after LPS. Consistent with this, lack of PTRF impaired the TLR4 signaling, as shown by the decreased p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS transcription.Conclusion. PTRF is a crucial regulator of TLR4 signaling in the development of sepsis. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00221899
- Volume :
- 208
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Journal of Infectious Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 91828081
- Full Text :
- https://doi.org/10.1093/infdis/jit364