Linked Life Data

21263386

Source:http://linkedlifedata.com/resource/pubmed/id/21263386

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2011-4-26
pubmed:abstractText
In examining the liver's response to sepsis, our laboratory has found that septic hepatocytes exhibit a higher degree of necrosis when compared with septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, receptor interacting protein 1 (RIP1), has been shown to be critical for determining whether a cell's death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes' fate is apoptotic versus necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1-silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days after cecal ligation and puncture, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, necrostatin 1 (Nec1), and examined the mortality of Nec1-treated mice, there was no difference from the RIP1 siRNA-treated mice (20.0% vs. 22.2%, respectively). Furthermore, we carried out a series of comparative histological studies, which indicated that septic mice pretreated with Nec1 exhibited a preservation of liver glycogen stores (represented by periodic acid Schiff stain) versus siRNA-treated mice, which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed that Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual-signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating prosurvival signaling through nuclear factor ?B (NF-?B).
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1540-0514
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
499-505
pubmed:dateRevised
2011-10-27
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
The dual functions of receptor interacting protein 1 in fas-induced hepatocyte death during sepsis.
pubmed:affiliation
Division of Surgical Research/Department of Surgery, Rhode Island Hospital, Providence, Rhode Island, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural