IMPAIRED HEPATOCELLULAR REGENERATION IN MURINE SEPSIS IS DEPENDENT ON REGULATORY PROTEIN LEVELS

被引:10
作者
Abcejo, Arnoley [1 ]
Andrejko, Kenneth M. [1 ]
Ochroch, E. Andrew [1 ]
Raj, Nichelle R. [1 ]
Deutschman, Clifford S. [1 ]
机构
[1] Univ Penn, Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA
来源
SHOCK | 2011年 / 36卷 / 05期
关键词
Retinoblastoma protein; E2F; PCNA; thymidine kinase; DNA polymerase alpha; dihydrofolate reductase; cyclin D1; cdk-4; NECROSIS-FACTOR RECEPTOR; DEFICIENT LIVER-REGENERATION; MICE LACKING TYPE-1; HEPATIC REGENERATION; CARBON-TETRACHLORIDE; ORGAN DYSFUNCTION; SIGNAL TRANSDUCER; GENE-EXPRESSION; APOPTOSIS; INJURY;
D O I
10.1097/SHK.0b013e31822d60ff
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Sepsis is a poorly understood syndrome. Therefore, we examined the mechanisms underlying failed regeneration in sham-operated (SO), mildly septic (cecal ligation and single puncture [CLP]), and severely septic (cecal ligation with two punctures [2CLP]) C57Bl6 mice. Relative to no operation (T0) or SO, CLP, but not 2CLP, increased the number of cells staining for proliferating cell nuclear antigen, a marker for cell division. Levels of the retinoblastoma protein (pRb) were detected at T0 and after SO. CLP increased pRb abundance, whereas 2CLP decreased it. Changes in phosphorylated pRb were similar but more profound. The abundance of the transcription factor E2F was unaltered by SO, CLP, or 2CLP. However, E2F DNA binding activity, although unchanged after SO, increased after CLP and decreased after 2CLP. The abundance of cyclin D1 in nuclear fractions increased following CLP but decreased after 2CLP. Neither SO nor 2CLP altered the abundance of the cyclin-dependent kinase (cdk) 4. However, cdk-4 abundance increased after CLP. Finally, CLP increased the steady-state abundance of the mRNAs encoding thymidine kinase, DNA polymerase alpha, and dihydrofolate reductase, all required for DNA replication. No changes were noted after 2CLP. We conclude that 2CLP impaired hepatocyte proliferation following 2CLP in part via impaired cyclin D1/cdk-4-induced phosphorylation of pRb, maintaining the association between pRb and E2F and inhibited E2F transcriptional activity.
引用
收藏
页码:471 / 477
页数:7
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