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Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis.

Publication ,  Journal Article
Vilatoba, M; Eckstein, C; Bilbao, G; Smyth, CA; Jenkins, S; Thompson, JA; Eckhoff, DE; Contreras, JL
Published in: Surgery
August 2005

BACKGROUND: Evidence is emerging that the endoplasmic reticulum (ER) participates in initiation of apoptosis induced by the unfolded protein response and by aberrant Ca(++) signaling during cellular stress such as ischemia/reperfusion injury (I/R injury). ER-induced apoptosis involves the activation of caspase-12 and C/EBP homologous protein (CHOP), and the shutdown of translation initiated by phosphorylation of eIF2alpha. Sodium 4-phenylbutyrate (PBA) is a low molecular weight fatty acid that acts as a chemical chaperone reducing the load of mutant or unfolded proteins retained in the ER during cellular stress and also exerting anti-inflammatory activity. It has been used successfully for treatment of urea cycle disorders and sickle cell disease. Thus, we hypothesized that PBA may reduce ER-induced apoptosis triggered by I/R injury to the liver. METHODS: Groups of male C57BL/6 mice were subjected to warm ischemia (70% of the liver mass, 45 minutes). Serum aspartate aminotransferase was assessed 6 hours after reperfusion; apoptosis was evaluated by enzyme-linked immunosorbent assays of caspase-12 and plasma tumor necrosis factor alpha, Western blot analyses of eIF2alpha, and reverse transcriptase-polymerase chain reaction of CHOP expression. RESULTS: A dose-dependent decrease in aspartate aminotransferase was demonstrated in mice given intraperitoneal PBA (1 hour before and 12 hours after reperfusion), compared with vehicle-treated controls; this effect was associated with reduced pyknosis, parenchymal hemorrhages, and neutrophil infiltrates in PBA-treated mice, compared with controls. In a lethal model of total liver I/R injury, all vehicle-treated controls died within 3 days after reperfusion. In contrast, 50% survival (>30 days) was observed in animals given PBA. The beneficial effects of PBA were associated with a greater than 45% reduction in apoptosis, decreased ER-mediated apoptosis characterized by significant reduction in caspase-12 activation, and reduced levels of both phosphorylated eIF2alpha and CHOP. Significant reductions in plasma levels of tumor necrosis factor alpha and liver myeloperoxidase content were demonstrated after PBA treatment. CONCLUSIONS: Reduction in ER stress-induced hepatocellular injury was achieved by the administration of PBA. Targeting the ER-associated cell death pathway might offer a novel approach to reduce I/R injury to the liver.

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Published In

Surgery

DOI

ISSN

0039-6060

Publication Date

August 2005

Volume

138

Issue

2

Start / End Page

342 / 351

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transcription Factors
  • Transcription Factor CHOP
  • Surgery
  • Reperfusion Injury
  • Phenylbutyrates
  • Neutrophils
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Chicago
ICMJE
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Vilatoba, M., Eckstein, C., Bilbao, G., Smyth, C. A., Jenkins, S., Thompson, J. A., … Contreras, J. L. (2005). Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery, 138(2), 342–351. https://doi.org/10.1016/j.surg.2005.04.019
Vilatoba, Mario, Christopher Eckstein, Guadalupe Bilbao, Cheryl A. Smyth, Stacie Jenkins, J Anthony Thompson, Devin E. Eckhoff, and Juan L. Contreras. “Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis.Surgery 138, no. 2 (August 2005): 342–51. https://doi.org/10.1016/j.surg.2005.04.019.
Vilatoba M, Eckstein C, Bilbao G, Smyth CA, Jenkins S, Thompson JA, et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery. 2005 Aug;138(2):342–51.
Vilatoba, Mario, et al. “Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis.Surgery, vol. 138, no. 2, Aug. 2005, pp. 342–51. Pubmed, doi:10.1016/j.surg.2005.04.019.
Vilatoba M, Eckstein C, Bilbao G, Smyth CA, Jenkins S, Thompson JA, Eckhoff DE, Contreras JL. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery. 2005 Aug;138(2):342–351.
Journal cover image

Published In

Surgery

DOI

ISSN

0039-6060

Publication Date

August 2005

Volume

138

Issue

2

Start / End Page

342 / 351

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Transcription Factors
  • Transcription Factor CHOP
  • Surgery
  • Reperfusion Injury
  • Phenylbutyrates
  • Neutrophils
  • Mice, Inbred C57BL
  • Mice
  • Male