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TIMP-3 ameliorates hepatic ischemia/reperfusion injury through inhibition of tumor necrosis factor-alpha-converting enzyme activity in rats.

AbstractBACKGROUND:
Tumor necrosis factor (TNF)-alpha and its receptors play a critical role in the inflammatory cascade after hepatic ischemia/reperfusion injury. TNF-alpha converting enzyme (TACE) or disintegrin and metalloproteinase (ADAM)-17 is a metalloproteinase disintegrin that specifically cleaves precursor TNF-alpha to its mature form and is involved in the ectodomain shedding of TNF receptors. The regulation of TACE is poorly understood and its role in liver injury and/or regeneration is unknown.
METHODS:
Male Wistar rats were subjected to 10 or 30 min of partial warm hepatic ischemia followed by 3 to 24 hr of reperfusion. Serum and/or hepatic TACE, TNF-alpha, TNF receptor 1 (TNFR1), and interleukin (IL)-6 levels were assessed by enzyme-linked immunosorbent assay, real-time reverse-transcriptase polymerase chain reaction, and/or Western blot.
RESULTS:
Low levels of TACE were detected in normal liver tissue. Both 10 and 30 min warm ischemia resulted in a rise in TACE expression which peaked six hr after reperfusion. TNF-alpha, TNFR1, and IL-6 levels were up-regulated in a pattern similar to TACE messenger RNA (mRNA) levels. Moreover, selective inhibition of TACE activity by specific inhibitor tissue inhibitor of metalloproteinase (TIMP)-3 at dosages of 100 or 1000 ng/kg body weight showed significant decrease of circulating TNF-alpha and serum alanine transferase (ALT) levels and histological improvement of hepatic ischemia/reperfusion injuries.
CONCLUSIONS:
TACE expression and its activity, as measured by increases in TNF-alpha, TNFR1, and IL-6 levels, are increased following hepatic ischemia/reperfusion injury, implying that TACE plays an important role in hepatic ischemia/reperfusion injury. Amelioration of hepatic ischemia/reperfusion injury after inhibition of TACE activity by TIMP-3 suggests that TACE inhibition may play an important role in preventing liver ischemia/reperfusion injury warranting further experimental and clinical study.
AuthorsZhen-Ya Tang, George Loss, Ian Carmody, Ari J Cohen
JournalTransplantation (Transplantation) Vol. 82 Issue 11 Pg. 1518-23 (Dec 15 2006) ISSN: 0041-1337 [Print] United States
PMID17164725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Interleukin-6
  • Receptors, Tumor Necrosis Factor, Type I
  • Tissue Inhibitor of Metalloproteinase-3
  • Tnfrsf1a protein, rat
  • Tumor Necrosis Factor-alpha
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, rat
Topics
  • ADAM Proteins (antagonists & inhibitors)
  • ADAM17 Protein
  • Animals
  • Humans
  • Interleukin-6 (analysis, metabolism)
  • Liver (drug effects, enzymology, pathology)
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor, Type I (analysis, metabolism)
  • Reperfusion Injury (enzymology, pathology, prevention & control)
  • Tissue Inhibitor of Metalloproteinase-3 (pharmacology, therapeutic use)
  • Tumor Necrosis Factor-alpha (analysis, metabolism)

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