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

Tang, Zhen-Ya, Loss, George, Carmody, Ian and Cohen, Ari J. (2006) TIMP-3 ameliorates hepatic ischemia/reperfusion injury through inhibition of tumor necrosis factor-alpha-converting enzyme activity in rats. Transplantation, 82 11: 1518-1523. doi:10.1097/01.tp.0000243381.41777.c7


Author Tang, Zhen-Ya
Loss, George
Carmody, Ian
Cohen, Ari J.
Title TIMP-3 ameliorates hepatic ischemia/reperfusion injury through inhibition of tumor necrosis factor-alpha-converting enzyme activity in rats
Journal name Transplantation   Check publisher's open access policy
ISSN 0041-1337
1534-6080
Publication date 2006-12-15
Sub-type Article (original research)
DOI 10.1097/01.tp.0000243381.41777.c7
Volume 82
Issue 11
Start page 1518
End page 1523
Total pages 6
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
BACKGROUND. Tumor necrosis factor (TNF)-α and its receptors play a critical role in the inflammatory cascade after hepatic ischemia/reperfusion injury. TNF-α converting enzyme (TACE) or disintegrin and metalloproteinase (ADAM)-17 is a metalloproteinase disintegrin that specifically cleaves precursor TNF-α 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-α, 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-α, 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-α 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-α, 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.
Keyword TACE
TNF-alpha
TIMP-3
Liver
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Mon, 14 Mar 2011, 08:52:03 EST