Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

Jon Cardinal, Pinhua Pan, Rajeev Dhupar, Mark Ross, Atsunori Nakao, Michael Lotze, Timothy Billiar, David Geller, Allan Tsung

Research output: Contribution to journalArticle

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Abstract

The nuclear protein high mobility group box 1 (HMGB1) is an important inflammatory mediator involved in the pathogenesis of liver ischemia/reperfusion (I/R) injury. Strategies aimed at preventing its release from stressed or damaged cells may be beneficial in preventing inflammation after I/R. Cisplatin is a member of the platinating chemotherapeutic agents and can induce DNA lesions that are capable of retaining high mobility group proteins inside the nucleus of cells. In vitro studies in primary cultured rat hepatocytes show that nontoxic concentrations of cisplatin can sequester HMGB1 inside the nucleus of hypoxic cells. Similarly, the in vivo administration of nontoxic doses of cisplatin prevents liver damage associated with a well-established murine model of hepatic I/R as measured by lower circulating serum aminotransferase levels, lower hepatic inflammatory cytokine levels including tumor necrosis factor α and interleukin-6, lower inducible NO synthase expression, and fewer I/R-associated histopathologic changes. The mechanism of action in vivo appears to involve the capacity of cisplatin to prevent the I/R-induced release of HMGB1 as well as to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation, respectively. Conclusion: Low, nontoxic doses of cisplatin can sequester HMGB1 inside the nucleus of redox-stressed hepatocytes in vitro and prevent its release in vivo in a murine model of hepatic I/R. Furthermore, cell survival and stress signaling pathways are altered by low-dose cisplatin. Therefore, platinating agents may provide a novel approach to mitigating the deleterious effects of I/R-mediated disease processes.

Original languageEnglish
Pages (from-to)565-574
Number of pages10
JournalHepatology
Volume50
Issue number2
DOIs
Publication statusPublished - 2009
Externally publishedYes

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Reperfusion Injury
Cisplatin
Reperfusion
Liver
Ischemia
Cell Nucleus
Hepatocytes
Cell Survival
High Mobility Group Proteins
Autophagy
Nuclear Proteins
Transaminases
Mitogen-Activated Protein Kinases
Nitric Oxide Synthase
Oxidation-Reduction
Interleukin-6
Tumor Necrosis Factor-alpha
Cytokines
Inflammation
DNA

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury. / Cardinal, Jon; Pan, Pinhua; Dhupar, Rajeev; Ross, Mark; Nakao, Atsunori; Lotze, Michael; Billiar, Timothy; Geller, David; Tsung, Allan.

In: Hepatology, Vol. 50, No. 2, 2009, p. 565-574.

Research output: Contribution to journalArticle

Cardinal, J, Pan, P, Dhupar, R, Ross, M, Nakao, A, Lotze, M, Billiar, T, Geller, D & Tsung, A 2009, 'Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury', Hepatology, vol. 50, no. 2, pp. 565-574. https://doi.org/10.1002/hep.23021
Cardinal, Jon ; Pan, Pinhua ; Dhupar, Rajeev ; Ross, Mark ; Nakao, Atsunori ; Lotze, Michael ; Billiar, Timothy ; Geller, David ; Tsung, Allan. / Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury. In: Hepatology. 2009 ; Vol. 50, No. 2. pp. 565-574.
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