Preconditioning with death ligands FasL and TNF-α protects the cirrhotic mouse liver against ischaemic injury

Jang, J.-H.; Moritz, W.; Graf, A.; Clavien, P.-A.
April 2008
Gut;Apr2008, Vol. 57 Issue 4, p492
Academic Journal
Background: lschaemic preconditioning is the pre-emptive proven strategy to reduce ischaemic injury in the liver, but it can be harmful in the elderly or in patients with liver diseases. lschaemic preconditioning induces a protective effect via activation of oxidative stress. We hypothesised that Fas ligand and tumour necrosis factor α can induce a similar response. Therefore, we tested if death ligands could mimic ischaemic preconditioning. Methods: lschaemia was maintained for 60 mm in cirrhotic mice. Death ligands were given 40 mm before ischaemia. lschaemic injury was assessed by histology and biochemical assays. To elucidate the mechanism, we used zinc protophorphyrin, an inhibitor of haem oxygenase-1 (HO-1), and gadolinium chloride, an inhibitor of Kupffer cells. Results: Compared with the control group, death ligand preconditioning strongly reduced all markers of injury: serum transaminase levels, necrosis and apoptosis. Preconditioning caused an upregulation of HO-1, predominantly in macrophages. When zinc protophorphyrin or gadolinium chloride was applied prior to preconditioning, the beneficial effect of preconditioning was lost. Conclusion: These results demonstrate that ischaemic preconditioning can be replaced by death ligand preconditioning in the cirrhotic liver to prevent ischaemic injury. The protective mechanism depends on HO-1 induction in macrophages. These results open doors for novel hepato-protective strategies in liver surgery and transplantation.


Related Articles

  • Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNFa gene. Smith, Robert M.; Suleman, Naushaad; McCarthy, Joy; Sack, Michael N. // Cardiovascular Research;Aug2002, Vol. 55 Issue 3, p553 

    Objective: Tumor necrosis factor alpha (TNFa) is known to mimic ischemic preconditioning (IP). However, it is not known whether TNFa-preconditioning is mediated by �established� preconditioning signaling or via novel signaling cascades. Moreover, whether TNFa is required to...

  • OX40:OX40L Axis: Emerging Targets for Immunotherapy of Human Disease. Salek-Ardakani, Shahram; Song, Aihua; Humphreys, Ian R.; Croft, Michael // Current Immunology Reviews;2006, Vol. 2 Issue 1, p37 

    Recent advances in our understanding of the mechanisms through which T cells are activated have led to new therapeutic approaches in the treatment of immunological disorders. An emerging target for selective immune intervention has been the manipulation of T cell costimulatory pathways....

  • Intratracheal instillation versus intratracheal inhalation:... Osier, M.; Baggs, R.B.; Oberdorster, G. // Environmental Health Perspectives Supplements;Sep97 Supplement 5, Vol. 105, p1265 

    Studies the roles that macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor alpha (TNF-alpha) may play in the observed differences in bronchoalveolar lavage (BAL) parameters. Methodology used; Analysis of the results; Conclusions.

  • Cunning factor: macrophage migration inhibitory factor as a redox-regulated target. Kudrin, Alex; Ray, David // Immunology & Cell Biology;Apr2008, Vol. 86 Issue 3, p232 

    Macrophage migration inhibitory factor (MIF) has an amazing history of rediscoveries and controversies surroundings its true biological function. It has been classified as a powerful cytokine capable of inducing tumour necrosis factor (TNF)-α, IL-1β, IL-6, IL-8, PGE2 along with its ability...

  • Burning up TNF toxicity for cancer therapy. Leist, Marcel; Jäättelä, Marja // Nature Medicine;Jul2002, Vol. 8 Issue 7, p667 

    Cites a study that shows that tumor necrosis factor (TNF) loses its toxicity but still kills tumors in heat treated mice. Association between the tumor killing capacity and the systemic toxicity of the cytokine TNF; Failure of heat treatment to protect against TNF induced lethality in mice.

  • Tumor Necrosis Factor (TNF). Vohr, Hans-Werner // Encyclopedic Reference of Immunotoxicology;2005, p674 

    The article presents an encyclopedia definition for tumor necrosis factor (TNF). The TNF-α and TNF-β lymphotoxin are types of TNF produced by macrophages and T lymphocytes. It was first described as cytotoxins for tumor cells. It is also known as cachectin.

  • Effect of soluble interleukin-6 receptor a and interleukin-6 secreted by polymorphonuclear leukocytes on tumor necrosis factor-a expression and its production by peripheral blood mononuclear cells. Jablonska, E. // Mediators of Inflammation;Oct2002, Vol. 11 Issue 5, p325 

    Background: It has recently been shown that soluble interleukin-6 receptor (sIL-6R) alone or complexed with interleukin (IL)-6, besides their regulatory role in a wide variety of both normal and abnormal biologic reactions mediated by IL-6, could be an effective stimulator of the cell function....

  • Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Schofield, Louis; Hewitt, Michael C.; Evans, Krystal; Siomos, Mary-Anne; Seeberger, Peter H. // Nature;8/15/2002, Vol. 418 Issue 6899, p785 

    Examines whether anti-glycosylphosphatidylinositol (GPI) vaccination could prevent pathology and fatalities in the Plasmodium berghei/rodent model of severe malaria. Use of tumor-necrosis factor-alpha production of macrophages as a biochemical marker of malarial endotoxin activity in vitro;...

  • Macrophages: Interferons promote artery lesions. Bird, Lucy // Nature Reviews Immunology;Sep2010, Vol. 10 Issue 9, p616 

    The article reports on the study conducted by P. Goossens and colleagues which shows that myeloid type I interferons promote atherosclerosis by enhancing the recruitment of macrophages to lesions. The researchers found that the in vitro incubation of bone marrow derived macrophages with...


Read the Article


Sign out of this library

Other Topics