Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice

Contreras, Juan L.; Vilatobá, Mario; Eckstein, Christopher; Bilbao, Guadalupe; Thompson, John A.; Eckhoff, Devin E.

doi:10.1016/j.surg.2004.05.015

Cited by 106 publications

(94 citation statements)

References 26 publications

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“…The potential utility of siRNA sequences as therapeutic agents has been previously described in the literature (11,21,25). The liver, in particular, seems an ideal target organ for RNA interference, due in part to its reticuloendothelial function and relative ease of transfection.…”

Section: Discussionmentioning

confidence: 97%

Interleukin-1β is the primary initiator of pulmonary inflammation following liver injury in mice

Glasgow

Ramachandran

Blackwell

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hepatic injury can lead to systemic and pulmonary inflammation through activation of NF-κB-dependent pathways and production of various proinflammatory cytokines. The exact mechanism remains unknown, although prior research suggests interleukin-1β (IL-1β) plays an integral role. Cultured murine alveolar macrophages were used to identify an optimized IL-1β-specific short interfering RNA (siRNA) sequence, which then was encapsulated in liposomes and administered intraperitoneally to transgenic HLL mice (5′-HIV-LTR-Luciferase). A 35% hepatic mass cryoablation in HLL and IL-1 receptor 1 knockout mice (IL1R1KO) was performed as a model for liver-induced pulmonary inflammation. IL-1β siRNA pretreatment effectively and significantly reduced circulating IL-1β levels at 4 h post-hepatic injury. IL-6 also was suppressed in mice with impaired IL-1 signaling pathways. NF-κB activation in the noninjured liver of HLL reporter mice pretreated with IL-1β siRNA was found to be reduced compared with controls. Pulmonary NF-κB activity in this group also was diminished relative to controls. C-X-C chemokine levels in the lung remained significantly lower in IL-1 pathway-deficient mice. Similarly, lung myeloperoxidase content was unchanged from baseline at 24 h post-liver injury in IL-1β siRNA-treated animals, whereas all other control groups demonstrated marked pulmonary neutrophilic infiltration. In conclusion, liver injury-induced lung inflammation in this model is mediated predominantly by IL-1β. Knockdown of IL-1β expression before hepatic injury led to significant reductions in both cytokine production and NF-κB activation. This translated to reduced pulmonary neutrophil accumulation. Pretreatment with IL-1β siRNA may represent a novel intervention for preventing liver-mediated pulmonary inflammation.

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Section: Discussionmentioning

confidence: 97%

Interleukin-1β is the primary initiator of pulmonary inflammation following liver injury in mice

Glasgow

Ramachandran

Blackwell

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…For example, systemic application of caspase-8 siRNA inhibits caspase-8 expression in mouse liver and is capable of preventing Fas (CD95)-mediated apoptosis of hepatocytes (24). Intraportal administration of siRNA caspase-8 and caspase-3 inhibits the expression of caspase-8 and caspase-3 and attenuates warm IRI to the liver (25). siRNA targeting Fas has been shown to protect mice against renal IRI (26).…”

Section: Introductionmentioning

confidence: 99%

Preventing Renal IschemiaReperfusion Injury Using Small Interfering RNA by Targeting Complement 3 Gene

Zheng

Feng

Chen

et al. 2006

American Journal of Transplantation

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The complement system is one of the important mediators of renal ischemia-reperfusion injury (IRI). We hypothesized that efficient silencing of C3, which is the central component on which all complement activation pathways converge, could be achieved using small interfering RNA (siRNA), and that this would result in overall inhibition of complement activation, thereby preventing IRI in kidneys. A series of experiments was conducted, using a mouse model of IRI and vector-delivered C3-specific siRNA. We demonstrated the following: (1) renal expression of C3 increases as a result of IRI; (2) by incorporation into a pRNAT U6.1 vector, siRNA can be delivered to renal cells in vivo; (3) systemically delivered siRNA is effective in reducing the expression of C3 in an experimentally induced mouse kidney model of IRI; (4) similarly, siRNA reduces complement-mediated IRI-related effects, both in terms of renal injury (as evidenced by renal function and histopathology examination) and mouse mortality and (5) silencing the production of C3 diminishes in vivo production of TNF-a . This study implies that siRNA represents a novel approach to preventing IRI in kidneys and might be used in a variety of clinical settings, including transplantation and acute tubular necrosis.

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“…These findings can be translated into therapeutic use for liver protection in many conditions, such as liver transplantation, partial hepatectomy, shock, sepsis and acute liver failure of other etiologies. Hence, neutralization of CD95L may serve as a new targeted therapy to attenuate liver ischemia reperfusion injury [53][54][55][56][57][58][59] . Fig.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

et al. 2018

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Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. Death receptors are important mediators of ischemiareperfusion injury, notably the signaling pathways of the death receptor CD95 (Apo-1/Fas) and its corresponding ligand CD95L. This study investigates, for the first time, whether the inhibition of CD95L protects the liver against ischemia-reperfusion injury. Warm ischemia was induced in the median and left liver lobes of C57BL/6 mice for 45 min. CD95Fc, a specific inhibitor of CD95L, was applied prior to ischemia. Hepatic injury was assessed via consecutive measurements of liver serum enzymes, histopathological assessment of apoptosis and necrosis and caspase assays at 3, 6, 12, 18 and 24 h after reperfusion. Serum levels of liver enzymes, as well as characteristic histopathological changes and caspase assays indicated pronounced features of apoptotic and necrotic liver damage 12 and 24 h after ischemiareperfusion injury. Animals treated with the CD95L-blocker CD95Fc, exhibited a significant reduction in the level of serum liver enzymes and showed both decreased histopathological signs of parenchymal damage and decreased caspase activation. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. CD95Fc could therefore emerge as a new pharmacological therapy for liver resection, transplantation surgery and acute liver failure.

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Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice

Cited by 106 publications

References 26 publications

Interleukin-1β is the primary initiator of pulmonary inflammation following liver injury in mice

Interleukin-1β is the primary initiator of pulmonary inflammation following liver injury in mice

Preventing Renal IschemiaReperfusion Injury Using Small Interfering RNA by Targeting Complement 3 Gene

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

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