Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury

Lentsch, Alex B.; Kato, Atsushi; Yoshidome, Hiroyuki; McMasters, Kelly M.; Edwards, Michael J.

doi:10.1053/jhep.2000.9323

Cited by 419 publications

(316 citation statements)

References 52 publications

Supporting

Mentioning

295

Contrasting

Unclassified

Order By: Relevance

“…1,4,23 Neutrophils, however, are generally considered the effector cells causing the direct hepatocellular damage. 24,25 Recently, T cells, particularly of the CD4 phenotype, have been revealed as the key players regulating KC and neutrophil function.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] The mechanisms underlying liver IRI are complex but are known to involve interactions between both nonparenchyma cells, such as Kupffer cells (KC), and parenchyma cells, such as hepatocytes. Local leukocyte sequestration and activation (neutrophils, macrophages, and T cells) leads to the formation of reactive oxygen species, secretion of pro-inflammatory cytokines/chemokines, complement activation, and vascular cell adhesion molecule activation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

et al. 2008

View full text Add to dashboard Cite

We have documented the key role of toll-like receptor 4 (TLR4) activation and its signaling pathway mediated by interferon (IFN) regulatory factor 3, in the induction of inflammation leading to the hepatocellular damage during liver ischemia/reperfusion injury (IRI). Because type I IFN is the major downstream activation product of that pathway, we studied its role in comparison with IFN-␥. Groups of type I (IFNAR), type II (IFNGR) IFN receptordeficient mice, along with wild-type (WT) controls were subjected to partial liver warm ischemia (90 minutes) followed by reperfusion (1-6 hours). Interestingly, IFNAR knockout (KO) but not IFNGR KO mice were protected from IR-induced liver damage, as evidenced by decreased serum alanine aminotransferase and preservation of tissue architecture. IRtriggered intrahepatic pro-inflammatory response, assessed by tumor necrosis factor (TNF-␣), interleukin 6 (IL-6), and chemokine (C-X-C motif) ligand 10 (CXCL-10) expression, was diminished selectively in IFNAR KO mice. Consistent with these findings, our in vitro cell culture studies have shown that: (1) although hepatocytes alone failed to respond to lipopolysaccharide (LPS), when co-cultured with macrophages they did respond to LPS via macrophage-derived IFN-␤; (2) macrophages required type I IFN to sustain CXCL10 production in response to LPS. This study documents that type I, but not type II, IFN pathway is required for IR-triggered liver inflammation/damage. Type I IFN mediates potential synergy between nonparenchyma and parenchyma cells in response to TLR4 activation. (HEPATOLOGY 2008;47:199-206.) L iver ischemia/reperfusion injury (IRI) occurs in multiple clinical settings including surgical interventions, trauma, and transplantation. 1-3 The mechanisms underlying liver IRI are complex but are known to involve interactions between both nonparenchyma cells, such as Kupffer cells (KC), and parenchyma cells, such as hepatocytes. Local leukocyte sequestration and activation (neutrophils, macrophages, and T cells) leads to the formation of reactive oxygen species, secretion of pro-inflammatory cytokines/chemokines, complement activation, and vascular cell adhesion molecule activation. Because IRI develops in the absence of exogenous antigens, it has been considered as an innate immune-mediated pro-inflammatory response.It was demonstrated that the mammalian sentinel tolllike-receptor (TLR) system plays a critical role in the development of IRI. 4-7 Indeed, TLR4 activation proved essential in the induction of inflammation in a warm liver IRI mouse model. In the absence of TLR4 but not TLR2 signaling, livers were protected from IRI, and intrahepatic induction of tumor necrosis factor (TNF-␣) and interleukin 1 (IL-1␤) was abolished. 7 It was also shown, by using bone marrow chimeras, that TLR4 expression on hematopoietic rather than parenchyma cells was instrumental in promoting liver IR-mediated damage. 8 TLR4 activation triggers 2 distinct signaling pathways leading to the induction of different immune-related genes. The MyD88...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The late phase is characterized by neutrophil infiltration causing further damage to the parenchyma, mainly through a protease-dependent pathway. 17,45 Moreover, endothelial cell swelling, a local imbalance in vasoconstrictors and vasodilators, and activation of the coagulation system, together with the influx of neutrophils, will lead to microcirculatory disturbances, a phenomenon known as no-reflow. 46 This no-reflow further aggravates the damage and is reflected by microscopic tissue necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] These include alternative clamping techniques such as ischemic preconditioning 8,[20][21][22][23] and intermittent clamping [24][25][26] as well as pharmacological intervention with antioxidants such as ␣-tocopherol and ascorbic acid. [27][28][29][30][31][32] We evaluated whether those strategies cross-protect the liver against (accelerated) outgrowth of micrometastases in this model.…”

mentioning

confidence: 99%

Ischemia/Reperfusion Accelerates the Outgrowth of Hepatic Micrometastases in a Highly Standardized Murine Model *

Bilt¹,

Kranenburg²,

Nijkamp³

et al. 2005

Hepatology

159

131

View full text Add to dashboard Cite

Mortality in colorectal cancer is associated with the development of liver metastases. Surgical removal of these tumors is the only hope for cure, but recurrence is common. During liver surgery, ischemia/reperfusion (I/R) often occurs as a result of hemorrhage or vascular clamping. Although the adverse effects of I/R on postoperative liver function are well documented, the influence of I/R on the outgrowth of residual micrometastases is unknown. We used a highly standardized mouse model of partial hepatic I/R to study the effects of I/R on the outgrowth of preestablished colorectal micrometastases. Five days following intrasplenic injection of C26 colon carcinoma cells, the vascular structures of the left lobe were clamped for 45 minutes under hemodynamically stable conditions. Tissue glutathione, plasma liver enzymes, hepatocellular necrosis, and tumor growth were assessed over time. I/R caused oxidative stress and early liver tissue damage. The outgrowth of micrometastases in occluded liver lobes was accelerated five-to sixfold compared with nonoccluded lobes and was associated with areas of necrotic liver tissue surrounded by inflammatory cells and apoptotic hepatocytes. Accelerated tumor growth and tissue necrosis were completely prevented by occluding blood flow intermittently. In contrast, ischemic preconditioning or treatment with the antioxidants ␣-tocopherol or ascorbic acid failed to protect against late tissue necrosis and tumor growth, although early hepatocellular damage was largely prevented by these methods. In conclusion, I/R is a strong stimulus of recurrent intrahepatic tumor growth. Measures to prevent I/R-induced late tissue necrosis cross-protect against this phenomenon. (HEPATOLOGY 2005;42:165-175.)

show abstract

“…This is based on the observation that preventing neutrophil influx into tissues, either by depleting the number of circulating neutrophils or by preventing neutrophil adhesion, significantly reduces microvascular dysfunction and organ injury in animal models of ischemia/reperfusion damage [49,50].…”

Section: Neutrophil Activationmentioning

confidence: 99%

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Cutrn

Perrelli

Cavalieri

et al. 2002

Free Radical Biology and Medicine

150

View full text Add to dashboard Cite

Abstract-Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-␣, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.

show abstract

Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury

Cited by 419 publications

References 52 publications

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion

Ischemia/Reperfusion Accelerates the Outgrowth of Hepatic Micrometastases in a Highly Standardized Murine Model *

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Contact Info

Product

Resources

About