Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion

2005 ◽  
Vol 289 (5) ◽  
pp. G969-G976 ◽  
Author(s):  
Charles C. Caldwell ◽  
Tomohisa Okaya ◽  
Andre Martignoni ◽  
Thomas Husted ◽  
Rebecca Schuster ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Recruitment ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Hepatic Ischemia ◽  
Activated Neutrophils ◽  
Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion results in an acute inflammatory response culminating in the recruitment of activated neutrophils that directly injure hepatocytes. Recent evidence suggests that CD4+ lymphocytes may regulate this neutrophil-dependent injury, but the mechanisms by which this occurs remain to be elucidated. In the present study, we sought to determine the type of CD4+ lymphocytes recruited to the liver after ischemia-reperfusion and the manner in which these cells regulated neutrophil recruitment and tissue injury. Wild-type and CD4 knockout (CD4−/−) mice were subjected to hepatic ischemia-reperfusion. CD4+ lymphocytes were recruited in the liver within 1 h of reperfusion and remained for at least 4 h. These cells were comprised of conventional (αβTCR-expressing), unconventional (γδTCR-expressing), and natural killer T cells. CD4−/− mice were then used to determine the functional role of CD4+ lymphocytes in hepatic ischemia-reperfusion injury. Compared with wild-type mice, CD4−/− mice had significantly greater liver injury, yet far less neutrophil accumulation. Adoptive transfer of CD4+ lymphocytes to CD4−/− mice recapitulated the wild-type response. In wild-type mice, neutralization of interleukin (IL)-17, a cytokine released by activated CD4+ lymphocytes, significantly reduced neutrophil recruitment in association with suppression of MIP-2 expression. Finally, oxidative burst activity of liver-recruited neutrophils was higher in CD4−/− mice compared with those from wild-type mice. These data suggest that CD4+ lymphocytes are rapidly recruited to the liver after ischemia-reperfusion and facilitate subsequent neutrophil recruitment via an IL-17-dependent mechanism. However, these cells also appear to attenuate neutrophil activation. Thus the data suggest that CD4+ lymphocytes have dual, opposing roles in the hepatic inflammatory response to ischemia-reperfusion.

L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver

1998 ◽  
Vol 275 (6) ◽  
pp. G1341-G1352 ◽  
Author(s):  
Surinder S. Yadav ◽  
David N. Howell ◽  
Wenshi Gao ◽  
Douglas A. Steeber ◽  
Robert C. Harland ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Mutant Mice ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin −/−, ICAM-1 −/−, and L-selectin/ICAM-1 −/−) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 min, survival was better in mutant L-selectin and L-selectin/ICAM-1 mice vs. wild-type mice and ICAM-1 mutants. In conclusion, L-selectin is critical in the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injury and appears to involve L-selectin and ICAM-1 receptors.

scholarly journals Intravital Imaging of Neutrophil Recruitment Reveals the Efficacy of FPR1 Blockade in Hepatic Ischemia-Reperfusion Injury

2017 ◽  
Vol 198 (4) ◽  
pp. 1718-1728 ◽  
Author(s):  
Masaki Honda ◽  
Takayuki Takeichi ◽  
Shintaro Hashimoto ◽  
Daiki Yoshii ◽  
Kaori Isono ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Recruitment ◽  
Intravital Imaging ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice

2007 ◽  
Vol 292 (4) ◽  
pp. G1141-G1149 ◽  
Author(s):  
Satoshi Kuboki ◽  
Rebecca Schuster ◽  
John Blanchard ◽  
Timothy A. Pritts ◽  
Hector R. Wong ◽  
...  
Keyword(s):  
Heat Shock ◽  
Liver Injury ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Accumulation ◽  
Hepatic Ischemia ◽  
Recombinant Hsp70 ◽  
Hepatic Ischemia Reperfusion

It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-κB activation, and attenuated serum levels of tumor necrosis factor-α and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 μg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.

Mechanisms of hypothermic protection against ischemic liver injury in mice

2002 ◽  
Vol 282 (4) ◽  
pp. G608-G616 ◽  
Author(s):  
Atsushi Kato ◽  
Saurabh Singh ◽  
Kenneth R. McLeish ◽  
Michael J. Edwards ◽  
Alex B. Lentsch
Keyword(s):  
Transcription Factor ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dry Weight ◽  
Nuclear Factor Κb ◽  
Neutrophil Accumulation ◽  
Hepatic Ischemia

Hepatic hypothermia can safely prolong the duration of hepatic inflow occlusion during complex liver resectional surgeries. The mechanism(s) by which hypothermia protects against this form of liver ischemia-reperfusion injury are not completely understood. In this study, we sought to determine whether hypothermia protects against ischemia-reperfusion injury by altering the hepatic inflammatory response. Mice undergoing 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion had their body temperatures regulated at 35–37°C (normothermic) or unregulated, in which rectal temperature dropped as low as 25°C by the end of ischemia (hypothermic). Hypothermic mice had less liver injury vs. normothermic mice, as assessed histologically, by serum transaminase levels (89% decrease), and by liver wet-to-dry weight ratios (91% decrease). Neutrophil accumulation was absent in hypothermic mice (99% reduction vs. normothermic mice). Production of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 were reduced by up to 92%. Activation of the transcription factor nuclear factor-κB was not reduced in hypothermic mice, but activation of c-Jun NH2-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 were greatly diminished. These data suggest that hypothermia suppresses the hepatic inflammatory response through selective inhibition of JNK and AP-1.

Mild hypothermia reduces the inflammatory response and hepatic ischemia/reperfusion injury in rats

2006 ◽  
Vol 26 (6) ◽  
pp. 734-741 ◽  
Author(s):  
Matthias Behrends ◽  
Ryutaro Hirose ◽  
Natalie J. Serkova ◽  
John L. Coatney ◽  
Melanie Bedolli ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury

2006 ◽  
Vol 291 (6) ◽  
pp. H2980-H2986 ◽  
Author(s):  
Mark R. Duranski ◽  
John W. Elrod ◽  
John W. Calvert ◽  
Nathan S. Bryan ◽  
Martin Feelisch ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Guanylyl Cyclase ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Wild Type ◽  
Hepatic Ischemia ◽  
No Signaling ◽  
Hepatic Ischemia Reperfusion ◽  
Endothelial Nitric Oxide

Previous studies have shown that endothelial nitric oxide (NO) synthase (eNOS)-derived NO is an important signaling molecule in ischemia-reperfusion (I-R) injury. Deficiency of eNOS-derived NO has been shown to exacerbate injury in hepatic and myocardial models of I-R. We hypothesized that transgenic overexpression of eNOS (eNOS-TG) would reduce hepatic I-R injury. We subjected two strains of eNOS-TG mice to 45 min of hepatic ischemia and 5 h of reperfusion. Both strains were protected from hepatic I-R injury compared with wild-type littermates. Because the mechanism for this protection is still unclear, additional studies were performed by using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC with 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) and HO-1 with zinc (III) deuteroporphyrin IX-2,4-bisethyleneglycol (ZnDPBG) in wild-type mice increased hepatic I-R injury, whereas pharmacologically activating these enzymes significantly attenuated I-R injury in wild-type mice. Interestingly, ODQ abolished the protective effects of eNOS overexpression, whereas ZnDPBG had no effect. These results suggest that hepatic protection in eNOS-TG mice may be mediated in part by NO signaling via the sGC-cGMP pathway and is independent of HO-1 signal transduction pathways.

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