A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

He, Songqing; Atkinson, Carl; Qiao, Fei; Cianflone, Katherine; Chen, Xiaoping; Tomlinson, Stephen

doi:10.1172/jci38289

Cited by 88 publications

(137 citation statements)

References 59 publications

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“…Survival in the 60% hepatectomy and 40% SOLT groups seemed to be higher than in the 100% OLT group and this may reflect the damage induced by shear stress and portal hypertension. Our histopathological, immunohistological and biochemical findings revealed that liver damage and apoptotic induction were observed in the early postoperative period after liver surgery, as in previous studies [3,12,13,18,[29][30][31] . Paradoxically, the early postoperative period may have a therapeutic potential for a subsequent course after liver surgery.…”

Section: Discussionsupporting

confidence: 88%

“…The survival study was performed on 10 rats in each group. Cell signaling involved in proliferation, differentiation and apoptosis was confirmed at the early postoperative period after liver surgery and subsequently progressive necrosis was observed, as described previously [3,12,13,18,[29][30][31] . Serum and plasma were collected at 6 h after surgery (n = 5, in each group).…”

Section: Methodsmentioning

confidence: 65%

“…In particular, many researchers have focused on TIMP-1 and TIMP-2 during liver regeneration [25][26][27][28] . Although shear stress with portal hypertension and CIWR injury trigger the liver regeneration cascade after liver surgery, these injuries also cause fatal liver damage [29][30][31] . Initial damage is confirmed at the early postoperative period after liver surgery [3,12,13,18,[29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

“…Although shear stress with portal hypertension and CIWR injury trigger the liver regeneration cascade after liver surgery, these injuries also cause fatal liver damage [29][30][31] . Initial damage is confirmed at the early postoperative period after liver surgery [3,12,13,18,[29][30][31] . Therapeutic strategies to reduce this damage have the advantage of improving clinical results after liver surgery and overcoming the current issue of insufficient liver volume in the field of liver surgery.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

Hori¹,

Üemoto²,

Chen³

et al. 2014

WJH

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AIM:To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage. METHODS:Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OSinduced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography. RESULTS:Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT. CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage viathe Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery. Hori T et al . Hepatic damage after liver surgeryCore tip: Although shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery, these injuries also cause fatal liver damage. Postoperative liver damage is still a critical matter in the field of liver surgery. Oxidative stress and extracellular matrices are important for liver regeneration after surgery and these may be important keys to overcome current problems in the field of liver surgery. Here, we investigated oxidative stress-mediated damage and the behavior of extracellular matrices in various rat models with liver surgery.Hori T, Uemoto S, Chen F, Gardner LB, Baine AMT, Hata T, Kogure T, Nguyen JH. ��idative stress and e�tracellular ma��idative stress and e�tracellular matrices after hepatectomy and liver transplantation in rats. World

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

Hori¹,

Üemoto²,

Chen³

et al. 2014

WJH

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“…Wikipathways analysis for these genes identified the IL-6 signaling pathway (IL-6-STAT3 pathway) (p = 3.84E-02) (Table S9). Complement activation activates IL-6 signaling pathway, which is closely related to the liver proliferation rate (39). Additionally, as a member of IL-6 signaling pathway, C/EBPβ activates PGC-1α during liver proliferation with an amplitude of induction that exceeds the fasting response (28).…”

Section: Stat3-c/ebpβ-pgc-1α Was Screened Out By Weighted Gene Co-expmentioning

confidence: 99%

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

Zhang¹,

Huang²,

Jing³

et al. 2017

Theranostics

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The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE -/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro . Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPβ-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an “igniter”; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an “ignition amplifier”, then triggered the hepatocyte state transition from activation to proliferation as a “starter”, causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.

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What is critical for liver surgery and partial liver transplantation: Size or quality?

et al. 2010

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Major liver resections and partial orthotopic liver transplantation (OLT) have become established procedures in liver surgery; for many patients, these techniques offer the only curative option.1 Yet, many patients develop postoperative complications because the remnant livers or grafts are too small or of poor quality to sustain sufficient organ function. This somewhat new and poorly defined phenomenon has been termed ''small-for-size syndrome'' (SFSS) to describe this scenario. The concept is, in fact, not a new one, because as early as the 1970s, Thomas E. Starzl described the complicated postoperative course of a young woman subjected to an almost 90% hepatectomy and who was subsequently characterized by prolonged hyperbilirubinemia, encephalopathy, and coagulopathy.2 In an unconventional way for a review, we will start with three case reports to illustrate the scope and clinical relevance of SFSS after liver surgery and transplantation.Case 1: A 47-year-old healthy man, whose wife was listed for OLT due to a symptomatic nonresectable hemangioendothelioma of the liver, offered to be considered for living donor liver transplantation (LDLT). Following the standard work-up for this procedure, he underwent a right hemi-hepatectomy including the middle hepatic vein to serve as allograft for his wife. The remnant left hemi-liver was estimated by computed tomographic (CT) volumetry to weigh 450 g, i.e., around 32% of the whole liver. The ratio of the remnant liver weight to body weight (RLBW) was 0.65%. The donor had a difficult postoperative course developing mild encephalopathy and hyperbilirubinemia lasting 20 days peaking at 178 lmol/L (10.4 mg/ dL) by day five, and severe coagulopathy (prothrombin time <30%) that normalized by day 7. The donor eventually recovered fully, and was discharged in good general condition 22 days after surgery.Case 2: A 42-year-old male was listed for OLT because of Child B cirrhosis (Model for End-Stage Liver Disease [MELD] score: 21) and a small (3 cm) hepatocellular carcinoma (HCC) related to hepatitis B virus infection. He received the right hemi-liver containing the middle hepatic vein from his wife (graft weighing 620 g), who had an uneventful postoperative course. The ratio of graft size in grams to her husband's body weight (80 kg) (graft-to-recipient weight ratio [GRWR]) was 0.7%. The postoperative period was complicated by encephalopathy, hyperbilirubinemia (up to 262 lmol/L, 15.3 mg/dL) for 2 weeks, and prolonged coagulopathy with a factor V level below 20% at day 4. As a result of the delayed graft function, the patient required intensive care unit treatment for 1 week before the liver graft function improved. He was able to be discharged in good general condition on postoperative day 21.Case 3: A 58-year-old male presented with multiple colorectal liver metastases in the right hemi-liver as well as in segment II, III, and 10 months after resection of the primary rectal tumor followed by 5 cycles of chemotherapy containing Folfox and Avastin. A

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A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

Cited by 88 publications

References 59 publications

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

What is critical for liver surgery and partial liver transplantation: Size or quality?

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