• Adherens junction
• Endothelial barrier function
• FAK inhibitor
• Focal adhesion kinase
• Ischemia-reperfusion injury
• Permeability

• Animals
• Reperfusion Injury/enzymology
• Reperfusion Injury/physiopathology
• Reperfusion Injury/metabolism
• Reperfusion Injury/pathology
• Capillary Permeability
• Mice, Knockout
• Focal Adhesion Kinase 1/metabolism
• Focal Adhesion Kinase 1/genetics
• Disease Models, Animal
• Endothelial Cells/enzymology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Endothelial Cells/drug effects
• Mice, Inbred C57BL
• Male
• Signal Transduction
• Humans
• Oxidative Stress
• Cell Adhesion
• Cells, Cultured
• Human Umbilical Vein Endothelial Cells/enzymology
• Human Umbilical Vein Endothelial Cells/metabolism
• Mice
• Mesenteric Vascular Occlusion/physiopathology
• Mesenteric Vascular Occlusion/metabolism
• Mesenteric Vascular Occlusion/enzymology
• Mesenteric Vascular Occlusion/pathology
• Mesenteric Vascular Occlusion/genetics

• Apoptosis
• Hepatic ischemia–reperfusion injury
• Herbs
• Inflammation
• Natural ingredients
• Oxidative stress

• Animals
• Reperfusion Injury/drug therapy
• Reperfusion Injury/prevention & control
• Humans
• Phytochemicals/therapeutic use
• Phytochemicals/pharmacology
• Liver/drug effects
• Liver/pathology
• Liver/metabolism
• Protective Agents/pharmacology
• Protective Agents/therapeutic use
• Liver Diseases/drug therapy
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use

• Alzheimer’s disease
• gene expression signature
• immune pathways
• multimorbidity
• neuroinflammation
• periodontitis

• Mice
• Animals
• Gene Expression Profiling/methods
• Liver Transplantation/adverse effects
• Protein Interaction Maps/genetics
• Transcriptome
• Reperfusion Injury/genetics
• Reperfusion Injury/metabolism

• National Natural Science Foundation of China
• Wuhan Municipal Science and Technology Bureau

• Humans
• Neutrophils
• Reperfusion Injury/etiology
• Neutrophil Infiltration
• Lung
• Lung Transplantation

• I01 BX002730 BLRD VA
• P01 AI116501 NIAID NIH HHS
• R01 HL094601 NHLBI NIH HHS
• R01 HL151078 NHLBI NIH HHS

• C-reactive protein
• Cardiovascular disease
• Inflammation
• Innate immunity
• ischemia/reperfusion injury

• Large-for-size liver transplantation
• animal model
• complications of liver transplantation
• liver transplantation
• pediatric liver transplantation

• Inflammatory cytokines
• Keap1-Nrf2
• Mycotoxins
• Probiotics
• TLR4/NF-κB

• Anti-inflammatory therapy
• Drug delivery nanosystems
• Inflammation
• Ischemia and reperfusion injury
• Liver transplant

• Humans
• Inflammation/drug therapy
• Ischemia
• Liver
• Pharmaceutical Preparations
• Reperfusion Injury/drug therapy

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome. With the prevalence of obesity and type 2 diabetes, NAFLD is becoming the most common liver disorder worldwide. More than 10% of NAFLD patients progress to an inflammatory and fibrotic form called nonalcoholic steatohepatitis (NASH), which can lead to end-stage liver disease. Liver sinusoidal endothelial cells (LSEC) are highly specialized cells located at the interface between the flowing blood in the liver and the other liver cells. The current review highlights the recent knowledge of the role of LSEC in the development of NASH, and how LSEC change their structure and function during NAFLD progression. Moreover, the review discusses the pathogenic role of nanometer-sized particles called extracellular vesicles that mediate intercellular communication in the NASH liver. The current manuscript has a special emphasis on the role of adhesion molecules expressed on the LSEC surface in the recruitment of circulating leukocytes to the liver, a critical step in liver inflammation in NASH. Furthermore, the review shed some lights on LSEC-targeted potential therapeutic strategies in NASH.

Nonalcoholic steatohepatitis (NASH) has become a growing public health problem worldwide, yet its pathophysiology remains unclear. Liver sinusoidal endothelial cells (LSEC) have unique morphology and function, and play a critical role in liver homeostasis. Emerging literature implicates LSEC in many pathological processes in the liver, including metabolic dysregulation, inflammation, angiogenesis, and carcinogenesis. In this review, we highlight the current knowledge of the role of LSEC in each of the progressive phases of NASH pathophysiology (steatosis, inflammation, fibrosis, and the development of hepatocellular carcinoma). We discuss processes that have important roles in NASH progression including the detrimental transformation of LSEC called “capillarization”, production of inflammatory and profibrogenic mediators by LSEC as well as LSEC-mediated angiogenesis. The current review has a special emphasis on LSEC adhesion molecules, and their key role in the inflammatory response in NASH. Moreover, we discuss the pathogenic role of extracellular vesicles and their bioactive cargos in liver intercellular communication, inflammation, and fibrosis. Finally, we highlight LSEC-adhesion molecules and derived bioactive product as potential therapeutic targets for human NASH.

• NASH
• adhesion
• angiogenesis
• extracellular vesicles
• fibrosis
• inflammation
• liver sinusoidal endothelial cells (LSEC)
• steatosis

Compared to adults, neonates are at increased risk of infection. There is a growing recognition that dynamic qualitative and quantitative differences in immunity over development contribute to these observations. The liver plays a key role as an immunologic organ, but whether its contribution to the acute innate immune response changes over lifetime is unknown. We hypothesized that the liver would activate a developmentally-regulated acute innate immune response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic expression and activity of the NF-κB, a key regulator of the innate immune response, at different developmental ages (p0, p3, p7, p35, and adult). Ontogeny of the NF-κB subunits (p65/p50) revealed a reduction in Rela (p65) and Nfkb1 (p105, precursor to p50) gene expression (p0) and p65 subunit protein levels (p0 and p3) vs. older ages. The acute hepatic innate immune response to LPS was associated by the degradation of the NF-κB inhibitory proteins (IκBα and IκBβ), and nuclear translocation of the NF-κB subunit p50 in all ages, whereas nuclear translocation of the NF-κB subunit p65 was only observed in the p35 and adult mouse. Consistent with these findings, we detected NF-κB subunit p65 nuclear staining exclusively in the LPS-exposed adult liver compared with p7 mouse. We next interrogated the LPS-induced hepatic expression of pro-inflammatory genes (Tnf, Icam1, Ccl3, and Traf1), and observed a gradually increase in gene expression starting from p0. Confirming our results, hepatic NF-κB subunit p65 nuclear translocation was associated with up-regulation of the Icam1 gene in the adult, and was not detected in the p7 mouse. Thus, an inflammatory challenge induces an NF-κB-mediated hepatic innate immune response activation across all developmental ages, but nuclear translocation of the NF-κB subunit p65 and associated induction of pro-inflammatory genes occurred only after the first month of life. Our results demonstrate that the LPS-induced hepatic innate immune response is developmentally regulated by the NF-κB subunit p65 in the mouse.

• LPS
• NF-κB
• Nfkb1 (p50)
• Rela (p65)
• innate immunity
• liver

Donation after circulatory death (DCD) can expand the donor pool effectively. A gap remains in outcome between DCD livers and living donor livers, warranting improved DCD liver quality and urgent resolution. Bone marrow mesenchymal stem cells (BMMSCs) can regulate immunity, participate in the anti-inflammatory response, and secrete cytokines. We investigated the effect of BMMSCs combined with normothermic machine perfusion (NMP) on DCD liver quality, and the role of microcirculation therein. Rat thoracic aortas were clipped to obtain DCD livers, and a rat NMP system was established. The DCD livers were grouped by preservation method: normal, static cold storage (SCS), NMP (P), and BMMSCs plus NMP (BP); storage time was up to 8 h. Liver function in outflow perfusate was detected by biochemical methods; liver tissue histopathology was observed by hematoxylin–eosin staining; hepatocyte ultrastructure was observed by transmission electron microscopy; hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling; liver microcirculation–related indicators were detected by immunofluorescence, immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay. Compared with SCS, P and BP significantly improved liver function and liver histological damage, reduced hepatocyte apoptosis, and repaired hepatocyte mitochondrial damage after 6 h in vitro. BP also significantly inhibited intrahepatic macrophage activation and intercellular adhesion, improved endothelial damage, and significantly improved endothelin 1–nitric oxide balance and microcirculation perfusion. In conclusion, BP can improve DCD liver microcirculation and quality. The mechanism may be the improvement of improve hepatic sinusoidal endothelial injury and microcirculation perfusion by inhibiting macrophage activation and intercellular adhesion.

• Bone marrow mesenchymal stem cells
• Donation after circulatory death
• Ischemia–reperfusion injury
• Microcirculation
• Normothermic machine perfusion

• endothelial cell activation
• ischemia/reperfusion injury
• organ-on-a-chip
• thrombolysis

• 3-14350 Ministry of Science and Technology, Israel

• fibroblasts
• ischemia reperfusion injury
• liver regeneration
• mesenchymal stem cells
• microvesicles

• Animals
• Colitis
• Formyl peptide receptor 1
• Immunity

• Animals
• Connective Tissue/immunology
• Cornea/immunology
• Cornea/microbiology
• Cornea/physiopathology
• Gene Expression Regulation
• Intercellular Adhesion Molecule-1/metabolism
• Keratitis/complications
• Keratitis/immunology
• Keratitis/metabolism
• Keratitis/physiopathology
• Mast Cells/cytology
• Mice
• Mice, Inbred C57BL
• Mycoses/complications
• Neutrophil Infiltration
• Vasodilation

C-reactive protein circulates as a pentameric protein (pCRP). pCRP is a well-established diagnostic marker as plasma levels rise in response to tissue injury and inflammation. We recently described pro-inflammatory properties of CRP, which are mediated by conformational changes from pCRP to bioactive isoforms expressing pro-inflammatory neo-epitopes [pCRP* and monomeric C-reactive protein (mCRP)]. Here, we investigate the role of CRP isoforms in renal ischemia/reperfusion injury (IRI).

Rat kidneys in animals with and without intraperitoneally injected pCRP were subjected to IRI by the time of pCRP exposure and were subsequently analyzed for monocyte infiltration, caspase-3 expression, and tubular damage. Blood urea nitrogen (BUN) was analyzed pre-ischemia and post-reperfusion. CRP effects on leukocyte recruitment were investigated via intravital imaging of rat-striated muscle IRI. Localized conformational CRP changes were analyzed by immunohistochemistry using conformation specific antibodies. 1,6-bis(phosphocholine)-hexane (1,6-bisPC), which stabilizes CRP in its native pentameric form was used to validate CRP effects. Leukocyte activation was assessed by quantification of reactive oxygen species (ROS) induction by CRP isoforms ex vivo and in vitro through electron spin resonance spectroscopy. Signaling pathways were analyzed by disrupting lipid rafts with nystatin and subsequent ROS detection. In order to confirm the translational relevance of our findings, biopsies of microsurgical human free tissue transfers before and after IRI were examined by immunofluorescence for CRP deposition and co-localization of CD68⁺ leukocytes.

The application of pCRP aggravates tissue damage in renal IRI. 1,6-bisPC reverses these effects via inhibition of the conformational change that leads to exposure of pro-inflammatory epitopes in CRP (pCRP* and mCRP). Structurally altered CRP induces leukocyte–endothelial interaction and induces ROS formation in leukocytes, the latter can be abrogated by blocking lipid raft-dependent signaling pathways with Nystatin. Stabilizing pCRP in its native pentameric state abrogates these pro-inflammatory effects. Importantly, these findings are confirmed in human IRI challenged muscle tissue.

These results suggest that CRP is a potent modulator of IRI. Stabilizing the native pCRP conformation represents a promising anti-inflammatory therapeutic strategy by attenuation of leukocyte recruitment and ROS formation, the primary pathomechanisms of IRI.

• C-reactive protein
• conformational change
• ischemia/reperfusion injury
• leukocyte recruitment
• rat models
• reactive oxygen species
• therapeutic targets
• translational medical research

To evaluate the effects of mineralocorticoid receptor (MR) antagonists on mortality and inflammatory responses after hemorrhagic shock (HS) in rats.

One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone (EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha (TNF-α) concentrations, and arterial blood gas at 8 h after HS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery.

The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups (P = 0.888).

Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.

• Hemorrhagic shock
• Mortality
• Inflammatory response
• Mineralocorticoid receptor antagonist
• Cytokine

The aim of the current study was to identify the protective effect of hydrogen gas against liver injury during CO₂ pneumoperitoneum. Rats were randomly divided into three groups: control group (C group), pneumoperitoneum group (P15 group) and hydrogen group (H₂ group). Rats in the C group were subjected to anesthesia for 90 min. Rats in the P15 group received an abdominal insufflation of CO₂ for 90 min at an intra-abdominal pressure of 15 mmHg. Rats in the H₂ group received a hypodermic injection of hydrogen gas (0.2 mL/kg) and after 10 min they received an abdominal insufflation of CO₂ for 90 min at an intra-abdominal pressure of 15 mmHg. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to evaluate liver function. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) content were measured to evaluate oxidative stress. Nuclear factor E2-related factor 2 (Nrf2) and Nrf2 downstream target genes, apoptosis-related genes and inflammatory cytokine mRNA and protein expression were detected. Liver injury was detected under the microscope. Our results revealed that liver function, antioxidants content, inflammation and liver injury were improved after hydrogen preconditioning in H₂ group compared with P15 group. Overall, our results revealed that subcutaneous hydrogen injection could exert a protective effect against liver injury during CO₂ pneumoperitoneum through reducing oxidative stress, cell apoptosis and inflammatory cytokines release.

• CO2 pneumoperitoneum
• hydrogen
• ischemia-reperfusion
• liver

The liver is one of the main organs in the body, performing several metabolic and immunological functions that are indispensable to the organism. The liver is strategically positioned in the abdominal cavity between the intestine and the systemic circulation. Due to its location, the liver is continually exposed to nutritional insults, microbiota products from the intestinal tract, and to toxic substances. Hepatocytes are the major functional constituents of the hepatic lobes, and perform most of the liver’s secretory and synthesizing functions, although another important cell population sustains the vitality of the organ: the hepatic immune cells. Liver immune cells play a fundamental role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. Here we discuss the location of these pivotal cells within the different liver compartments, and how their frequency and tissular location can dictate the fate of liver immune responses.

• hepatic leukocytes
• hepatocytes
• immune response
• liver

• hepatic injury
• necrosis
• hepatic inflammation
• liver regeneration

• Animals
• Chemokines, CXC/metabolism
• Cytokines/metabolism
• Humans
• Inflammation Mediators/metabolism
• Liver/metabolism
• Liver/pathology
• Liver/physiopathology
• Liver Diseases/metabolism
• Liver Diseases/physiopathology
• Liver Regeneration
• Reperfusion Injury/metabolism
• Reperfusion Injury/physiopathology
• Signal Transduction

• R01 DK056029 NIDDK NIH HHS

During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell—endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection.

• Ischemic preconditioning
• delay phenomenon
• vascular delay

• CINC
• ENA-78
• ET
• Endothelium
• GM-CSF
• GdCl(3)
• HO-1
• HSC
• Hepatocyte
• I/R
• ICAM-1
• IL
• INF-γ
• KC
• KLF2
• Kruppel-like factor 2
• Kupffer cells
• LSEC
• MIP-2
• NAD
• NFκB
• NO
• PPAR
• ROS
• TNF
• TXA(2)
• Transplantation
• cytokine-induced neutrophil chemoattractant-1
• eNOS
• endothelial nitric oxide synthase
• endothelin
• epithelial neutrophil activating protein-78
• gadolinium chloride
• granulocyte-macrophage colony-stimulating factor
• heme oxygenase-1
• hepatic stellate cells
• interferon-gamma
• interleukin
• intracellular adhesion molecule-1
• ischemia-reperfusion
• liver sinusoidal endothelial cells
• macrophage inflammatory protein-2
• nicotinamide adenine dinucleotide
• nitric oxide
• nuclear factor kappa B
• peroxisome proliferator-activated receptor
• reactive oxygen species
• thromboxane A2
• tumour necrosis factor

• amiodarone
• hemostatic system
• hypochlorous acid.
• idiosyncratic drug-induced liver injury
• neutrophils

• Animals
• Boronic Acids/administration & dosage
• Boronic Acids/adverse effects
• Bortezomib
• Chemokine CXCL2/genetics
• Chemokine CXCL2/metabolism
• Disease Models, Animal
• Fatty Liver/complications
• Fatty Liver/drug therapy
• Fatty Liver/immunology
• Humans
• Inflammation Mediators/metabolism
• Interleukin-1beta/genetics
• Interleukin-1beta/metabolism
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Proteasome Inhibitors
• Pyrazines/administration & dosage
• Pyrazines/adverse effects
• Rats
• Rats, Zucker
• Reperfusion Injury/complications
• Reperfusion Injury/drug therapy
• Reperfusion Injury/immunology
• Transcription Factor RelA/genetics
• Transcription Factor RelA/metabolism
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/metabolism

• R01 DK065982-05 NIDDK NIH HHS
• P01 HL066196-05 NHLBI NIH HHS
• P30 DK052574-09 NIDDK NIH HHS
• R01 DK065982 NIDDK NIH HHS
• P01 HL066196 NHLBI NIH HHS
• P01 HL66196 NHLBI NIH HHS
• P30 DK052574 NIDDK NIH HHS
• DK065982 NIDDK NIH HHS

• Animals
• CD18 Antigens/genetics
• CD18 Antigens/immunology
• Cell Adhesion Molecules/blood
• Cell Adhesion Molecules/immunology
• Disease Models, Animal
• Endotoxemia/drug therapy
• Endotoxemia/genetics
• Endotoxemia/immunology
• Endotoxins/administration & dosage
• Endotoxins/immunology
• Endotoxins/toxicity
• Garlic/chemistry
• Humans
• Intestine, Small/drug effects
• Intestine, Small/immunology
• Male
• Neutrophil Infiltration/drug effects
• Neutrophils/drug effects
• Neutrophils/immunology
• Plant Oils/administration & dosage
• Plant Oils/pharmacology
• Rats
• Rats, Wistar

• copper
• ischemia/reperfusion injury
• neutrophils
• icam-1

• Alanine Transaminase/blood
• Animals
• Copper/deficiency
• Intercellular Adhesion Molecule-1/metabolism
• Liver/metabolism
• Liver/physiopathology
• Male
• Neutrophils/metabolism
• Peroxidase/analysis
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury/blood
• Reperfusion Injury/physiopathology

• R01 DK055030 NIDDK NIH HHS
• R01 DK055030-08 NIDDK NIH HHS
• R01 DK056029 NIDDK NIH HHS
• DK-55030 NIDDK NIH HHS