Susceptibility of Rat Steatotic Liver to Ischemia-Reperfusion Is Treatable With Liver-Selective Matrix Metalloproteinase Inhibition.

Background And Aims: This study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury.

Approach And Results: Hepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition.

Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program.

Background: Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided.

Methods: This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity).

Incomplete Differentiation of Engrafted Bone Marrow Endothelial Progenitor Cells Initiates Hepatic Fibrosis in the Rat.

Normal liver sinusoidal endothelial cells (LSECs) promote quiescence of hepatic stellate cells (HSCs). Prior to fibrosis, LSECs undergo capillarization, which is permissive for HSC activation, the proximate event in hepatic fibrosis. The aims of this study were to elucidate the nature of and mechanisms leading to capillarization and to determine how LSECs promote HSC quiescence and why "capillarized LSECs" lose control of HSC activation.

Liver Complications Following Treatment of Hematologic Malignancy With Anti-CD22-Calicheamicin (Inotuzumab Ozogamicin).

Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome; SOS). We studied patients who received an anti-CD22/calicheamicin conjugate (inotuzumab ozogamicin; InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22 cells in the normal liver, but nonspecific uptake of ADCs by liver sinusoidal endothelial cells (LSECs).

Liver-Selective MMP-9 Inhibition in the Rat Eliminates Ischemia-Reperfusion Injury and Accelerates Liver Regeneration.

Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental.

Liver Sinusoidal Endothelial Cell: An Update.

This update focuses on two main topics. First, recent developments in our understanding of liver sinusoidal endothelial cell (LSEC) function will be reviewed, specifically elimination of blood-borne waste, immunological function of LSECs, interaction of LSECs with liver metastases, LSECs and liver regeneration, and LSECs and hepatic fibrosis. Second, given the current emphasis on rigor and transparency in biomedical research, the update discusses the need for standardization of methods to demonstrate identity and purity of isolated LSECs, pitfalls in methods that might lead to a selection bias in the types of LSECs isolated, and questions about long-term culture of LSECs.

VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration.

In liver injury, recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (sprocs) is necessary for normal liver regeneration. Hepatic vascular endothelial growth factor (VEGF) is a central regulator of the recruitment process. We examine whether stromal cell-derived factor 1 [sdf1, or CXC ligand 12 (CXCL12)] acts downstream from VEGF to mediate recruitment of BM sprocs, what the sdf1 receptor type [CXC receptor (CXCR)-4 or CXCR7] is on sprocs, and whether sdf1 signaling is required for normal liver regeneration.

Liver sinusoidal endothelial cells in hepatic fibrosis.

Capillarization, lack of liver sinusoidal endothelial cell (LSEC) fenestration, and formation of an organized basement membrane not only precedes fibrosis, but is also permissive for hepatic stellate cell activation and fibrosis. Thus, dysregulation of the LSEC phenotype is a critical step in the fibrotic process. Both a vascular endothelial growth factor (VEGF)-stimulated, nitric oxide (NO)-independent pathway and a VEGF-stimulated NO-dependent pathway are necessary to maintain the differentiated LSEC phenotype.

An amphipathic alpha-helical peptide from apolipoprotein A1 stabilizes protein polymer vesicles.

L4F, an alpha helical peptide inspired by the lipid-binding domain of the ApoA1 protein, has potential applications in the reduction of inflammation involved with cardiovascular disease as well as an antioxidant effect that inhibits liver fibrosis. In addition to its biological activity, amphipathic peptides such as L4F are likely candidates to direct the molecular assembly of peptide nanostructures. Here we describe the stabilization of the amphipathic L4F peptide through fusion to a high molecular weight protein polymer.

Liver sinusoidal endothelial cells and liver regeneration.

Liver sinusoidal endothelial cells (LSECs) have long been noted to contribute to liver regeneration after liver injury. In normal liver, the major cellular source of HGF is the hepatic stellate cell, but after liver injury, HGF expression has been thought to increase markedly in proliferating LSECs. However, emerging data suggest that even after injury, LSEC expression of HGF does not increase greatly.

Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice.

The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6 weeks after the start of GO therapy or 4 weeks after the last dose (whichever was later), and after 6 months.

Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells.

Background & Aims: After liver injury, bone marrow-derived liver sinusoidal endothelial cell progenitor cells (BM SPCs) repopulate the sinusoid as liver sinusoidal endothelial cells (LSECs). After partial hepatectomy, BM SPCs provide hepatocyte growth factor, promote hepatocyte proliferation, and are necessary for normal liver regeneration. We examined how hepatic vascular endothelial growth factor (VEGF) regulates recruitment of BM SPCs and their effects on liver injury.

Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats.

The ability of the liver to regenerate is crucial to protect liver function after injury and during chronic disease. Increases in hepatocyte growth factor (HGF) in liver sinusoidal endothelial cells (LSECs) are thought to drive liver regeneration. However, in contrast to endothelial progenitor cells, mature LSECs express little HGF.

Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats.

Background & Aims: Capillarization, characterized by loss of differentiation of liver sinusoidal endothelial cells (LSECs), precedes the onset of hepatic fibrosis. We investigated whether restoration of LSEC differentiation would normalize crosstalk with activated hepatic stellate cells (HSC) and thereby promote quiescence of HSC and regression of fibrosis.

Methods: Rat LSECs were cultured with inhibitors and/or agonists and examined by scanning electron microscopy for fenestrae in sieve plates.

The effects of old age on hepatic stellate cells.

Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24-27 mths) and mice (2-3 mths versus 20-22 mths). Desmin-positive HSC doubled in old age in both mice and rats.

15th International Symposium on Cells of the Hepatic Sinusoid, 2010.

This is a meeting report of the presentations given at the 15th International Symposium on Cells of the Hepatic Sinusoid, held in 2010. The areas covered include the contributions of the various liver cell populations to liver disease, molecular and cellular targets involved in steatohepatitis, hepatic fibrosis and cancer and regenerative medicine. In addition to a review of the science presented at the meeting, this report provides references to recent literature on the topics covered at the meeting.

Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity.

Many liver sinusoidal endothelial cell (LSEC)-dependent processes, including drug-induced liver injury, ischemia-reperfusion injury, acute and chronic rejection, fibrosis, and the HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome, may have a lobular distribution. Studies of the mechanism of this distribution would benefit from a reliable method to isolate LSEC populations from different regions. We established and verified a simple method to isolate periportal, midlobular, and centrilobular LSEC.

Three-dimensional structured illumination microscopy of liver sinusoidal endothelial cell fenestrations.

Fenestrations are pores in liver sinusoidal endothelial cells that filter substrates and debris between the blood and hepatocytes. Fenestrations have significant roles in aging and the regulation of lipoproteins. However their small size (<200 nm) has prohibited any functional analysis by light microscopy.

Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.

Background & Aims: Damage to hepatic sinusoidal endothelial cells (SECs) initiates sinusoidal obstruction syndrome (SOS), which is most commonly a consequence of myeloablative chemoirradiation or ingestion of pyrrolizidine alkaloids such as monocrotaline (Mct). This study examines whether SECs are of bone marrow origin, whether bone marrow repair can be a determinant of severity of liver injury, and whether treatment with progenitor cells is beneficial.

Methods: Mct-treated female rats received infusion of male whole bone marrow or CD133(+) cells at the peak of sinusoidal injury.

Vascular disorders of the liver.

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association.

Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis.

The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis.

Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence.

Unlabelled: Capillarization precedes hepatic fibrosis. We hypothesize that capillarization of sinusoidal endothelial cells (SEC) is permissive for hepatic stellate cell (HSC) activation and therefore permissive for fibrosis. We examined whether freshly isolated SECs prevent activation of HSCs and promote reversion to quiescence, and whether this effect was lost in capillarization.

Hepatic microvasculature in liver injury.

Injury to the hepatic microvasculature, the hepatic sinusoids, manifests in several ways. The sinusoidal endothelial cells (SECs) may lose porosity and scavenger function (capillarization); SECs may loosen from their tetherings to the space of Disse or even detach completely (ischemia-reperfusion injury, early sinusoidal obstruction syndrome, peliosis hepatis, early acetaminophen toxicity); the space of Disse may be completely denuded of sinusoidal lining cells that then embolize and obstruct the sinusoid (early sinusoidal obstruction syndrome); or the sinusoid may be obstructed by fibrosis (hepatic sinusoidal fibrosis, late sinusoidal obstruction syndrome). In many of these microvascular injuries, the change to the sinusoid is a primary event that may lead to hepatocyte hypoxia with liver dysfunction and disruption of the portal circulation.