Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease?

Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease(ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, micro RNA, and lipid-originated metabolites(retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells(hepatocytes). Therefore, understanding the comprehensive roles of hepatic nonparenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of nonparenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD.     

Iron in nonhemochromatotic liver disorders

Iron is essential for cellular functions, but in excessive amounts it is toxic to cells. The harmful effects are related to increased oxidative stress and production of reactive oxygen species causing oxidative damage to lipids, proteins, and nucleic acids. Heavy iron overload as occurs in primary and secondary hemochromatosis can cause fibrosis of various parenchymal organs such as the liver, heart, and pancreas. Lesser degrees of hepatic iron deposition are also associated with, and seem to be risk factors for, certain nonhemochromatotic liver diseases. Porphyria cutanea tarda is associated with hepatic iron overload and responds to iron-reduction therapy. Other recent evidence indicates that the prevalence of HFE gene mutations is increased in chronic viral hepatitis and that patients with chronic hepatitis C harboring especially the C282Y mutation are more likely to suffer from advanced hepatic fibrosis or cirrhosis and to do so at younger ages. In this article we review selected nonhemochromatotic disorders in which iron can play an important comorbid role.     

Hepatotoxicity of iron overload: mechanisms of iron-induced hepatic fibrogenesis

While iron is a vital requirement for normal cellular physiology, excessive intestinal absorption of iron as seen in hemochromatosis leads to its deposition in parenchymal cells of various organs such as the liver, heart, and pancreas, resulting in cellular toxicity, tissue injury, and organ fibrosis. Cellular injury is induced by iron-generated oxyradicals and peroxidation of lipid membranes. In the liver, lipid peroxidation results in damage to hepatocellular organelles, such as mitochondria and lysosomes, which is thought to contribute to hepatocyte necrosis and apoptosis, and ultimately lead to the development of hepatic fibrogenesis. Hepatic stellate cells are central to the development of hepatic fibrosis, as they can be activated into collagen-producing myofibroblasts. Numerous potential stimuli associated with hepatic iron overload and iron-induced hepatocellular injury have been assessed in an attempt to explain stellate cell transformation in hemochromatosis. Stellate cell activation and fibrosis appear to be regulated by a series of events involving cellular interaction between resident and nonresident cells of the liver, the sequestration of free iron versus the transport and storage of mobilizable iron, and extracellular matrix remodeling as well as intracellular signaling events associated with inflammatory and fibrogenic cytokines.     

Is ultrasonography useful in the assessment of diffuse parenchymal liver disease?

One hundred twenty-five patients investigated at the Royal Brisbane Hospital, who underwent both hepatic ultrasonography and liver biopsy between 1980 and 1983, were scored quantitatively for ultrasound features of loss of detail, echogenicity, and attenuation, as well as for histologic features of fat, fibrosis, and inflammation. Strong correlations were found between the score for fat content and each of the three ultrasound features, and between the score for hepatic fibrosis and loss of detail and echogenicity, but there was no strong correlation with attenuation. Hepatic inflammation did not correlate with any of the ultrasound features. The correlations for fat were strongest when the interval between ultrasonography and liver biopsy was less than or equal to 7 days. Although ultrasonography had a positive predictive value of 98% in the diagnosis of diffuse parenchymal abnormality, it did not distinguish fat from fibrosis nor reliably diagnose cirrhosis. Ultrasonography gave false-positive results in only 2 patients, but in 17 patients, false-negative ultrasound examinations were encountered. These findings indicate that ultrasound is not a useful screening investigation for parenchymal liver disease, nor is it useful in gauging hepatic pathology. However, abnormal hepatic ultrasonography in patients with suspected liver disease strongly suggests the presence of diffuse liver disease.     

Hepatic stellate cells: it's role in normal and pathological conditions

Hepatic fibrosis is a dynamic and sophisticatedly regulated wound healing response to chronic hepatocellular injury. This fibrotic process results from the accumulation of extracellular matrix (ECM) including collagen, proteoglycan, and adhesive glycoproteins which are principally produced by hepatic stellate cells (HSC), a mesenchymal cell type located between parenchymal cell plates and sinusoidal endothelial cells in the space of Disse. In physiological conditions, quiescent HSCs play important roles in the regulation of retinoid homeostasis and ECM remodeling by producing ECM components as well as metalloproteases and its inhibitor. However during hepatic fibrogenesis, HSCs are known to be activated or "transdifferentiated" to myofibroblast-like cells which play a pivotal role in ECM remodeling and hepatic blood flow regulation. Activation of HSC is now well established as the key process involved in the development of hepatic fibrosis. Both basic morphology and functions of HSCs in normal conditions and its role in pathological fibrosis will be discussed in this review.     

The Role of Mesothelial Cells in Liver Development,Injury, and Regeneration

Mesothelial cells (MCs) cover the surface of visceral organs and the parietal walls of cavities, and they synthesize lubricating fluids to create a slippery surface that facilitates movement between organs without friction. Recent studies have indicated that MCs play active roles in liver development, fibrosis, and regeneration. During liver development, the mesoderm produces MCs that form a single epithelial layer of the mesothelium. MCs exhibit an intermediate phenotype between epithelial cells and mesenchymal cells. Lineage tracing studies have indicated that during liver development, MCs act as mesenchymal progenitor cells that produce hepatic stellate cells, fibroblasts around blood vessels, and smooth muscle cells. Upon liver injury, MCs migrate inward from the liver surface and produce hepatic stellate cells or myofibroblast depending on the etiology, suggesting that MCs are the source of myofibroblasts in capsular fibrosis. Similar to the activation of hepatic stellate cells, transforming growth factor β induces the conversion of MCs into myofibroblasts. Further elucidation of the biological and molecular changes involved in MC activation and fibrogenesis will contribute to the development of novel approaches for the prevention and therapy of liver fibrosis.     

New results on ageing of connective tissue (author's transl)]

Some new results on ageing of connective tissue are demonstrated, regarding not only mesenchymal, but also parenchymal organs of human and rat (both sexes). These results show that ageing of connective tissue is more a dynamic process (with measurable metabolic parameters of the several connective tissue cells and their products) than a passive or so-called degenerative connective tissue process. The bradytrophy concept of connective tissue cannot be accepted any longer. Then connective tissue cells can produce metabolic rates of the same level like parenchymal cells. The different organs possess partly common basic processes partly differences in connective tissue ageing, dependent on the composition and patterns of proteoglycans resp. of GAG and collagen types, furthermore dependent on localisation, structure and function. The results on ageing of connective tissue are useful for better understanding of ageing processes of parenchymal organs. Then their ageing is influenced essentially by the ageing of the own connective tissues. The turnover, more than the number of mesenchymal and parenchymal cells, decreases with ageing. More old than young cells seem to exist in old tissues and organs. The performance of ageing connective tissue cells can be constant or increase or decrease. Many mesenchymal and parenchymal organs develop a so-called "ageing-fibrosis".     

Molecular therapy for hepatic injury and fibrosis： Where are we？

Hepatic fibrosis is a wound healing response,involvingpathways of inflammation and fibrogenesis.In responseto various insults,such as alcohol,ischemia,viral agents,and medications or hepatotoxins,hepatocyte damagewill cause the release of cytokines and other solublefactors by Kupffer cells and other cell types in the liver.These factors lead to activation of hepatic stellate cells,which synthesize large amounts of extracellular matrixcomponents.With chronic injury and fibrosis,liverarchitecture and metabolism are disrupted,eventuallymanifesting as cirrhosis and its complications.Inaddition to eliminating etiology,such as antiviral therapyand pharmacological intervention,it is encouragingthat novel strategies are being developed to directlyaddress hepatic injury and fibrosis at the subcellular andmolecular levels.With improvement in understandingthese mechanisms and pathways,key steps in injury,signaling,activation,and gene expression are beingtargeted by molecular modalities and other molecular orgene therapy approaches.This article intends to providean update in terms of the current status of moleculartherapy for hepatic injury and fibrosis and how far weare from clinical utilization of these new therapeuticmodalities.     

肝纤维化血清学无创检测研究进展

肝纤维化指肝脏细胞外基质弥漫性的过度沉积,是机体对于肝实质损伤的一种修复反应及许多慢性肝病共同的病理过程,也是各种慢性肝病向肝硬化发展的重要步骤.迄今为止,临床尚缺乏特异性有效逆转或阻止肝纤维化进展的药物,尽早对肝纤维化进行诊断具有重要意义.目前肝纤维化的诊断主要靠组织病理学、血清学标志物及影像学手段.肝活检被认为是肝...     

Gliotoxin ameliorates development of fibrosis and cirrhosis in a thioacetamide rat model

Activation of hepatic stellate cells causes most of the pathological changes in cirrhosis. The fungal metabolite gliotoxin was shown to induce apoptosis of hepatic stellate cells in vitro. We examined whether gliotoxin may prevent or reverse liver fibrosis in a rat model of thioacetamide-inducedcirrhosis, and whether gliotoxin administration in vivo causes apoptosis of activated stellate cells. Gliotoxin treatment resulted in a significant decrease in liver fibrosis in rats, but did not improve liver functions. We observed a significant reduction in the numbers of activated hepatic stellate cells in the gliotoxin-treated rats. Gliotoxin administration also resulted in parenchymal apoptosis of hepatocytes and hepatic stellate cells. In conclusion, gliotoxin reduces hepatic fibrosis, an effect accompanied by reduction of the numbers of activated hepatic stellate cells in the liver.     

Liver fibrosis in hepatitis B: a dynamic process

Liver fibrosis is a common complication of chronic hepatitis B leading to the progressive destruction of normal tissue architecture or the replacement of hepatocytic tissue with fibrous tissue. The final outcome of this process is liver cirrhosis, which is the major cause of morbidity and mortality in chronic viral hepatitis. Fibrogenesis is closely related to activation of the main type of fibrocompetent cells in the liver: hepatic stellate cells. Experimental models have allowed a better understanding of the dynamics of fibrosis, the biological processes related to its progression and regression and the development of new anti-fibrotic drugs. Nevertheless, it is universally accepted that such an anti-fibrotic treatment will be efficient only after hepatitis B virus eradication. Furthermore, early fibrosis is more amenable to regression than more advanced and highly organized liver cirrhosis.     

Advances in antifibrotic therapy

Sustained progress in defining the molecular pathophysiology of hepatic fibrosis has led to a comprehensive framework for developing antifibrotic therapies. Indeed, the single greatest limitation in bringing new drugs to the clinical setting is a lack of clarity regarding clinical trial and treatment end points, not a lack of promising agents. A range of treatments, including those developed for other indications, as well as those specifically developed for hepatic fibrosis, are nearing or in clinical trials. Most are focused on attacking features of either hepatic injury and/or activated stellate cells and myofibroblasts, which are the primary sources of extracellular matrix (scar) proteins. Thus, features of injury and stellate cell activation provide a useful template for classifying these emerging agents and point to a new class of therapies for patients with fibrosing liver disease.     

Pathophysiology of hepatic fibrosis

Hepatic fibrosis is a common sequel to most forms of chronic liver disease and an essential component in the development of cirrhosis. Basic and clinical scientists have increasingly realized the importance of all elements of the liver in fibrogenesis, as well as of structural-functional relationships between liver cells and matrix components of the liver. Important is the recognition that hepatic stellate cells play a central role based on their ability to undergo activation following liver injury of any cause. The study brings about the newest information on pathophysiology of hepatic fibrosis. On the basis of better knowledge of the pathophysiology of fibrogenesis the development of new therapeutic approaches will become possible.     

Nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a common liver disorder that represents the hepatic manifestation of the metabolic syndrome, a variably defined aggregate of disorders related to obesity, insulin resistance, type II diabetes, hypertension and hyperlipidemia. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury that carries a risk for progressive fibrosis, cirrhosis, and end-stage liver disease. Hepatocellular carcinoma (HCC) is a documented complication in an as yet unknown percentage of cases of NASH cirrhosis. The diagnosis of nonalcoholic steatohepatitis requires histopathologic evaluation because the lesions of parenchymal injury and fibrosis cannot be detected by imaging studies or laboratory tests. This article will briefly discuss prevalence studies and the pathophysiology of NAFLD and focus on current discussions related to the specific lesions in the pathology of NASH, including the challenges of pediatric NASH and NASH-related cirrhosis.     

Inhibitory effect of acyclic retinoid (polyprenoic acid) on hepatic fibrosis in CCl4-treated rats

A study was conducted to examine the inhibitory effect of acyclic retinoid (polyprenoic acid) on the development of hepatic fibrosis induced by CCl4 in rats. Oral administration of the compound brought about a significant reduction in both serum and tissue levels of immunoreactive prolyl hydroxylase, a key enzyme of collagen formation. The result indicated that the rate of collagen synthesis in the liver was decreased which was consistent with histological findings. Acyclic retinoid also decreased both AST and ALT activities in serum, demonstrating the reduction in hepatic parenchymal damage. This cytoprotective effect on parenchymal cells may be related, at least in part, to inhibition of hepatic fibrosis. No significant side effects were observed, despite a long-term administration of the acyclic retinoid. The present findings suggest the potential scope of therapy of hepatic fibrosis by retinoid.     

Idiopathic pulmonary fibrosis. Quantitative assessment of lung pathology. Comparison of a semiquantitative and a morphometric histopathologic scoring system.

The objective of this study was to determine the accuracy of a semiquantitative method of assessing the relative degree of cellularity and fibrosis compared with a morphometric analysis of specific histopathologic features in idiopathic pulmonary fibrosis (IPF). Morphometric analysis was performed on biopsy tissue from 20 patients. Morphometry showed that approximately 70% of parenchymal tissue was abnormal: 35% cellular consolidation and fibrosis, 20% honeycomb changes, 10% thick alveolar septa, and 5% small airways within abnormal parenchymal tissue. The prominent components of the abnormal parenchymal tissue were extracellular fibers, an abundance of interstitial cells, and epithelial cell hyperplasia. Correlation between four groupings of pathologic features, identified by a semiquantitative analysis, and each of the components of the parenchymal lesions showed significant correlations between (1) the fibrotic or reparative factor (alveolar wall metaplasia, fibrosis, honeycombing, and smooth muscle and vascular changes) and components of honeycomb lesions (extracellular fibers, interstitial cells, and epithelial injury and repair), and (2) the inflammatory and exudative factor and extracellular fibers in the lesions. These results support that the scoring system used by the pathology panel provides an accurate assessment of pathologic features useful in the assessment of the extent and severity of the histopathologic lesions of IPF.     

肝窦内皮细胞调控肝脏微环境影响肝纤维化的研究进展

肝窦内皮细胞不仅是血液和肝细胞进行物质交换的重要中介细胞,也是慢性肝损伤因素导致肝纤维化和肝硬化的重要肝非实质细胞。它主要通过与肝星状细胞、肝细胞、Kupffer细胞的相互作用和介导肝脏硬度、肝脏血管再生从而调控肝脏微循环,参与肝纤维化的发展。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver

Stem cells responsible for tissue maintenance and repair are found in a number of organs. However, hepatic stem cells assumed to play a key role in liver development and regeneration remain to be well characterized. To address this issue, we set up a culture system in which primitive hepatic progenitor cells formed colonies. By combining this culture system with fluorescence-activated cell sorting (FACS), cells forming colonies containing distinct hepatocytes and cholangiocytes were identified in the fetal mouse liver. These cells express both CD49f and CD29 (alpha6 and beta1 integrin subunits), but do not mark for hematopoietic antigens such as CD45, TER119, and c-Kit. When transplanted into the spleen, these cells migrated to the recipient liver and differentiated into liver parenchymal cells. Our data demonstrate that hepatic progenitor cells are enriched by FACS and suggest approaches to supplanting organ allografting and improving artificial-organ hepatic support.     

Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells

The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. The impact of ethanol on hepatocytes can be characterized as a condition of organelle stress with multifactorial changes in hepatocellular function accumulating during ethanol exposure. These changes include oxidative stress, mitochondrial dysfunction, decreased methylation capacity, endoplasmic reticulum stress, impaired vesicular trafficking and altered proteasome function. Injury to hepatocytes is attributed, in part, to ethanol metabolism by the hepatocytes. Changes in the structural integrity of hepatic sinusoidal endothelial cells, as well as enhanced inflammation in the liver during ethanol exposure are also important contributors to injury. Activation of hepatic stellate cells initiates the deposition of extracellular matrix proteins characteristic of fibrosis. Kupffer cells, the resident macrophages in the liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides via toll-like receptor 4. This sensitization enhances the production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species that contribute to hepatocyte dysfunction, necrosis and apoptosis of hepatocytes and the generation of extracellular matrix proteins leading to fibrosis. In this review we provide an overview of the complex interactions between parenchymal and non-parenchymal cells in the liver during the progression of ethanol-induced liver injury.