Cellular and Molecular Mechanisms of Hepatic Fibrosis (original) (raw)
Related papers
Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”
Cells
This Special issue contains 48 contributions highlighting novel findings and current concepts in basic and clinical liver fibrosis research. These articles emphasize issues on pathogenesis, cellular mediators, modulators, molecular pathways, disease-specific therapies, scoring systems, as well as novel preclinical animal models for the study of liver fibrogenesis. This editorial aims to briefly summarize the content of these papers.
Genesis of hepatic fibrosis and its biochemical markers
Scandinavian Journal of Clinical …, 2008
Liver fibrosis is characterized by an abnormal hepatic accumulation of extracellular matrix (ECM) that results from both increased deposition and reduced degradation of collagen fibres. Fibrotic liver injury results in activation of the hepatic stellate cell (HSC). Surrogate markers are gradually being substituted for biomarkers that reflect the complex balance between synthesis and degradation of the extracellular matrix. Once the hepatic stellate cell is activated, the preceding matrix changes and recurrent injurious stimuli will perpetuate the activated state. The ECM directs cellular differentiation, migration, proliferation and fibrogenic activation or deactivation. The metabolism of the extracellular matrix is closely regulated by matrix metalloproteinases (MMP) and their specific tissue inhibitors (TIMP). Although liver biopsy combined with connective tissue stains has been a mainstay of diagnosis, there is a need for less invasive methods. These diagnostic markers should be considered in combination with liver function tests, ultrasonography and clinical manifestations.
Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update
World Journal of Gastroenterology, 2014
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
Liver Fibrosis: Underlying Mechanisms and Innovative Therapeutic Approach. A Review Article
Biomedical and Pharmacology Journal, 2021
Liver fibrosis is considered: “a pathological repairing process in liver injuries leading to extracellular cell matrix (ECM) accumulation evidencing chronic liver diseases”. Chronic viral hepatitis, alcohol consumption, autoimmune diseases as well as non-alcoholic steatohepatitis are from the main causes of liver fibrosis (Lee et al., 2015; Mieli-Vergani et al., 2018). Hepatic stellate cells (HSCs) exist in the sinus space next to the hepatic epithelial cells as well as endothelial cells (Yin et al., 2013). Normally, HSCs are quiescent and mainly participate in fat storage and in the metabolism of vitamin A. HSCs are produced during liver injury and then transformed into myofibroblasts. The activated HSCs resulted in a sequence of events considered as marks fibrosis. The activation of HSCs mostly express alpha smooth muscle actin (α-SMA). Moreover, ECM is synthesized and secreted by HSCs that affects markedly the structure and function of the liver tissue leading to fibrosis (Tsuchi...
Hepatic Stellate Cells and Liver Fibrosis
Comprehensive Physiology, 2011
Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer.
Current Opinion in Gastroenterology, 2009
Purpose of review-This review will summarize the most significant work that contributed to the understanding of liver fibrosis progression and resolution, which in turn has yielded new areas of therapeutic targeting. Recent findings-Liver fibrosis is the result of an imbalance between production and dissolution of extracellular matrix. Stellate cells, portal myofibroblasts, and bone marrow derived cells converge in a complex interaction with hepatocytes and immune cells to provoke scarring in response to liver injury. Uncovering the specific effects of growth factors on these cells, defining the interaction of different cell population during liver fibrosis and characterizing the genetic determinants of fibrosis progression will enable the discovery of new therapeutic approaches. Summary-The outcome of improved understanding of liver fibrosis process, especially the regulation and activation of stellate cells, is reflected in the development of new therapeutic strategies, which are validated in animal models.
New Concepts on Pathogenesis and Diagnosis of Liver Fibrosis; A Review Article
Middle East Journal of Digestive Diseases, 2016
Liver fibrosis is a potentially reversible response to hepatic insults, triggered by different chronic diseases most importantly viral hepatitis, alcoholic, and nonalcoholic fatty liver disease. In the course of the chronic liver disease, hepatic fibrogenesis may develop, which is attributed to various types of cells, molecules, and pathways. Activated hepatic stellate cell (HSC), the primary source of extracellular matrix (ECM), is fundamental in pathophysiology of fibrogenesis, and thus is the most attractable target for reversing liver fibrosis. Although, liver biopsy has long been considered as the gold standard for diagnosis and staging of hepatic fibrosis, assessing progression and regression by biopsy is hampered by its limitations. We provide recent views on noninvasive approaches including serum biomarkers and radiologic techniques.
Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets
World journal of gastroenterology, 2016
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in ...
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The “Initiation” phase of hepatic stellate cells activation overlaps and continues with the “Perpetuation” phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
Cooperation of Liver Cells in the Process of Liver Fibrosis
Advances in Anatomy Embryology and Cell Biology, 2001
Fibrosis is the common response to chronic liver injury from various origins including metabolic diseases, viral infections, alcohol abuse, and various chemicals. Liver fibrosis is characterized by both quantitative and qualitative changes in the composition and distribution of extracellular matrix (ECM) that are reflected by a three-to fivefold net increase of ECM and replacement of low-density basement membranelike material by interstitial type matrix abundant in fibril-forming collagens {Friedman 1993; Gressner 1998). This gross remodeling of ECM in the fibrotic liver represents an imbalance between the deposition and degradation of ECM molecules. Hepatic stellate cells, which are involved in the regulation of ECM production and degradation (Table 10), have been found to play a pivotal role in the initiation and progression of hepatic fibrosis (Friedman 1993, 2000; Gressner 1998). Following acute or chronic liver injury, hepatic stellate cells transdifferentiate: they proliferate, lose lipid droplets, change morphology from the star-shaped cells to that of myofibroblasts with the expression of smooth muscle a-actin (reviewed by Gressner 1998), and migrate to sites of tissue damage (Ikeda et al. 1999; Marra et al. 1998b). Activation of stellate cells that initiates the development of the inflammatory process results from multiple interactions between many cell types (injured hepatocytes, Kupffer cells, endothelial cells, platelets, infiltrating inflammatory cells) mediated by cytokines and reactive oxygen species, and from the changes in the composition of the perisinusoidal matrix (Arthur 2000; Gressner 1998). In the case of chronic liver damage, HSC activation persists during the "perpetuation phase" (Friedman 1993; Gressner 1998), and progressive accumulation of ECM leads to liver fibrosis, and finally to cirrhosis. The key role of hepatic stellate cells in the development of liver fibrosis may be deduced from the correlation between the number of HSC and the extent of liver fibrosis observed both in experimental liver injury (Friedman 1993) or in patients with chronic hepatitis C treated with interferon (Sakaida et al.1999). 14.1 Factors Involved in the Activation of Hepatic Stellate Cells Fibrogenesis is regarded as a dynamic process related to the extent and duration of parenchymal cell injury. The cascade of events that leads in vivo to the development of liver fibrosis is initiated by noxious agents that may be different in various kinds of liver damage.lt is, however, widely believed that injury to hepatocytes and/or Kupffer and endothelial cells results in the release of many substances that cause transformation of quiescent stellate cells into myofibroblast-like cells. The activation ofHSC may 97