Antifibrotic Therapies in the Liver (original) (raw)

Liver fibrosis: a dynamic and potentially reversible process

Histology and histopathology, 2010

In any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.e., the dynamic process leading to increased deposition of ECM and much more) can lead to different patterns of fibrosis and is sustained by myofibroblast-like cells (MFs) of different origin, with activated hepatic stellate cells (HSC/MFs) being the major cell type involved. Major pro-fibrogenic mechanisms also include oxidative stress, as well as derangement of epithelial-mesenchymal interactions ...

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...

Changing the pathogenetic roadmap of liver fibrosis? Where did it start; where will it go?

Journal of Gastroenterology and Hepatology, 2008

The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes -formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) -the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrixproducing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelialmesenchymal transition, by influx of bone marrow-derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-b) plays a central role, which is controlled by the bonemorphogenetic protein (BMP)-7, an important antagonist of TGF-b action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials.

Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options

2007

Despite intensive studies, the clinical opportunities for patients with fibrosing liver diseases have not improved. This will be changed by increasing knowledge of new pathogenetic mechanisms, which complement the "canonical principle" of fibrogenesis. The latter is based on the activation of hepatic stellate cells and their transdifferentiation to myofibroblasts induced by hepatocellular injury and consecutive inflammatory mediators such as TGF-β. Stellate cells express a broad spectrum of matrix components. New mechanisms indicate that the heterogeneous pool of (myo-)fibroblasts can be supplemented by epithelial-mesenchymal transition (EMT) from cholangiocytes and potentially also from hepatocytes to fibroblasts, by influx of bone marrow-derived fibrocytes in the damaged liver tissue and by differentiation of a subgroup of monocytes to fibroblasts after homing in the damaged tissue. These processes are regulated by the cytokines TGF-β and BMP-7, chemokines, colony-stimulating factors, metalloproteinases and numerous trapping proteins. They offer innovative diagnostic and therapeutic options. As an example, modulation of TGF-β/BMP-7 ratio changes the rate of EMT, and so the simultaneous determination of these parameters and of connective tissue growth factor (CTGF) in serum might provide information on fibrogenic activity. The extension of pathogenetic concepts of fibrosis will provide new therapeutic possibilities of interference with the fibrogenic mechanism in liver and other organs.

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.

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

Cells

Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extr...

Hepatic fibrosis: From bench to bedside

Journal of Gastroenterology and Hepatology, 2002

Antifibrotic therapies are preferentially targeted to the activated mesenchymal cells in the liver that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent hepatic stellate cells and (myo-) fibroblasts. Their activation is triggered and maintained by several fibrogenic modulators and cytokines, but also by mechanical stress. Whereas many agents inhibit stellate cell/myofibroblast proliferation and collagen synthesis in vitro , only few of them are tolerable or effective in suitable animal models in vivo. An antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, sho-saiko-to which contains the related compound baicalein, for halofuginone, another plant-derived agent, for the phosphodiesterase inhibitor pentoxifylline and for LU135252, an oral inhibitor of the endothelin-A-receptor. The retrospective finding that interferon-a therapy for hepatitis C may halt or even reverse fibrosis, has to be confirmed in prospective randomized trials. Strategies to inhibit the profibrogenic cytokines transforming growth factor (TGF)-b or connective tissue growth factor (e.g. by soluble decoy receptors) are evolving, but have not been convincing yet. Drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically up-regulated on activated stellate cells, for example those for platelet-derived growth factors or collagen type VI. In addition, blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Combined with the evolving validation of serological markers of fibrogenesis and fibrolysis an effective and individualized treatment of liver fibrosis can be anticipated.

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