Liver Fibrosis-Novel Therapy Perspective

Cells

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative t...

F1000 - Post-publication peer review of the biomedical literature, 2000

Gastroentérologie Clinique et Biologique, 2007

Journal of Clinical Investigation, 2013

Cellular targets and multicellular fibrogenic units Activated myofibroblasts, representing a spectrum of similar ECM-producing cells that mainly derive from hepatic stellate cells and portal fibroblasts, are the major producers of the fibrotic ECM and the most downstream cellular effectors of liver fibrosis (Figure 1). Very few hepatic myofibroblasts in fibrosis stem from BM-derived fibrocytes (12). Moreover, complete epithelial-mesenchymal transition (EMT) of hepatocytes and bile duct epithelia to myofibroblasts may be a rare event-while an "incomplete" EMT of these cells with acquisition of a fibrogenic phenotype is common (28). Myofibroblasts and their products are primary targets for antifibrotic therapies, which in principle would address all types of fibrosis, including advanced fibrosis. Importantly, additional cellular elements that are either upstream of the myofibroblasts or tightly linked to fibrogenic activation within cellular units may provide a basis for complementary and more disease-specific antifibrotic approaches. A combination therapy approach may be more effective, given that crosstalk between different cell types generally underlies fibrogenic activation. Conceptually, three major multicellular functional units can be defined according to their constituent cell types: (a) perisinusoidal/vascular-pericytes, i.e., hepatic stellate Conflict of interest: The authors have declared that no conflict of interest exists.

Seminars in Liver Disease, 2015

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...

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...

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.

Current medicinal …, 2008

The progress of research on the molecular pathogenesis of liver fibrosis and the consequent discoveries are likely to open new possibilities for therapeutic approaches to the management of this disease in the future. A key step towards this goal is a deeper comprehension of both the complex molecular and cellular mechanisms and the signaling involved in the development of hepatic fibrosis. It is not yet clear, in fact, what role apoptosis, cytokines, oxidants and other molecules play and what relationships exist between them in favouring or delaying the onset of these adverse mechanisms. At present, a unique mechanism is recognized to be the main reason for the cause and development of liver fibrosis: sustained hepatic stellate cell activation and transformation. Therefore, in this review, after considering the cause, development of fibrosis and interrelation between molecular and cellular profibrotic mechanisms, the part played in counteracting both of these actions by some anti-oxidants and anti-fibrotic molecules such as cytokines, prostacyclin and others will be taken into consideration. The gene therapy and the possible therapeutic use of liver stem cells and tissue engineering will also be dealt with briefly. At the moment, however, the efficacy of these novel strategies still needs to be further validated in animal studies and confirmed in clinical trials. Some data that are already available from in vitro and animal studies demonstrating the effectiveness of novel approaches to inhibiting or treating liver fibrosis can only offer moderate hope.

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 ...