Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis (original) (raw)
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Targeting fibrosis with selective drug carriers
Arab Journal of Gastroenterology, 2010
This review summarises the progress that has been made in recent years in the field of drug delivery to the hepatic stellate cells (HSCs). HSCs are the crucial cells in the pathogenesis of liver fibrosis and consequently the main target cell for antifibrotic therapies. To enhance cell specificity, such antifibrotic drugs can be coupled to drug carriers that accumulate in this cell type. In recent years, several drug carriers directed at HSCs have become available and many drugs have now been coupled to these carriers. Using this strategy, high drug accumulation in HSCs has been achieved. Several drugs, such as kinase inhibitors, viral vectors, apoptosis-inducing drugs and drugs that inhibit cell proliferation or inflammation, have been targeted to HSCs. Receptor-mediated endocytosis subsequently leads to the release of internalised drugs and the pharmacological effects of these drugs have been demonstrated in HSCs. The selective delivery of drugs to HSCs may therefore provide a new approach to study crucial pathways or new treatments in liver fibrosis. This method may also be applied to those drugs whose adverse effects have prevented their systemic application in the past.
Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell
Current Tissue Microenvironment Reports
Purpose of Review Treatment of liver fibrosis benefits from hepatic stellate cell (HSC)-specific delivery. Since the description of first carrier to HSC, many developments have taken place in this area. The purpose is to give an overview of the different carriers and homing moieties that are available for HSC targeting and illustrate the opportunities and hurdles they provide. Recent Findings There is a growing number of homing devices to deliver drugs to HSC, and options to deliver siRNA to HSC have emerged. Other developments include controlling corona formation, development of linker technology, and design of theranostic approaches. We are on the eve of reaching the clinic with innovative HSC-specific compounds. Summary An overview of different core molecules is presented together with an overview of targeting strategies toward different receptors on HSC, providing a versatile toolbox. Many therapeutics, ranging from small chemical entities and proteins to RNA- or DNA-modulating ...
Reprint of: Targeting fibrosis with selective drug carriers
Arab Journal of Gastroenterology, 2010
This review summarises the progress that has been made in recent years in the field of drug delivery to the hepatic stellate cells (HSCs). HSCs are the crucial cells in the pathogenesis of liver fibrosis and consequently the main target cell for antifibrotic therapies. To enhance cell specificity, such antifibrotic drugs can be coupled to drug carriers that accumulate in this cell type. In recent years, several drug carriers directed at HSCs have become available and many drugs have now been coupled to these carriers. Using this strategy, high drug accumulation in HSCs has been achieved. Several drugs, such as kinase inhibitors, viral vectors, apoptosis-inducing drugs and drugs that inhibit cell proliferation or inflammation, have been targeted to HSCs. Receptor-mediated endocytosis subsequently leads to the release of internalised drugs and the pharmacological effects of these drugs have been demonstrated in HSCs. The selective delivery of drugs to HSCs may therefore provide a new approach to study crucial pathways or new treatments in liver fibrosis. This method may also be applied to those drugs whose adverse effects have prevented their systemic application in the past.
Journal of Gastroenterology and Hepatology, 2012
Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)-b is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells, stimulating collagen gene transcription, and suppressing matrix metalloproteinases expression. Thus, TGF-b as well as its intracellular mediators, Smad proteins, can be potential therapeutic targets for liver fibrosis. Constitutive phosphorylation and nuclear accumulation of Smad3 is the common feature of activated stellate cells. We have synthesized a novel small compound that inhibits Smad3-dependent collagen gene transcription by promoting nuclear import of a transcriptional repressor, YB-1. Another insight into anti-fibrotic strategies is the contribution of bone marrow-derived cells to the regression of liver fibrosis. Administration of granulocyte-colony stimulating factor enhanced the migration of bone marrow-derived cells into fibrotic liver tissue and accelerated the regression of experimental liver fibrosis. We have recently identified novel unknown factors expressed by bone marrow-derived cells that not only ameliorate liver fibrosis but also accelerate regeneration of fibrotic liver.
Addressing Liver Fibrosis with Liposomes Targeted to Hepatic Stellate Cells
Journal of Liposome Research, 2007
Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of liver fibrosis is mainly based on the removal of the underlying cause of the disease and liver transplantation, which is the only treatment for patients with advanced fibrosis. Hepatic stellate cells (HSC) are considered to be key players in the development of liver fibrosis. Chronically activated HSC produces large amounts of extracellular matrix and enhance fibrosis by secreting a broad spectrum of cytokines that exert pro-fibrotic actions in other cells, and in an autocrine manner perpetuate their own activation. Therefore, therapeutic interventions that inhibit activation of HSC and its pro-fibrotic activities are currently under investigation worldwide. In the present study we applied targeted liposomes as drug carriers to HSC in the fibrotic liver and explored the potential of these liposomes in antifibrotic therapies. Moreover, we investigated effects of bioactive compounds delivered by these liposomes on the progression of liver fibrosis. To our knowledge, this is the first study demonstrating that lipid-based drug carriers can be selectively delivered to HSC in the fibrotic liver. By incorporating the bioactive lipid DLPC, these liposomes can modulate different processes such as inflammation and fibrogenesis in the fibrotic liver. This dual functionality of liposomes as a drug carrier system with intrinsic biological effects may be exploited in new approaches to treat liver fibrosis.
Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update
Current Issues in Molecular Biology
Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.
New Therapeutic Approaches to Liver Fibrosis: A Practicable Route?
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.
Lipid nanoparticulate drug delivery system for the treatment of hepatic fibrosis
Archives of Hepatitis Research, 2021
HSC becomes a cellular target for the treatment of hepatic fi brosis [1]. Low therapeutic effi cacy and undesirable systemic effect of standard conventional therapies limit their clinical applications in this fi eld.Nano-material based drug delivery systems such as Lipid, polymeric, inorganic and protein nanoparticles have been shown an exceptional potential for novel therapeutic approaches to deliver anti-fi brotic nutrients