Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Abstract

The response to injury is one of wound healing and fibrogenesis, which ultimately leads to fibrosis. The fibrogenic response to injury is a generalized one across virtually all organ systems. In the liver, the injury response, typically occuring over a prolonged period of time, leads to cirrhosis (although it should be pointed out that not all patients with liver injury develop cirrhosis). The fact that many different diseases result in cirrhosis suggests a common pathogenesis. The study of hepatic fibrogenesis over the past 2 decades has been remarkably active, leading to a considerable understanding of this process. It has been clearly demonstrated that the hepatic stellate cell is a central component in the fibrogenic process. It has also been recognized that other “effector” cells are important in the fibrogenic process, including resident fibroblasts, bone marrow derived cells, fibrocytes, and even perhaps cells derived from epithelial cells (i.e., through epithelial to mesenchymal transition or EMT). A key aspect of the biology of fibrogenesis is that the fibrogenic process is dynamic; thus, even advanced fibrosis (or cirrhosis) is reversible. Together, an understanding of the cellular basis for liver fibrogenesis, along with multiple aspects of the basic pathogenesis of fibrosis, have highlighted many exciting potential therapeutic opportunities. Thus, while the most effective “anti-fibrotic” therapy is treatment of the underlying disease, in situations in which this not possible, specific anti-fibrotic therapy is likely to not only become feasible, but will soon become a reality. The goal of this review is to highlight the mechanisms underlying fibrogenesis that may be translated into future anti-fibrotic therapies and to review the current state of clinical development.

Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis

“…Excess ECM can be degraded by MMPs. Thus, understanding and controlling the molecular mechanisms involved in the activation of HSCs, production or degradation of ECM, and reduction of the number of activated myofibroblasts is important for developing novel therapies for liver fibrosis [16][17][18][19][20][21]. The current therapeutic approach for liver fibrosis is divided into five categories, as discussed below.…”

Therapeutic effects of serum extracellular vesicles in liver fibrosis

“…The long-term nature of the inflammatory and injury processes in these diseases is frequently associated with the development of hepatic fibrosis, a pathology in which insoluble collagen and matrix components are deposited in excessive amounts in the interstitial spaces, which can severely compromise liver function [2]. While fibrosis may reduce or resolve in some individuals after treatment of the underlying disease, many patients are non-responsive to this approach and are reliant on direct fibrosis therapy for which approved drugs are lacking [3,4]. A new lead in liver fibrosis research has come from studies of extracellular vesicles (EVs) which are derived from numerous cell types in the body and comprise exosomes, microvesicles and apoptotic bodies [5].…”

Біохімічні Маркери Функціональних Порушень Печінки Хворих На Системний Червоний Вовчак

“…Патологію печінки у хворих СЧВ на піці активності хвороби зазвичай пов'язують із самою хворобою, та деякі автори вважать основною причиною її виник-нення вживання гепатотоксичних препаратів базис-ної терапії [3][4][5]8]. Уточнення характеру ураження печінки при даній нозології має не лише теоретич-не, а й практичне значення, оскільки при її патології частіше спостерігається затяжний та прогресуючий перебіг хвороби.…”