Regression of Liver Fibrosis

Abstract

Liver fibrosis is the final common pathway of chronic or iterative liver damage. Advanced chronic fibrosis is described as cirrhosis with a loss of architecture and attendant functional failure and the development of life-threatening complications. However, compelling evidence from rodent models and human studies indicates that if the injury is removed liver fibrosis is reversible. Hepatocytes, activated hepatic stellate cells, endothelial and immune cells, particularly macrophages, cooperate in the establishment and resolution of liver fibrosis. Here the authors provide a short overview of the mechanisms regulating the profibrotic and proresolution response, with the aim of highlighting potential new therapeutic targets. Liver disease is a major unmet medical need; currently, the sole approaches are the withdrawal of the injurious stimulus and liver transplantation. The authors conclude with a brief review of the feasibility of macrophage-based cell therapy for liver fibrosis.

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

“…In contrast, in chronic liver diseases an imbalance of pro-fibrogenic and antifibrogenic mechanisms causes persistent activation of proliferating, contractile, and migrating myofibroblasts that lead to excessive production of ECM [8,9]. The liver's fate to either pass into an anti-fibrotic scar-dissolving stage or to proceed into an uninhibited fibrosis-promoting stage is hereby mainly regulated by non-parenchymal cells (NPCs), including Kupffer cells and other immune cells [10][11][12]. Thus, hepatocyte apoptosis and release of damage-associated patterns (DAMPs) by hepatocytes not only activate HSCs directly but also induce recruitment and activation of lymphocytes and macrophages that contribute to promotion of HSC trans-differentiation and myofibroblast activation by producing pro-inflammatory and pro-fibrogenic cytokines [13,14].…”

Ultrastructural Characteristics of Rat Hepatic Oval Cells and Their Intercellular Contacts in the Model of Biliary Fibrosis: New Insights into Experimental Liver Fibrogenesis

“…Unfortunately, the precise mechanisms underlying liver fibrogenesis are not well understood. Hepatic fibrogenesis has a dynamic nature and is a complex process that involves marked accumulation of the extracellular matrix (ECM) components, activation of cells capable of producing matrix materials, cytokine release, and tissue remodeling regulated by matrix metalloproteinases and their inhibitors [1, 4–9]. It is assumed that hepatic stellate cells (HSCs) and myofibroblasts play a crucial role in the process of liver fibrosis, including extensive remodeling of ECM components and deposition of fibrillary collagen types I and III.…”

“…It is assumed that hepatic stellate cells (HSCs) and myofibroblasts play a crucial role in the process of liver fibrosis, including extensive remodeling of ECM components and deposition of fibrillary collagen types I and III. It is frequently emphasized that activated HSCs/myofibroblasts, especially the transitional form of HSCs (T-HSCs), defined as the main fibrogenic cell type in the liver, constitute a major source of fibril-forming ECM in this organ [5, 6, 9–13]. …”

Aging as a complex of typical pathophysiological processes

“…Анализ источников литературы показывает, что все возрастные изменения тканей укладываются в классификации альтеративных процессов: повреждения клеток либо их последствий в качестве стойких адаптивных изменений (табл.). Некоторые из альтеративных процессов модифицируемы и обратимы [14,15,16], более того, современная биомедицинская наука предлагает множество решений этой проблемы в контексте старения. Выделяются несколько подходов: индукция репарации и регенерации различными факторами, замещение поврежденных клеток стволовыми и дифференцированными (клеточная терапия), дедифференцировка эпигенетическими подходами и гормонами, элиминирование поврежденных клеток таргетными цитотоксикантами (сенолитиками), замена тканей и органов и многие другие тактики [14,17].…”