Mechanisms of Hepatic Fibrogenesis

Abstract

Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

Cellular and molecular mechanisms in liver fibrogenesis

“…If persistent liver fibrogenesis may be envisaged as a major driving force for the progression of CLD towards cirrhosis, liver failure and hepatocellular carcinoma (HCC), CLD fibrogenic progression has then a very significant clinical impact which is best described by the following facts [1,[6][7][8][9]]. …”

“…6. Progression of a CLD towards cirrhosis has been estimated to take at least 10 -15 years and sometimes to require even 30 or more years, but it may be also extremely rapid in particular clinical settings, such as in children affected by biliary atresia, in patients with HCV recurrence after OLT, or in HCV-HIV co-infected patients [1,[6][7][8][9]]. CLD progression is still then difficult to predict although a number of clinical features have been identified that may serve as predictors for the development of advanced fibrosis and cirrhosis, including: male gender, age <50 years, age at infection (particularly for HCV chronic infection), daily alcohol intake, hepatic iron content, obesity and diabetes mellitus as well as individual factors (differences in immune responses vs infectious agents and related auto-antigens, differences in drug metabolism).…”

“…In the last two decades experimental and clinical studies have provided considerable evidence indicating that liver fibrosis and, possibly, even cirrhosis should be considered as potentially reversible processes [1,3,6,11]. As outlined by several researchers in authoritative reviews [1,3,6,11], critical issues in fibrosis and cirrhosis reversal, providing that the etiological agent or condition may be eliminated or efficiently counteracted by means of selective therapy, are represented by the induction of hepatic MFs apoptosis and by an increased degradation of excess ECM.…”

“…When trying to synthetically describe this first stage (see Figure 1), a number of concepts should be taken in mind [1][2][3][4][5][6]: i) perpetuation of hepatic injury, a typical hallmark of CLD progression, depends not only from chronic exposure to the specific etiology but also results from chronic injury itself and chronic inflammatory response, through a number of final mediators (with a prevailing role of reactive oxygen species or ROS); ii) chronic activation of inflammatory response and recruitment/activation of cells involved in either innate or acquired immunity can progressively result in what one may define pro-fibrogenic environment, in which synthesis and release of growth factors, cytokines, chemokines, ROS and other mediators will from one side impair significantly hyperplasia/regeneration of hepatic tissue and on the other side will favor chronic activation of wound healing and fibrogenesis; iii) the profibrogenic environment will, in turn, lead to persistent activation of MF-like cells and then increased deposition of ECM components which is paralleled by altered/inefficient remodeling; iv) emerging evidence suggests a major role for hypoxia and angiogenesis in sustaining and, likely, driving fibrogenesis as well as vascular changes that become more and more relevant during CLD progression; v) liver fibrosis in this first stage is potentially reversible, as shown by both experimental and clinical studies; fibrosis reversion may depend on the removal of exposure to the specific etiology or to effective therapy.…”

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

“…Progressive fibrosis, increased hepatic vascular tone, and ongoing inflammation due to permanent liver injury are major causes of decompensation, morbidity, and mortality. These processes incite continuous extracellular matrix (ECM) protein remodeling, which reflects the progression of liver disease 2, 3, 4, 5, 6. During ECM remodeling, matrix metalloproteinases (MMPs) generate small peptide fragments, known as neoepitopes, that are released into the circulation.…”