Pathobiology of liver fibrosis: a translational success story

Abstract

Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…Fibrosis is a pathological state similar to an aberrant scarring process; it is characterized by the abnormal accumulation of extracellular matrix (ECM) components as a consequence of a chronic inflammatory response [118,119]. It is well known that myofibroblast (MFB) is the main cell type with the capacity to synthesize collagen in the fibrotic state [119,120].…”

Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p

“…6e8 There is optimism that these various approaches will result in the development of effective antifibrotic therapies even when the underlying primary disease persists. 5 Many studies have found that alterations in HSC activation are orchestrated by dynamic changes in the expression and/or action of a host of soluble or cell-associated signaling molecules, 6,9 but an additional mechanism of HSC regulation has recently come to light with our finding that fibrogenic pathways in HSCs are modulated by exosomes. 10 Exosomes, produced by most if not all cells of the body, are nanosized membranous vesicles that are capable of delivering complex molecular payloads to recipient cells, which may become functionally reprogrammed according to the molecular cues received.…”

CXCL6‐EGFR‐induced Kupffer cells secrete TGF‐β1 promoting hepatic stellate cell activation via the SMAD2/BRD4/C‐MYC/EZH2 pathway in liver fibrosis

“…This excessive deposition of ECM proteins at sites of tissue damage, resulting from, for example, viral infection or alcoholic liver disease, is a consequence of a dysregulated wound‐healing response. Although reversible if the source of the injury is eliminated, unchecked liver fibrosis can develop into cirrhosis and even liver failure due to portal hypertension, with the only treatment option being transplantation 1, 2. Chronic liver disease is a major cause of mortality worldwide and correlates with an increased risk of hepatocellular carcinoma 3…”