Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues

Abstract

The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.

Collagen proportionate area is an independent predictor of long‐term outcome in patients with non‐alcoholic fatty liver disease

“…The NAS score is a problematic endpoint, given its high inter and intra‐observer variability, its heavy reliance on steatosis, the exclusion of portal inflammation and the poor correlation with clinical outcomes . Although it is indisputable that inflammation (loosely termed as steatohepatitis) is one of the key drivers of the fibrogenic process, it is not easy to quantify and characterise in its multicellular complexity . Therefore, the extent of fibrotic transformation constitutes the hard end‐point of this pathophysiological process.…”

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles

“…In response to liver injuries such as alcoholic liver and non-alcoholic fatty liver disease (NAFLD) diseases, Kupffer cells are activated and a polarization to an M1-like phenotype is promoted in resident as well as monocyte-derived macrophages (24,25). When injury ends, there is a switch to M2 restorative macrophages that release anti-inflammatory cytokines, regenerative growth factors, and matrix degrading metalloproteinase (MMP) expression, which promote tissue repair (26).…”

Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis

“…Liver fibrosis results from the repair of chronic liver injuries and eventually leads to cirrhosis and end stage liver disease. The fibrotic response involves over deposition of ECM proteins in the liver 27 and reflects a balance between ECM production and degradation, such that fibrosis is reversible in its initial stages 28 . There are several cellular sources of ECM in the liver, including hepatic stellate cells (HSC), portal fibroblasts, bone marrow-derived cells, and fibroblasts derived from hepatocyte EMT [29][30][31][32] .…”