Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Abstract

Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts

“…Liver myofibroblasts used to test antifibrotic drugs L Aoudjehane et al degradation of ECM. 11,25,26 Our results suggest that at least part of this inter-patient variability in fibrosis progression is dependent on the HLMF themselves; their activation and ECM production (in our case, evaluated from α-SMA and Coll1 transcription) and their proliferation vary between subjects, displaying a regular-Gaussian-distribution for the three parameters. We can therefore advance the hypothesis that subjects who spontaneously display higher activation Liver myofibroblasts used to test antifibrotic drugs L Aoudjehane et al and/or proliferation rates of their HLMF are predisposed to being rapid fibrosers, although our present experiments did not allow us to draw any conclusions, because the HLMF were obtained from patients undergoing surgery for metastases, without fibrosing disease and without significant liver fibrosis (data not shown).…”

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

“…The progression of liver fibrosis is promoted by oxidative stress [12,13], although this is likely to be just one of multiple processes involved. In the present study, oxidative stress in the liver of octn1 -/-was much greater than that in wild-type mice at 1 and 2 weeks after treatment with DMN (Fig.…”

“…In particular, hepatic stellate cells (HSCs) are activated by oxidative stress to collagen-producing myofibroblasts, which promote liver fibrosis by producing ECM [12,13]. Oxidative stress may also injure parenchymal cells, leading to further 6 progression of liver injury.…”

“…Total RNA was extracted according to the standard ISOGEN procedure (Nippon Gene, Toyama, Japan) and used for cDNA synthesis with oligo (dT) [12][13][14][15][16][17][18] …”

Lights on MAIT cells, a new immune player in liver diseases

“…However LI-MAIT cells could potentially aggravate liver pathologies. LI-MAIT cells can produce IL-17, which plays a major role in the pathogenesis of several chronic liver disease, of alcoholic, metabolic, viral or autoimmune origin, and contribute to the progression of liver fibrosis [17]. Using a mouse model, Harley et al have demonstrated the pathogenic role of IL-17 in the progression of non-alcoholic fatty liver disease (NAFLD) since IL-17 deficient mice were protected against NAFLD [18].…”