Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis

Abstract

Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date.

Keywords: hepatic stellate cells; mesenchymal stromal cells; miRNA; natural killer cells; tumor necrosis factor-stimulated gene; urokinase plasminogen activator receptor.

Figure 1

Cellular alterations during hepatic fibrosis: Multiple factors can cause liver injury. These factors induce liver inflammation through various pathways and cellular systems. Normal liver parenchyma contains a hepatocyte layer with microvilli and layers of fenestrated liver sinusoidal endothelium cells (LSECs), and a higher number of quiescent hepatic stellate cells (qHSCs), Kupffer cells (KCs), and natural killer cells (NKs). It also contains a normal amount of basement-forming collagens (Types IV and VI). Upon injury, the HSCs become activated and secrete a large amount of ECM, which leads to the loss of both endothelial fenestrations and hepatocyte microvilli, resulting in impairment of bidirectional metabolic exchange of portal venous flow. TNF-α can mediate a dual and opposing effect by acting on TNF receptors expressed on the endothelial cells. The LSECs also promote vascular leakage of plasma proteins and initiate the exocytosis of Weibel–Palade bodies (WPBs, denoted as a yellow oval), bringing P-selectin to the cell surface, which initiates diapedesis. Replacement of fibrillary collagen occurs, consisting of collagen I, III, and fibronectin. Furthermore, there is infiltration of immune cells, such as neutrophils and monocytes, and the injured area recruits the NK-T cells and alters liver morphology.

Figure 2

suPAR as a serum biomarker: Upon inflammation and for controlling fibrin degradation, the uPAR is cleaved from the cell surface as Pro-uPA and activates in the uPA form. Plasminogen is converted to plasmin via either the plasminogen activator receptor or the urokinase receptor and helps in the degradation of the ECM by breaking fibrin strands during liver fibrosis. In patients with liver diseases, circulating suPAR levels increase with the increase in disease severity, and are indicative of an adverse prognosis.

Figure 3

The importance of balance between MMPs and TIMPs, and between HGF and TGF-β, as hepatoprotective and counteracting agents in liver fibrosis.

Figure 4

The role of TSG-6 in cellular growth and proliferation in fibrotic liver cells: TSG-6 has the potential to improve liver injury; it can induce proliferation, stemness, and increase the immunomodulatory mechanism of MSCs. TSG-6 reduces inflammation and changes in tissue repair via mechanisms such as reducing neutrophil infiltration and activation, and inhibiting inflammatory M1–M2 polarization of monocytes. M2 macrophages produce complex cytokines, and have various functions; they can be further divided into M2a, M2b, M2c, and M2d subtypes. M2a cells can prevent fibrosis by inducing regulatory T cells.

Figure 5

NK cell responses and targeted therapy: (1) NK cells are the first responders in the immune system, and can directly recognize and begin the cell death mechanism. (2) NK cells release exosomes with cytotoxic capabilities, and can contain miRNAs, cytokines, and NK cell surface receptors. (3) Activated NK cells selectively kill early or activated HSCs, but not quiescent HSCs. IFN-γ-producing NK cells directly induce HSC death, but also further enhance NK cell cytotoxicity against HSCs. Quiescent cells do not express elevated NK-activating ligand, and are hence resistant. (4) In proliferating cells, DPP4 is expressed at low levels, but in senescent cells, DPP4 mRNA levels increase, leading to the production of DPP4, which localizes on the cell surface and is exposed to the extracellular space. The localization of DPP4 enables selective elimination by immune cells such as NKs via ADCC.

Figure 6

The role of various miRNA families in liver fibrosis: Liver cells take and release exosomal microRNAs (miRNAs). Their role in liver fibrosis: Extracellular vesicles (EVs) derived from adipose tissue, HSCs, and neutrophils containing miR-155, -214, and -223, respectively, are taken up by liver cells, leading to increased insulin resistance by suppressing PPARγ. miR-214 in HSCs is shuttled by EVs to hepatocytes, resulting in inhibition of CCN2/Ccn2. Under a high-fat diet and alcohol consumption, miR-223 is elevated in hepatocytes, and attenuates NASH progression by targeting Cxcl10 and Taz. The miR-29 and miR-15 families regulate hepatic fibrosis in the following ways: (1) miR-29a targets AKT3 and PI3K, which helps to induce cell apoptosis through the caspase-9 cascade pathway; (2) PDGF and IGF receptors suppress the overall effect of the PI3K/AKT signaling pathway; (3) miR-16 targets HGF and SMAD7, and blocks the TGF-β/Smad signaling pathway; (4) miR-192 downregulates cyclin M1 and inhibits cell proliferation; (5) miR-1 promotes endothelial inflammation.