Effective Antifibrotic Drugs Research Articles

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice.

Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 (Surf4 LKO) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4 LKO mice compared with control Surf4 flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl4-induced liver fibrosis is significantly lower in Surf4 LKO mice than in Surf4 flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4 flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4 flox hepatocytes but not from Surf4 LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4 flox mice but does not further reduce liver fibrosis in Surf4 LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Orphan receptor GPR176 in hepatic stellate cells exerts a profibrotic role in chronic liver disease

Background & AimsChronic liver disease (CLD) remains a global health issue associated with a significant disease burden. Liver fibrosis, a hallmark of CLD, is characterised by the activation of hepatic stellate cells (HSCs) that gain profibrotic characteristics including increased production of extracellular matrix protein. Currently, no antifibrotic therapies are available clinically, in part because of the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for antifibrotic drug development. MethodsSmall interfering RNA-mediated knockdown of GPR176 was used to assess the in vitro function of GPR176 in HSCs and in precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed using the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knockout mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets. ResultsWe identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knockdown of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of GPR176 did not influence liver homeostasis, but Gpr176-/- mice developed less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression was correlated with in vitro HSC activation and with fibrosis stage in patients with CLD. ConclusionsGPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific antifibrotic candidate to treat CLD. Impact and implicationsThe lack of effective antifibrotic drugs is partly attributed to the insufficient knowledge about the mechanisms involved in the development of liver fibrosis. We demonstrate that the G-protein coupled receptor GPR176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens new avenues for the development of targeted interventions.

Metformin exerts anti-liver fibrosis effect based on the regulation of gut microbiota homeostasis and multi-target synergy

Liver fibrosis can progress to cirrhosis if left untreated. Therefore, identifying effective antifibrotic drugs is crucial. This study aimed to investigate the role and potential mechanism of metformin in treating hepatic fibrosis based on the synergistic effect of multiple targets and the “intestine-liver axis” theory. A CCl4-induced liver fibrosis mouse model was established. We measured liver function, liver fibrosis indicators, oxidative stress and inflammation indices. Hematoxylin and eosin and Masson's trichrome staining were used to detect collagen deposition. The expression of apoptotic proteins, TGF-β/Smads and TIMP-1/MMPs was assessed. 16S rRNA and untargeted metabolomics (liquid chromatography-mass spectrometry) were used to assess mouse intestinal flora and metabolites, performing a comprehensive correlation analysis. Metformin improved the general status and liver function and decreased liver collagen deposition in CCl4-induced liver fibrotic mice. Compared with the control group, IL-6, TNF-α and COX-2 serum levels in the liver fibrosis group increased. Although not significantly different, the serum inflammatory marker levels in the metformin group were lower than those in the model group. Metformin decreased serum MDA and increased serum SOD activity, which increased and decreased, respectively, in the model group. Furthermore, metformin inhibited liver cell apoptosis, TGF-β1 expression and TIMP-1, while promoting Smad7 expression, MMP-1 and MMP-2 in fibrotic mice. 16S rRNA analysis indicated that metformin significantly ameliorated the Bacteroides, Helicobacter, Parabacteroides and Parasutterella imbalance. We identified 385 differential metabolites between the metformin and model groups. Prevotella abundance significantly decreased in the metformin group and positively correlated with decreased taurocholic acid levels. Metformin potentially reverses liver fibrosis by inhibiting inflammation, mitigating oxidative stress damage and suppressing hepatocyte apoptosis via intestinal flora metabolite regulation. Metformin also regulates the TGF-β/Smads and TIMP-1/MMPs signalling pathways. This study provides a theoretical basis for the clinical use of metformin in patients with liver fibrosis.

Optimization of Sirius Red-Based Microplate Assay to Investigate Collagen Production In Vitro.

Tissue fibrosis is characterized by chronic fibroblast activation and consequently excessive accumulation of collagen-rich extracellular matrix. In vitro microplate-based assays are essential to investigate the underlying mechanism and the effect of antifibrotic drugs. In this study, in the absence of a gold-standard method, we optimized a simple, cost-effective, Sirius Red-based colorimetric measurement to determine the collagen production of fibroblasts grown on 96-well tissue culture plates. Based on our findings, the use of a serum-free medium is recommended to avoid aspecific signals, while ascorbate supplementation increases the collagen production of fibroblasts. The cell-associated collagens can be quantified by Sirius Red staining in acidic conditions followed by alkaline elution. Immature collagens can be precipitated from the culture medium by acidic Sirius Red solution, and after subsequent centrifugation and washing steps, their amount can be also measured. Increased attention has been paid to optimizing the assay procedure, including incubation time, temperature, and solution concentrations. The resulting assay shows high linearity and sensitivity and could serve as a useful tool in fibrosis-related basic research as well as in preclinical drug screening.

Niclosamide inhibits TGF-β1-induced fibrosis of human Tenon's fibroblasts by regulating the MAPK-ERK1/2 pathway

Preventing postoperative bleb scar formation is an effective way of improving glaucoma filtration surgery (GFS) outcome. Use of more effective antifibrotic drugs with fewer adverse effects may be a good way to address the problem. In the present study, we use a primary cell model, consisting of Tenon's fibroblasts obtained from patients with glaucoma, which were stimulated with TGF-β1 to induce the fibrotic phenotype. We explored the effects of niclosamide on TGF-β1-induced fibrosis in these cells and examined its underlying mechanism of action. A transcriptome sequencing assay was used to explore possible signaling pathways involved. Niclosamide inhibited cell proliferation and migration, and decreased the levels of alpha-smooth muscle actin, type I and type III collagen in human Tenon's fibroblasts induced by TGF-β1. Niclosamide also induced apoptosis and counteracted TGF-β1-induced cytoskeletal changes and extracellular matrix accumulation. Moreover, niclosamide decreased TGF-β1-induced phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) protein expression in human Tenon's fibroblasts. The results indicate that niclosamide inhibits TGF-β1-induced fibrosis in human Tenon's fibroblasts by blocking the MAPK-ERK1/2 signaling pathway. Thus, niclosamide is a potentially promising antifibrotic drug that could improve glaucoma filtration surgery success rate.

Shedding LIGHT and TL1A on Pulmonary Fibrosis

Abstract Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis (PF) and tissue remodeling in the clinic. Despite the advancements made in understanding the molecular pathways driving PF, there is still an unmet need to develop innovative and effective anti-fibrotic drugs. Our lab has identified two novel mediators of fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Using a well characterized mouse model of PF driven by bleomycin, we showed that blocking LIGHT or TL1A signaling in isolation, by genetic ablation or antibody-mediated neutralization, significantly reduces PF. In gain of function studies, the in vivo administration of LIGHT or TL1A in isolation recapitulated fibrosis symptoms reminiscent of human disease. Furthermore, our data suggest that LIGHT promotes thymic stromal lymphopoietin (TLSP) expression by epithelial cells, whereas TL1A activates fibroblasts to promote periostin expression. Both TSLP and periostin are drivers of PF. Importantly, we observed an upregulation of LIGHT and DR3 (the receptor for TL1A) in human lung biopsies of patients suffering SSc and IPF. We have found that LIGHT and TL1A can drive fibrosis independently of one another and that the in vivo co-administration of these TNFSF members synergize to maximize inflammation and collagen deposition. Using antagonistic fusion proteins to neutralize LIGHT and TL1A signaling, we will monitor PF in vivo and check whether greater efficacy is achieved when LIGHT and TL1A are targeted concomitantly post-disease onset. The relevance of this work on PF associated with ILDs in humans is tremendous.

Peptide-Based Nanoarchitectonics for the Treatment of Liver Fibrosis.

Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver-targeting molecules, antifibrotic molecules, and self-assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide-based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver-targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self-assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide-based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide-based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide-based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.

A biomimetic renal fibrosis progression model on-chip evaluates anti-fibrotic effects longitudinally in a dynamic fibrogenic niche.

Although renal fibrosis can advance chronic kidney disease and progressively lead to end-stage renal failure, no effective anti-fibrotic drugs have been clinically approved. To aid drug development, we developed a biomimetic renal fibrosis progression model on-chip to evaluate anti-fibrotic effects of natural killer cell-derived extracellular vesicles and pirfenidone (PFD) across different fibrotic stages. First, the dynamic interplay between fibroblasts and kidney-derived extracellular matrix (ECM) resembling the fibrogenic niche on-chip demonstrated that myofibroblasts induced by stiff ECM in 3 days were reversed to fibroblasts by switching to soft ECM, which was within 2, but not 7 days. Second, PFD significantly down-regulated the expression of α-SMA in NRK-49F in medium ECM, as opposed to stiff ECM. Third, a study in rats showed that early administration of PFD significantly inhibited renal fibrosis in terms of the expression levels of α-SMA and YAP. Taken together, both on-chip and animal models indicate the importance of early anti-fibrotic intervention for checking the progression of renal fibrosis. Therefore, this renal fibrosis progression on-chip with a feature of recapitulating dynamic biochemical and biophysical cues can be readily used to assess anti-fibrotic candidates and to explore the tipping point when the fibrotic fate can be rescued for better medical intervention.

TKF, a mexicanolide-type limonoid derivative, suppressed hepatic stellate cells activation and liver fibrosis through inhibition of the YAP/Notch3 pathway

BackgroundLiver fibrosis is a common scarring response and may ultimately lead to liver cancer, unfortunately, there is currently no effective antifibrotic drug approved for human use. Limonoids exhibit a broad spectrum of biological activities; however, the potential role of limonoids against fibrosis is largely unknown. PurposeThis study investigates the antifibrotic activities and potential mechanisms of TKF (3-tigloyl-khasenegasin F), a natural mexicanolide-type limonoid derivative. Study design/methodsTwo well-established mouse models (CCl4 challenge and bile duct ligation) were used to assess anti-fibrotic effects of TKF in vivo. Human hepatic stellate cell (HSC) line LX-2 and mouse primary hepatic stellate cells (pHSCs) also served as in vitro liver fibrosis models. ResultTKF administration significantly attenuated hepatic histopathological injury and collagen accumulation and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, and Timp1. In LX-2 cells and mouse pHSCs, TKF dose-dependently suppressed HSC activation and the expression levels of fibrogenic markers. Mechanistic studies showed that TKF inhibited Notch3-Hes1 and YAP signalings in vivo and in vitro. Furthermore, YAP inhibition or knockdown downregulated the Notch3 expression; however, Notch3 inhibition or knockdown did not affect the level of YAP in activated HSC. We revealed that TKF inhibited Notch3-Hes1 activation and downregulated hepatic fibrogenic gene expression via inhibiting YAP. ConclusionThe therapeutic benefit of TKF against liver fibrosis results from inhibition of YAP and Notch3-Hes1 pathways, indicating that TKF may be a novel therapeutic candidate for liver fibrosis.

Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy.

Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.

Hepatic fibrosis 2022: Unmet needs and a blueprint for the future.

Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell-cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver's endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

Tetrahydropalmatine attenuates liver fibrosis by suppressing endoplasmic reticulum stress in hepatic stellate cells.

Tetrahydropalmatine attenuates liver fibrosis by suppressing endoplasmic reticulum stress in hepatic stellate cells.

Radiological diagnosis of fibrosing interstitial lung diseases: innovations and controversies.

Following the introduction of new effective antifibrotic drugs, interest in fibrosing interstitial lung diseases (FILD) has been renewed. In this context, radiological evaluation of FILD plays a cardinal role. Radiological diagnosis is possible in about 50% of the cases, which allows the initiation of effective therapy, thereby avoiding invasive procedures such as surgical lung biopsy. Usual interstitial pneumonia (UIP) pattern may be diagnosed based on clinical, radiological, and pathological data. High-resolution computed tomography features of UIP have been widely described in literature; however, interpreting them remains challenging, even with specific expertise on the subject. Diagnostic difficulties are understandable given the continuous evolution of FILD classifications and their complexity. Both early-stage diseases and advanced or combined patterns are not easily classifiable, and many end up being labelled 'indeterminate´ or 'unclassifiable´. Especially in these cases, optimal patient management involves collaboration and communication between different specialists. Here, we discuss the most critical aspects of radiological interpretation in FILD diagnosis based on the most recent classifications. We believe that the clinicians´ awareness of radiological diagnostic issues of FILD would improve comprehension and dialogue between physicians and radiologists, leading to better clinical practice.

Hepatic Antifibrotic Pharmacotherapy: Are We Approaching Success?

The incidence rate and mortality of liver fibrosis caused by various etiologies are high throughout the world. Liver fibrosis, the subsequent cirrhosis and other serious related complications threaten the health of patients and represent a serious medical burden; yet, there is still a lack of approved methods to prevent or reverse liver fibrosis. Therefore, effective hepatic antifibrotic drugs are urgently needed. The activation and proliferation of hepatic stellate cells are still the mechanisms of fibrosis that remain the focus of therapeutic research. In recent years, significant progress has been made in the development and applicability of antifibrosis drugs. In this review, we summarize the effectiveness and safety of available antifibrosis drugs utilizing different targets. In addition, some characteristics of antifibrosis drugs in phase II and III trials are introduced in detail.

Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis.

The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human stellate cells, ranging from primary cells to cell lines with an HSC-origin, and human liver slices and stimulated them with two key profibrotic factors, i.e., transforming growth factor β (TGFβ) or platelet-derived growth factor BB (PDGF-BB). We demonstrated that freshly isolated HSCs showed the strongest and highest variety of responses to these profibrotic stimuli, in particular following PDGF-BB stimulation, while cell lines were limited in their responses. Moreover, we verified these gene expression profiles in human precision-cut liver slices and showed similarities with the TGFβ- and PDGF-BB-related fibrotic responses, as observed in the primary HSCs. With this study, we encourage researchers to get off the beaten track when testing antifibrotic compounds by including more HSC-related markers in their future work. This way, potential compounds will be screened more extensively, which might increase the likelihood of developing effective antifibrotic drugs.

A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression.

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg−1· d−1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-β/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-β1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-β-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-β/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (−173/−163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

Ginsenosides: potential therapeutic source for fibrosis-associated human diseases

Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epithelial–mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis.

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, and consequently, effective antifibrotic drugs are strongly desired. Although we have previously reported a validated Col1a1-Luc Tg rat model for fibrosis, there are only a few mouse models that enable the evaluation of fibrosis in a short time period and with high sensitivity. Therefore, we generated a Col1a1-internal ribosome entry site (IRES)-Luc knock-in (KI) mouse in which the IRES-luciferase gene construct was inserted into the 3′-UTR of the type I collagen alpha 1 gene (Col1a1). There was a high correlation between luciferase activity and hydroxyproline content in the KI mice, which is similar to the result that we have previously reported for the Col1a1-Luc Tg rat model. In a bleomycin (BLM)-induced lung fibrosis model, luciferase activity in the lung showed a significant increase 3 days after BLM treatment, while only a slight increase was observed in the hydroxyproline content. An ALK-5 inhibitor—R-268712—was effective in inhibiting the luciferase activity in both the in vivo BLM-induced lung fibrosis model and in vitro primary mouse lung fibroblasts. This suggests that fibroblasts are the major collagen-producing cells in lung fibrosis. In human lung fibroblasts, TGF-β stimulation induced α-smooth muscle actin as observed by immunostaining, suggesting that myofibroblast transdifferentiation (MTD) plays an important role in lung fibrosis. Together, these results indicated that ALK-5 inhibitors might affect lung fibrosis mainly via the inhibition of MTD. Thus, the Col1a1-IRES-Luc KI mouse might be useful for the evaluation of antifibrotic effects and their underlying mechanisms.