Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease

The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was funded for 13 years (2009–2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.

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Serum Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4) in Children with Chronic Hepatitis C: Relation to Liver Fibrosis and Viremia

Hepatitis Research and Treatment ◽

10.1155/2014/307942 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Mostafa M. Sira ◽

Behairy E. Behairy ◽

Azza M. Abd-Elaziz ◽

Sameh A. Abd Elnaby ◽

Ehab E. Eltahan

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Liver Fibrosis ◽

Chronic Hepatitis C ◽

Heavy Chain ◽

Trypsin Inhibitor ◽

Clinical Laboratory ◽

Treatment Naïve ◽

Liver Fibrogenesis ◽

Chronic Hcv

Liver fibrosis and viremia are determinant factors for the treatment policy and its outcome in chronic hepatitis C virus (HCV) infection. We aimed to investigate serum level of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and its relation to liver fibrosis and viremia in children with chronic HCV. ITIH4 was measured by ELISA in 33 treatment-naive children with proved chronic HCV and compared according to different clinical, laboratory and histopathological parameters. Liver histopathological changes were assessed using Ishak score and compared with aspartate transaminase-to-platelet ratio (APRI) and FIB-4 indices as simple noninvasive markers of fibrosis. ITIH4 was measured in a group of 30 age- and sex-matched healthy controls. ITIH4 was significantly higher in patients than in controls (54.2±30.78 pg/mL versus 37.21±5.39 pg/mL; P=0.021). ITIH4, but not APRI or FIB-4, had a significant direct correlation with fibrosis stage (P=0.015, 0.961, and 0.389, resp.), whereas, the negative correlation of ITIH4 with HCV viremia was of marginal significance (P=0.071). In conclusion, ITIH4 significantly correlated with higher stages of fibrosis indicating a possible relation to liver fibrogenesis. The trend of higher ITIH4 with lower viremia points out a potential antiviral properties and further studies in this regard are worthwhile.

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Neutrophils in respiratory viral infections

Mucosal Immunology ◽

10.1038/s41385-021-00397-4 ◽

2021 ◽

Author(s):

Cecilia Johansson ◽

Freja C. M. Kirsebom

Keyword(s):

Viral Infections ◽

Immune Cell ◽

Respiratory Infections ◽

Fungal Infections ◽

Severe Disease ◽

The Elderly ◽

Viral Control ◽

Immunological Mechanisms ◽

Respiratory Viral Infections ◽

Viral Respiratory Infections

AbstractViral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.

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Gli2-regulated activation of hepatic stellate cells and liver fibrosis by TGF-β signaling

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00310.2020 ◽

2021 ◽

Author(s):

Junyan Yan ◽

Baowei Hu ◽

Wenjie Shi ◽

Xiaoyi Wang ◽

Jiayuan Shen ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Conditional Knockout ◽

Rna Seq ◽

Expression Levels ◽

Liver Fibrogenesis ◽

Hh Signaling ◽

Signaling Activity

The Hedgehog (Hh) signaling pathway is correlated with hepatic stellate cells (HSCs) activation and liver fibrosis. Gli2 is a key transcription effector of Hh signaling. However, the role of Gli2 in HSC-mediated liver fibrosis progression is largely unknown. In the present study, we investigated the effect of Gli2 on liver fibrogenesis and its possible mechanism using conditional knockout (cKO) Gli2 mice and HSC models. Wild-type (WT) and GFAP-CreERT;Gli2flox/flox male mice were exposed to CCl4 for one month to induce liver fibrosis. Primary HSCs were isolated from mice and the transition of HSCs into a myofibroblastic phenotype was evaluated. Livers from mice underwent histological, immunohistochemical, and immunofluorescence analyses. The expression levels of proteins and genes were evaluated by Western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RNA-seq was used to screen differentially expressed genes. Results showed that CCl4 treatment induced liver fibrosis, promoted HSCs activation and proliferation, and up-regulated Hh signaling activity. The cKO of Gli2 in GFAP-CreERT;Gli2flox/flox mice decreased liver fibrosis as well as HSC activation and proliferation. In vitro studies showed that KO of Gli2 in HSCs blocked cell proliferation and activation by decrease of cyclin D1/D2 expression. The RNA-seq results revealed that the expression levels TGF-β1 ligands were down-regulated in Gli2 KO HSCs. Furthermore, overexpression of Gli2 rescued proliferation and activation of HSCs by up-regulation of TGF-β signaling activity. Our data demonstrated that Gli2 regulated HSC activation and liver fibrosis by TGF-β signaling, thus providing support for future Gli2-based investigations of liver fibrosis therapy.

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Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽

10.3390/cancers10060155 ◽

2018 ◽

Vol 10 (6) ◽

pp. 155 ◽

Cited By ~ 26

Author(s):

Martina Gatzka

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Small Molecule ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Tumor Therapy ◽

Metabolic Reprogramming ◽

Comprehensive Overview ◽

Small Molecule Drugs ◽

Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

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Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis

Cells ◽

10.3390/cells10123325 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3325

Author(s):

Sofia Karkampouna ◽

Danny van der Helm ◽

Mario Scarpa ◽

Bart van Hoek ◽

Hein W. Verspaget ◽

...

Keyword(s):

Liver Fibrosis ◽

Mouse Models ◽

Cardiac Fibrosis ◽

Ex Vivo ◽

Pressure Overload ◽

Collagen Type I ◽

Type I ◽

Liver Fibrogenesis ◽

End Stage

Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (αSMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of αSMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (αSMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in αSMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the αSMA expression. Temporal expression of CRIPTO in αSMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis. Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration.

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Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies

International Journal of Molecular Sciences ◽

10.3390/ijms221910303 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10303

Author(s):

Fangping Jia ◽

Xiao Hu ◽

Takefumi Kimura ◽

Naoki Tanaka

Keyword(s):

Fatty Acid ◽

Hepatitis C ◽

Liver Fibrosis ◽

Dietary Fat ◽

High Fat Diet ◽

Core Gene ◽

High Fat ◽

Virus Core ◽

Liver Fibrogenesis ◽

Isocaloric Diets

Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis.

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Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽

10.3390/cancers13225856 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5856

Author(s):

Myung-Chul Kim ◽

Zeng Jin ◽

Ryan Kolb ◽

Nicholas Borcherding ◽

Jonathan Alexander Chatzkel ◽

...

Keyword(s):

T Cell ◽

Immune Cells ◽

Immune Cell ◽

Single Cell Analysis ◽

Clear Cell ◽

Cd8 T Cell ◽

Cell Infiltration ◽

Cellular Mechanisms ◽

T Cell Infiltration ◽

Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

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Immune Cell-Derived Extracellular Vesicles – New Strategies in Cancer Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.771551 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pengxiang Yang ◽

Yong Peng ◽

Yuan Feng ◽

Zhuoying Xu ◽

Panfeng Feng ◽

...

Keyword(s):

Extracellular Vesicles ◽

Immune Cell ◽

Bilayer Membrane ◽

Innate Immune ◽

Antitumor Effects ◽

Comprehensive Overview ◽

Surface Receptors ◽

Effector Molecules ◽

Therapeutic Modalities ◽

Pass Through

Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00230.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. C789-C799 ◽

Cited By ~ 137

Author(s):

Ariane Mallat ◽

Sophie Lotersztajn

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Cell Injury ◽

Parenchymal Cell ◽

Chronic Liver ◽

Special Focus ◽

Chronic Liver Injury ◽

Cellular Mechanisms ◽

Extracellular Matrix Components ◽

Liver Fibrogenesis

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.

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PASS-Predicted Hepatoprotective Activity ofCaesalpinia sappanin Thioacetamide-Induced Liver Fibrosis in Rats

The Scientific World JOURNAL ◽

10.1155/2014/301879 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 16

Author(s):

Farkaad A. Kadir ◽

Normadiah M. Kassim ◽

Mahmood Ameen Abdulla ◽

Behnam Kamalidehghan ◽

Fatemeh Ahmadipour ◽

...

Keyword(s):

Liver Fibrosis ◽

Transforming Growth Factor ◽

Antioxidant Activities ◽

Smooth Muscle Actin ◽

Immunohistochemical Analysis ◽

Hepatoprotective Activity ◽

Nuclear Antigen ◽

Sprague Dawley ◽

Liver Fibrogenesis

The antifibrotic effects of traditional medicinal herbCaesalpinia sappan(CS) extract on liver fibrosis induced by thioacetamide (TAA) and the expression of transforming growth factorβ1 (TGF-β1),α-smooth muscle actin (αSMA), and proliferating cell nuclear antigen (PCNA) in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS) Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v) in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY), and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson’s trichrome staining, immunohistochemical analysis, and western blotting.In vivodetermination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1), and matrix metalloproteinases (MPPS) was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF-β1,αSMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.

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