text:
P- Reviewers: Guerra RR, Kc S, Tarantino G S- Editor: Qi Y L- Editor: Kerr C E- Editor: Zhang DN
Published online Jun 21, 2014. doi: 10.3748/wjg.v20.i23.7312
Revised: March 16, 2014
Accepted: April 28, 2014
Published online: June 21, 2014
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
Core tip: Cirrhosis is the end-stage condition of many types of chronic liver diseases but the underlying mechanisms are far from being clarified. Multiple cellular and molecular factors might be involved in the initiation and progression of cirrhosis. Activation of hepatic stellate cells is a pivotal event in the development of cirrhosis. Animal models are crucial for understanding the pathogenesis and the development of more efficient therapeutic strategies for cirrhosis, with which cirrhosis may become a treatable or even a reversible disease.
- Citation: Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20(23): 7312-7324
- URL: https://www.wjgnet.com/1007-9327/full/v20/i23/7312.htm
- DOI: http://dx.doi.org/10.3748/wjg.v20.i23.7312
Liver cirrhosis is the final common pathological pathway of liver damage arising from a wide variety of chronic liver diseases[1-3]. The etiology of cirrhosis varies geographically, with alcoholism, chronic hepatitis C virus infection, and nonalcoholic fatty lives disease (NAFLD) being the most common causes in western countries[4-6], whereas chronic hepatitis B is the primary cause of liver cirrhosis in the Asia-Pacific region[7-9]. Liver cirrhosis has many other causes, include inherited diseases such as hemochromatosis and Wilson’s disease[10-14], primary biliary cirrhosis, primary sclerosing cholangitis[15-18], and autoimmune hepatitis[14,19]. Some cases are idiopathic or cryptogenic. In recent decades, NAFLD has become a leading cause of chronic liver disease in Western countries such as the United States, with a prevalence of as high as 30% in the general population. Thus, NAFLD has attracted extensive attention as an important cause of chronic liver diseases[21-23].
Although the causes of liver cirrhosis are multifactorial, there are some pathological characteristics that are common to all cases of liver cirrhosis, including degeneration and necrosis of hepatocytes, and replacement of liver parenchyma by fibrotic tissues and regenerative nodules, and loss of liver function[24-27]. Fibrosis as a precursor of cirrhosis is a pivotal pathological process in the evolution of all chronic liver diseases to cirrhosis[2,28]. At present, effective strategies to treat liver cirrhosis are still lacking, partially because of a poor understanding of the molecular mechanisms leading to cirrhosis. Thus, a better understanding of the pathogenesis of liver cirrhosis would facilitate the development of more effective treatment options.
In this review, we aim to summarize the recent advance in the molecular pathogenesis, animal models, and therapeutic strategies for liver cirrhosis.
The liver is formed by parenchymal cells (i.e., hepatocytes) and other cells commonly known as nonparenchymal cells. The walls of hepatic sinusoids are lined by three different nonparenchymal cells: liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs). Both hepatic parenchymal and nonparenchymal cells are involved in the initiation and progression of liver fibrosis and cirrhosis.
HSCs, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells, reside in the space of Disse in the normal liver and their main function is storage of vitamin A and other retinoids[27,29]. Following multiple injurious insults and/or exposure to inflammatory cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, and interleukin (IL)-1, HSCs undergo the transition from a quiescent to activated state. HSC activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition[30,31]. Activation of HSCs is characterized by cell proliferation and migration, contraction after transforming into myofibroblasts, generation of a large amount of collagen and other extracellular matrix (ECM), ultimately leading to liver fibrosis[32-34].
LSECs constitute the sinusoidal wall, also called the endothelium, or endothelial lining. The structural characteristic of LSECs is the fenestrae on the surface of the endothelium[28,35,36] The endothelial fenestrae measure 150-175 nm in diameter, and act as a dynamic filter facilitating the exchange of fluids, solutes and particles between sinusoidal blood and the parenchymal cells[37-39]. LSECs have high endocytotic capacity[28,40]. Chronic alcohol abuse could result in defenestration, and a decrease in the number of fenestrae[37,41]. In cirrhotic liver, defenestration of sinusoidal endothelium and the presence of a subendothelial basement membrane are frequently present[35,42]. It is known that retinol deficiency can activate and transform HSCs into myofibroblasts with enhanced ECM production, resulting in perisinusoidal fibrosis and ultimately in cirrhosis[24,35]. Defenestration and capillarization of the hepatic endothelium are believed to be important in the initiation of perisinusoidal fibrosis by altering retinol metabolism. Studies in animals and humans have revealed that LSECs can secrete the cytokine IL-33 to activate HSCs and promote fibrosis. Defenestration and capillarization of LSECs lead to impaired substrate exchange and are considered major contributing factors for hepatic dysfunction in liver cirrhosis. On the contrary, differentiated LSECs can promote reversion of activated HSCs to quiescence and thereby accelerate regression and prevent progression of fibrosis through vascular endothelial growth factor (VEGF)-stimulated NO production[44,45].
KCs, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the lining walls of the sinusoids of the liver that form part of the reticuloendothelial system (RES). Studies in animal models have shown that KCs are implicated in the pathogenesis of various liver diseases[47,48]. KCs can be activated by many injurious factors such as viral infection, alcohol, high-fat diet, and iron deposition. Activated KCs destroy hepatocytes by producing harmful soluble mediators and serving as antigen-presenting cells during viral infection. KC-mediated hepatic inflammation is considered to aggravate liver injury and fibrosis[49,50]. KCs are involved in the activation of HSCs and formation of fibrosis. In vitro studies have shown that KC-conditioned medium can promote activation of cultured rat HSCs with enhanced matrix synthesis and cell proliferation by eliciting expression of PDGF receptor in HSCs. KC-derived TGF-β1 stimulates proliferation and collagen formation of HSCs derived from rats fed with high-fat diet and ethanol[52,53]. Alcohol can induce the circulating level of Gram-negative bacterial lipopolysaccharide (LPS), which is a strong activator of KCs. In genetic hemochromatosis, iron overload in KCs could induce the expression of intercellular adhesion molecule (ICAM)-1 on hepatocytes, therefore facilitating activation of HSCs and collagen deposition in the hepatic tissues. Gelatinase secreted by activated KCs triggers the phenotypic change in HSCs by degrading collagen type IV. KCs engulf apoptotic bodies and produce death ligands, including Fas ligand and TNF-α, thereby promotes inflammation and fibrogenesis. In addition, KCs activated by β-glucans increase portal pressure through the release of thromboxane A2 in normal and fibrotic livers.
Hepatocytes are the primary liver parenchymal cells, and play complicated roles in fibrosis and cirrhosis. Hepatocytes are targets for most hepatotoxic agents, including hepatitis viruses, alcohol metabolites, and bile acids. Chronic liver diseases either promotes apoptosis or trigger compensatory regeneration of hepatocytes. Damaged hepatocytes release reactive oxygen species (ROS) and fibrogenic mediators, induce activation of HSCs, and stimulate the fibrogenic actions of myofibroblasts. Apoptosis of hepatocytes is a common event in liver injury and contributes to tissue inflammation, fibrogenesis, and development of cirrhosis. Steatohepatitis enhances Fas-mediated hepatocyte apoptosis, which correlates with active nuclear factor (NF)-κB and disease severity. Both HCV infection and ethanol consumption induce hepatocyte apoptosis in animal models and humans, and induction may be related to downregulation of Bcl-2 signaling. Chronic HCV infection can induce hepatocyte G1 arrest and impair hepatocellular function and limit hepatic regeneration[63,64]. In CCl4-induced liver injury, hepatocyte apoptosis is induced at the early phase, which is followed by constant proliferation and if it persists, liver cirrhosis ensues at a later stage. Hepatocytes are the major sources of matrix metalloproteinases (MMP-2, MMP-3 and MMP-13) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2); all of which are involved in the pathogenesis of liver cirrhosis in CCl4-induced liver cirrhosis in rats. In the last fibrotic stage or cirrhosis, hypoxic hepatocytes become a predominant source of TGF-β1, further exacerbating hepatic fibrogenesis. Recently, it has been shown that hepatocyte telomere shortening and senescence can result in fibrotic scarring at the cirrhosis stage, presenting a novel explanation for the pathophysiology of cirrhosis.
Liver cirrhosis is orchestrated by a complex network of cytokine-mediated signaling pathways regulating the activation of HSCs and fibrogenesis.
PDGF is the strongest mitogen to HSCs among all polypeptide growth factors. PDGF family has four members, PDGF-A, -B, -C and -D. PDGF and its receptors are markedly overexpressed in fibrous tissues, and its activity increases with the degree of liver fibrosis[70-72]. A variety of factors such as viruses, chemicals, or mechanical damage to hepatocytes can induce KCs to synthesize and release PDGF. Upon binding to its specific receptor on the membrane of HSCs, PDGF activates corresponding signal molecules and transcription factors, leading to the activation of its downstream target genes and activation of HSCs[74,75]. PDGF has been shown to upregulate the expression of MMP-2, MMP-9 and TIMP-1, and inhibit the activity of collagenase, thereby reducing ECM degradation[69,75]. PDGF-B and PDGF-D are potent PDGF isoforms in PDGF receptor (PDGFR)β signaling within HSCs, as evidenced by PDGFRβ autophosphorylation and activation of extracellular signal-regulated kinase (ERK)1/2, C-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and protein kinase (PK)B/Akt pathways[75-77]. PDGF-D can activate HSCs and exerts mitogenic and fibrogenic effects, and therefore plays an important role in matrix remodeling in liver fibrosis.
TGF-β is the strongest known inducer of fibrogenesis in hepatic fibrosis[78,79]. TGF-β is mainly synthesized by HSCs/myofibroblasts, KCs, LSECs, and hepatocytes in the liver. The TGF-β1 family is composed of six members, and among them, TGF-β1 has been shown to play a key role in the initiation and maintenance of liver fibrosis[78-82]. The expression level of TGF-β1 is increased in fibrotic liver and reaches a maximum at cirrhosis. The pro-fibrogenesis effect of TGF-β1 is complicated, involving multiple aspects: the primary effect of TGF-β1 is to stimulate activation of HSCs, and the TGF-β1 autocrine loop in activated HSCs is an important positive feedback to the progression of liver fibrosis[80,81]. TGF-β1 induces expression of the matrix-producing genes and inhibits degradation of ECM by downregulating expression of MMPs and promoting TIMP, leading to excessive deposition of collagenous fibers and promoting the development of liver fibrosis[82,83]. In addition, TGF-β1 has been shown to inhibit DNA synthesis and induces apoptosis of hepatocytes. TGF-β1-induced apoptosis is thought to be responsible for tissue loss and decrease in liver size seen in cirrhosis. Given the critical role of TGF-β1 in the pathogenesis of liver cirrhosis, specific blockade of TGF-β1/Smad3 signaling has shown some therapeutic value for liver fibrosis.
TNF-α is mainly produced by monocyte, macrophage, HSCs, and KCs. It has proinflammatory activities and cytotoxic effects in these cells. In the process of liver fibrosis, TNF-α plays an important role in the activation of HSCs and synthesis of ECM[84,85]. TNF-α can reduce the spontaneous apoptosis of activated rat HSCs by upregulating the antiapoptotic factors NF-κB, Bcl-XL and p21WAF1, as well as downregulating the proapoptotic factor p53. However, the effects of TNF-α on HSCs and fibrosis are complicated and even paradoxical, as demonstrated by studies showing that TNF-α could induce apoptosis in HSCs. TNF-α has also been shown to exert antifibrogenic effect in rat HSCs by reducing glutathione and inhibiting pro-collagen α1 expression. In a rat model of nonalcoholic steatohepatitis (NASH), TNF-α antibody was shown to reduce the inflammation, necrosis and fibrosis in liver. TNF-α signaling through activation of KCs plays an essential role in the pathogenesis of liver fibrosis in animal models of NASH.
Interferon (IFN) is a family of soluble extracellular signaling molecules. Leukocytes synthesize IFN-α and IFN-β in response to virus infection, and T cells secrete IFN-γ upon stimulation with various antigens and mitogens. IFNs possess antiviral activity and is well-recognized for their antiviral effects. Patients treated with IFNs exhibit a regression of liver fibrosis even if viral eradication is not achieved, indicating that IFN itself has antifibrotic activity via triggering the apoptosis of HSCs. IFN-β could inactivate HSCs and decrease their production of α-smooth muscle actin (SMA) and collagen through inhibition of the TGF-β and PDGF pathways. Similarly, IFN-γ has been demonstrated to reduce ECM deposition in vivo by inhibiting HSC activation via TGFβ1/Smad3 signaling pathways[94,95]. Treatment of rats with fibrosis by IFN-γ led to a reduced production and deposition of collagen, laminin, fibronectin, and pro-collagen type I in liver. However, the effect of IFNs on fibrosis is not consistent, as demonstrated by a recent study showing that IFN-α and IFN-γ may exert opposite effects on apoptosis in HSCs. IFN-α was shown to elicit an antiapoptotic effect on activated HSCs, whereas IFN-γ was found to exert proapoptotic effect on HSCs by downregulating heat-shock protein 70.
ILs are a group of cytokines initially found to be expressed by leukocytes, but later on were shown to be produced by a wide variety of cells, such as CD4 T lymphocytes, monocytes, macrophages, and endothelial cells. ILs have a complicated role in immune response, inflammation, and liver fibrogenesis.
Pro-fibrogenic ILs: KCs and SECs can rapidly produce ILs in response to liver tissue damage. IL-1 can directly activate HSCs and stimulate them to produce MMP-9, MMP-13 and TIMP-1, resulting in liver fibrogenesis. In contrast, IL-1-receptor-deficient mice are less likely to sustain liver damage and exhibit reduced susceptibility to develop fibrosis. Deficiency of IL-1α or IL-1β also makes the mice less susceptible to develop liver fibrosis in animal models of steatohepatitis. Similarly, IL-1 receptor antagonists were found to protect rats from developing liver fibrosis in response to dimethylnitrosamine, and blocking IL-1 signaling could markedly attenuate alcohol-induced liver inflammation and steatosis. IL-1β was reported to increase the inflammatory and pro-steatotic chemokine monocyte chemoattractant protein-1 in hepatocytes, and augment Toll-like receptor (TLR4)-dependent upregulation of inflammatory signaling in macrophages.
Another profibrotic cytokine is IL-17, whose expression level increases with degree of liver fibrosis[101,102], indicating that IL-17 may be involved in disease progression and chronicity. Studies in mice have shown that IL-17 induces liver fibrosis through multiple mechanisms, including upregulation of TNF-α, TGF-β1, and collagen 1α, which is dependent on signal transducer and activator of transcription (STAT)3 signaling pathway, and promotion of myofibroblast-like change of HSCs[102,103].
Antifibrogenic ILs: IL-10 is a cytokine that downregulates the proinflammatory response and has a modulatory effect on hepatic fibrogenesis[104,105]. IL-10 may have therapeutic potential for patients with HCV-related liver fibrosis who do not respond to IFN-based therapy. IL-10 has been shown to exert antifibrotic effects through inhibiting HSC activity, and this was demonstrated in a rat model in which exogenous IL-10 was shown to reverse CCl4-induced hepatic fibrosis by inhibiting the expression of TGF-β1, MMP-2 and TIMP-1[104,106,107].
IL-22 is known to play a key role in promoting antimicrobial immunity, inflammation, and tissue repair at barrier surfaces. IL-22 has been shown to induce HSC senescence, restrict liver fibrosis, and accelerate the resolution of liver fibrosis during recovery in a mouse model.
IL-6 is a pleiotropic cytokine involved in inflammatory pathways, hematopoiesis and immune regulation. IL-6 can attenuate apoptosis and promote regeneration of hepatocytes through NF-κB signaling and the Ras-MAPK pathway. IL-6 reduces CCl4-induced acute and chronic liver injury and fibrosis. Pretreatment of fibrotic liver with IL-6 improves hepatic microenvironment and primes it for mesenchymal stem cell transplantation, leading to improvement in liver injury after fibrosis. Meanwhile, increased blood level of IL-6 has been found in patients with NAFLD, and IL-6 could induce insulin resistance and inflammation in the liver[112,113], suggesting that IL-6 may play a role in the development of NAFLD.
miRNAs represent a family of small noncoding RNAs controlling translation and transcription of many genes, which have recently emerged as post-transcriptional regulators. miRNAs play a key role in various hepatic pathologies, including hepatitis, cirrhosis and hepatoma[34,114]. miRNAs may play pro- and antifibrogenic roles, depending on cellular context and the nature of the stimuli.
miR-21 has an important role in the pathogenesis and progression of hepatic fibrosis. miR-21 can downregulate TGF-β expression and suppress HSC activation. TGF-β1 induces expression of miR-181a and miR-181b, and the latter can promote HSC proliferation by regulating p27 and the cell cycle. Elevation of serum level of miR-181b is suggested as a potential diagnostic biomarker for patients with cirrhosis.
miR-214-5p can increase expression of fibrosis-related genes (such as MMP-2, MMP-9, α-SMA, and TGF-β1) in LX-2 cells, and therefore, it may play crucial roles in HSC activation and progression of liver fibrosis.
miR-221 and miR222 are upregulated in human liver in a fibrosis progression-dependent manner and in mouse models of liver fibrosis. TGF-α or TNF-α induce expression of miR-222, which can bind to the CDKN1B (p27) 3’-untranslated region (UTR) and regulate expression of the corresponding protein.
Other fibrosis-associated miRNAs have been identified. For example, miR-199a, miR-199a*, miR-200a, and miR-200b were positively and significantly correlated with progression of liver fibrosis in both mouse and human studies. Overexpression of these miRNAs significantly increases the expression of fibrosis-related genes in HSCs. miR-571 is upregulated in human hepatocytes and HSCs in response to TGF-β.
miRNA-150 and miRNA-194 are reduced in HSCs isolated from experimental rats with liver fibrosis. It has been demonstrated that these two miRNAs inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac1 expression. In contrast, several miRNAs such as miR-29, miR 19b, miR-146a, and miR-133a are markedly downregulated in HSCs isolated from experimental animals with liver fibrosis, and restoration of these miRNAs attenuates hepatic fibrogenesis[30,122,123].
It is now thought that miRNAs can serve as biomarkers for HSC activation and liver fibrosis progression, and may represent therapeutic targets for hepatic fibrosis and cirrhosis.
Animal models are crucial to understanding the pathogenesis and development of therapeutic strategies for liver fibrosis and cirrhosis. So far, many types of animal model have been developed in mice, rats, rabbits, and pigs to mimic the complicated process of fibrosis and cirrhosis. Animal models of liver fibrosis and cirrhosis can be induced by one of the following approaches: (1) Fibrosis induced by chemical compounds and toxins. These agents cause direct injury to hepatocytes and trigger secondary inflammatory reaction in the liver, which in turn activate HSCs and result in fibrosis. Commonly used chemical agents include CCl4[124-126], thioacetamide[127,128] dimethylnitrosamine[129,130], dioxin, sodium arsenate, and ethanol[126,133,134]. These agents can be administered to experimental animals alone or in combination; (2) Special diet, such as choline-deficient, L-amino acid-defined, methionine-deficient diet[89,135,136], and high-fat diet[134,137,138]. Animals develop NAFLD and cirrhosis when they are fed these diets alone or in combination with other chemical agents; (3) Physical methods. Bile duct ligation creates obstruction of the extrahepatic bile duct[139,140], leading to cholestasis and subsequent injury to biliary epithelial cells and hepatocytes, infiltration of inflammatory cells in the portal area, fibrous tissue proliferation, and formation of liver fibrosis; (4) Fibrosis induced by immune reaction. Antigen-antibody complexes can provoke type III hypersensitive reactions. Deposition of immune complexes in the portal area and around the central vein area causes allergic reaction and inflammation, stimulating HSCs to secrete collagen, and fibrosis formation. Common immunogens include plant protein concanavalin A and xenogenic serum[142,143], such as serum from pigs, cattle, humans, and schistosoma. It was reported that 85.5% of rats immunized with subcutaneous injection of human serum albumin develop liver fibrosis and cirrhosis. Similarly, injection of the excretory-secretory (ES) antigens of Ascaris suum into golden hamsters also successfully induces hepatic fibrosis; and (5) Genetic modification. Forced overexpression of critical profibrotic genes and/or silencing of antifibrotic genes has been shown to induce cirrhosis in animals. For example, high-speed intravenous injection of naked plasmid DNA of TGF-β1 can induce transient and reversible liver fibrosis in mice. Mice with liver-specific deletion of CYLD exon7/8 [CYLD(FF)xAlbCre] exhibit a prominent biliary phenotype with ductular reaction and biliary-type fibrosis.
Recent developments in our understanding of the process of hepatic fibrogenesis have revealed that the process is dynamic and reversible. Animal and clinical evidence has confirmed that any degree of fibrosis and even cirrhosis are potentially reversible by reasonable therapeutic strategies[147-149]. At present, the therapeutic strategies for liver fibrosis include the following.
Removing the etiological factors is the most direct and perhaps most effective method of treating liver fibrosis. As such, treatments against HBV and HCV infections[150,151], abstinence from alcohol abuse, weight and blood lipid control, chelation of overloaded iron and copper are considered potentially effective therapies for a large proportion of liver fibrosis cases. In particular, the commonly used antiviral agents such as IFN-α, ribavirin, lamivudine, adefovir, entecavir, and especially pegylated IFN-α have been shown to exert antifibrotic effects[91,151,153-156].
Intrahepatic inflammation and immune response are direct causes of injury to hepatocytes and activation of HSCs. Therefore, anti-inflammatory and immunosuppressive therapies are important measures to inhibit fibrogenesis, especially for fibrosis and cirrhosis resulting from viral hepatitis, autoimmune hepatitis, and primary sclerosing cholangitis. The anti-inflammatory drug celecoxib and antioxidative agents taurine and vitamin E[158,159] all show some degree of antifibrotic effect. Likewise, glucocorticoids, azathioprine, colchicines and rapamycin[162,163] appear to exert anti-inflammatory, antifibrotic and immunomodulatory effects, and therefore may potentially be useful in the treatment of liver fibrosis.
HSCs play a critical role in hepatic fibrogenesis, and therefore are potential target cells of antifibrotic therapy. As such, inhibition of HSC activation is an attractive therapeutic approach for liver fibrosis. Inactivation of HSCs can be achieved by inhibiting the TGF-β1 signaling pathway and PDGF-B[165-167], and activated HSCs can be removed by inducing these cells to undergo apoptosis[27,31,164]. Some cytokines and growth factors such as insulin-like growth factor-1, IFN-α and IFN-γ have been found to induce apoptosis of HSCs[90,96,168]. Inhibitors of IκB kinase has also been shown to promote apoptosis of HSCs and exert antifibrotic effectd. Other pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I have been explored for their effects in inducing HSC apoptosis.
The hepatoprotective agent silymarin has been widely used in the management of chronic liver diseases and cirrhosis[129,169]. Ursodeoxycholic acid and tauroursodeoxycholic acid have shown protective effects against hepatocyte organelle injury, and have been confirmed as effective agents for the treatment of primary sclerosing cholangitis[170,171]. Calcium channel blockers (e.g., verapamil) also show hepatoprotective and antifibrotic effects by stabilizing the hepatic cellular membrane and lowering the portal vein pressure.
Hepatocyte apoptosis is a common event in liver injury and contributes to fibrogenesis and development of cirrhosis. Hence, preventing the hepatocytes from undergoing apoptosis and promoting hepatocytes regeneration can be useful therapeutic strategies for liver fibrosis and cirrhosis. Hepatocyte growth factor (HGF), an antifibrotic growth factor that induces apoptosis in HSCs and stimulates hepatocyte regeneration[173,174], has been attempted as a therapeutic agent for liver cirrhosis. In this respect, infusion of bone-marrow-derived cells and mesenchymal cells have been reported as a potentially effective method for the treatment of liver cirrhosis[175-177], because these cells can differentiate into hepatocyte-like cells in the liver and stimulate proliferation of hepatocytes by secreting some growth factors such as HGF. Furthermore, HGF-overexpressing human umbilical-cord-blood-derived mesenchymal stem cells have shown promising therapeutic effects on liver fibrosis.
Several critical genes implicated in the pathogenesis of liver cirrhosis such as TGF-β, PDGF-β, CTGF, and TIMP have been investigated as therapeutic targets for liver cirrhosis. Antisense oligonucleotides[167,180,181] and siRNAs[182-184] against these genes have been tested in vitro and in vivo. Recently, miRNA has been found to play a regulatory role in the pathogenesis of liver fibrosis and cirrhosis through regulating the expression of profibrotic or antifibrotic genes, and influencing the proliferation and activation of HSCs. As such, miRNA-based therapy can potentially be useful for the treatment of liver fibrosis. Furthermore, in order to target more directly the fibrogenic cells, attempts have been made to target the receptors of the profibrogenic proteins expressed on HSCs[184,186,187].
Evidence indicates that some traditional Chinese herbal medicines are effective in the treatment of liver fibrosis and cirrhosis, and have thus gained popularity worldwide[188,189]. These herbal medicines include the following categories: pure compounds (e.g., salvianolic acid B and oxymatrine). The mechanisms by which tetrandrine, glycyrrhetinic acid and curcumin), single agents (e.g., Salvia miltiorrhiza and Ganoderma lucidum), and composite formulae (e.g., Fuzheng Huayu Capsule, Biejiajian, Yi-Gan-Kang granule and Qinggan Huoxuefang). Chinese herbal medicines exert antifibrotic effect are far from clear but may include antiviral and anti-inflammatory effects, immune regulation, inhibition of HSC activity, and promotion of collagen degradation. Further randomized controlled clinical trials are needed and the possible adverse effects should be carefully evaluated.
In summary, the etiology of cirrhosis is multifactorial and the mechanisms underlying pathogenesis of cirrhosis are far from being clarified. Further studies, particularly with appropriate animal models, to unveil the molecular mechanisms leading to liver fibrosis and cirrhosis are essential for the development of effective therapeutic approaches.
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domain: literature


A warmer version of the premium favorite, the Outwell Camper. Strong insulation and unlike most other sleeping bags, 100% cotton in the lining which provides both a warm and comfortable sleeping bag. The sleeping bag can be opened up and used as a large duvet, and if you buy a right and a left sleeping bag, they can be assembled into a double sleeping bag.READ MORE
Comfort temp man: -6°C
Comfort temp woman: 0°C
Extreme temp: -23°C
Body length: 200 cm
Filling: 1400 g Isofill, 100% recycled polyester
Weight: approx 2700 g
A warmer version of the premium favorite, the Outwell Camper. The sleeping bag is suitable for the entire camping season from early spring to late autumn. Thanks to a soft cotton inner lining, it offers a significantly better feel than regular sleeping bags. The two-layer filling minimizes the risk of cold spots, and if it gets too warm, you can always open it at the foot end or fully and use it as a regular blanket. The zipper is protected with an insulated overlap edge that prevents heat leakage.
Assemble into double sleeping bag
A really good feature is that two sleeping bags can be attached together to form a double sleeping bag. If you want this option, then choose a sleeping bag with the zipper to the left and one with the zipper to the right.
Outwell Caring Choice
With Caring Choice, Outwell contributes to a more sustainable future by offering more environmentally friendly products. By using solution-dyed textiles instead of wet dyeing, chemical waste, water, and energy consumption are reduced. It also gives a longer lifespan to the dyeing as it becomes more UV-resistant. The insulation is also made from recycled polyester derived from PET bottles, which leads to lower carbon emissions and reduces waste. These initiatives are important steps on Outwell's journey towards sustainability and protecting our world for future generations.
Isofill are synthetic fibers with similar insulating properties as down but are more cost-effective to produce. The advantage of isofill is that it is less sensitive to moisture than down. The downside lies in a slightly worse weight/insulation performance.
|235 x 90 cm (LxW)
|48 x 46 x 25 cm
|Temp (T-comfort) woman
|Temp (T-limit) man
|Two layer offset
|Polycotton, 80% polyester / 20% cotton
|Cotton flannel, 100% cotton
|1400 g Isofill, 100% polyester
|2 way open - auto lock, L-shape
|Transport bag / storage
|Square transport bag


text:
Solid sound design is instrumental to a film or television programme’s success. A sound designer takes advantage of the huge variety of noises we hear in our everyday lives, thinking of experimental ways to create an audio environment that supports on-screen action and engages audiences.
Multi award winning sound designer and dubbing mixer John Cobban joined a small group of students and career starters to discuss his craft and career highlights spanning 25 years of crafting sound for numerous films, documentaries, dramas and animations, including Murder, Eve, Two Doors Down and latest BBC hit The Replacement.
Murder – BBC 2 / Touchpaper TV Excerpt from Ep 2 “The Lost Weekend” Directed by Paul Wright
Warriors – Saltire Film / BBC 1 Scotland. Directed by Stephen Bennett
Eve – CBBC / Leopard Drama. Excerpt from S1 Ep 4 ” The Bubble Burst” – Power Station sequence
One Thousand Pictures – RFK’s Last Journey – Lichen Films Ltd
This event was hosted by journalist Stephen Bennett and is part of the Career Close-Up programme supported by Skills Development Scotland.

domain: artistic


text:
Mother is the most special person in everyone’s life. No number of words can describe the greatness of a mother. But Bollywood has successfully tried to pay tribute to all the powerful mothers through emotional & fun-filled songs. These songs perfectly fit for the feelings we all have for our mothers and they are sure to touch your heart. Here are 7 songs that you can dedicate to your mom this Mother’s Day. Take a look:
# Tu Kitni Acchi Hai: If you are looking for a song that sums up how sweet and out of the world our mother is, then this is the song for you. Tu Kitni Acchi Hai maybe an old song from the film Raja Aur Rank but it sums up the feelings very aptly.
# Meri Maa: Let’s admit listening to this song from Taare Zameen Par has made us all cry. This song beautifully describes what role a mother plays in a child’s life. After all “Tujhe Sab Pata Hai Na? Meri Maa!” Dedicate this song to your mom to thank her for all the things she has done for you.
# Luka Chuppi: At some point, we all leave our nests and fly off to face greater challenges in life. But for our mother’s we are still the little kids who she loves and worries about. This song from Rang De Basanti featuring Aamir Khan, R Madhavan, Sharman Joshi, Waheeda Rehman truly strike a chord in the heart and will always be a special song for all of us.
# Ais Kyun Maa: This song from Neerja will make you miss your mom instantly Summing up the love-hate relationship between a mother and child, the song is all about how growing up is scary and how we wish everyone was as good and comforting as our mother. Sonam Kapoor and Shabana Azmi’s relationship in the film is just like any other mother-daughter and will make you call your mom right away.
#Meri Pyari Ammi: This song from Aamir Khan’s film Secret Superstar is a playful take on how the mothers are. The video will make you emotional for sure and will make you think how mom is exactly the way Amit Trivedi and Meghna Mishra describe mothers.
#Mumma: Featured in the film Dasvidanya, this is yet another song that has to be on every Mother’s Day song list. This underrated jewel from the Vinay Pathak-starrer film is an outstanding ode to how fabulous mothers are. So don’t forget to play this song for your mum today (May 12).
# Janam Janam: Shahid Kapoor starrer film Phata Poster Nikla Hero shows how caring a mom is and we all know how true that is. And as the song says, we all want our mother to stay with us forever.
This is the list of our favourite songs to dedicate this Mother’s day. What are your plans? Let us know in the comments section below. Also, stay tuned to CineBlitz for more such updates from Bollywood. Happy Mother’s Day to all!
IFFM Awards 2019: Gully Boy, Andhadhun, Tabu, Vijay Sethupathi, Shah Rukh Khan receive top honours
It was that evening of the year in Melbourne, when the annual awards night marked its gala presence in the cultural melting pot. 2019’s award function at the Indian Film Festival of Melbourne was a special one for many reasons.
It was that evening of the year in Melbourne, when the annual awards night marked its gala presence in the cultural melting pot. 2019’s award function at the Indian Film Festival of Melbourne was a special one for many reasons. Zoya Akhtar’s Gully Boy walked away with the top gong of Best Film honour, whereas Vijay Sethupathi won the Best Actor for his widely acclaimed film Tamil film Super Deluxe and Tabu was named Best Actress for her performance in Andhadhun.
Zoya said, “I am so excited. I am not going to forget this evening. This is my first award in the capacity of a producer. Gully Boy was our first production. This is a good start. No one makes a movie alone and this wouldn’t be possible without my producers, my co-writer, my incredible actors and every member of my cast and crew. 54 invincible artists worked on this album. I owe this night to all of them.”
Sriram said on his win as best director, “I am thankful and overwhelmed with the response to Andhadhun and this award. A French short film inspired this movie. It was 7 years ago and the movie took a long time to make.” Upon receiving her award, Tabu said, “It’s my first time in Australia but I will remember it for the rest of my life. Thank you Sriram for writing this for me. This character is catalyst for change of roles for women that are being written and will be written in future. Thank you for trusting me with this character”.
Additionally, IFFM bestowed upon superstar Shah Rukh Khan – the ‘Excellence In Cinema’ award.
Shah Rukh Khan, in his usual candour, said, “Thank you all of you in Melbourne. It’s an honour and privilege for me. Awards are odd because to me an art form be judged for its quality feels counter intuitive. Art is an expression and cinema is the ability to create emotions and share experiences through stories. To be an actor, is to live to know that each one is a mere illusion. When you are making a movie you can change a lot by changing the angle of the light and it strikes you that life is a lot like that as well. It’s the simple things that can alter your journey and pondering makes your story worth telling. I shot a film here 12 years ago and it was a straightforward film about a man who has lost hope in life picks on a team of girls and then they go on to win a world championship. This city had the simplicity I had seen nowhere else. When you get older like me, you realise things. I realised that film changed my life. It’s not the awards you get, it’s just the part of creating process that is an exhilarating experience for an artiste.”
Here’s a complete list of winners:
- IFFM Best Short Film: My Name Is Mohamed And Raghad, We Don’t Exist Here Anymore by Ali Mousawi AND Be My Brother by Genevieve Clay
- IFFM Diversity Award: Onir
- Telstra People’s Choice Award: Simmba
- Celebrating 20 years of Kuch Kuch Hota Hai: Karan Johar
- IFFM Best Director: Sriram Raghavan for Andhadhun
- IFFM Best Actor: Vijay Sethupathi for Super Deluxe
- IFFM Best Actress: Tabu for Andhadhun
- IFFM Best Indie film: Bulbul Can Sing
- IFFM Best Film: Gully Boy
- PWC Equality in Cinema award an honorary award): Chuskit & Super Deluxe
- IFFM Excellence in Cinema – Shah Rukh Khan
For more news and updates from the world of showbiz stay tuned to CineBlitz!
Nikaah, Halal, Phir Ussi Mod Par – 4 films that dealt with Triple Talaq
The Triple Talaq Bill is being introduced in the Rajya Sabha, and on this note we bring to you some films that explored the subject
The subject of triple talaq is not new to Bollywood. Time and again, filmmakers have dealt with this social issue faced by women in the Muslim communities. Here we check out five such films that have explored the topic on screen.
The film was a social comment on the Shariat law of divorce. The film was initially titled Talaq Talaq Talaq, but director BR Chopra had to change the title of the film to Nikaah after one of his friends pointed out that the title will dissuade Muslim families from watching a film that was propagating Talaq (divorce). Chopra changed the title to Nikaah but could not stop people from filing cases against the film.
Starring Raj Babbar, Deepak Parashar and Salma Agha — it was the story of a woman who is married to a man who does not have any time for her — resulting in an altercation that leads to the man spelling out Talaq three times to her.
Phir Ussi Mod Par
Another Muslim social that attempted to talk of the practice of Triple Talaq. It is the story of a woman of substance and fortitude who gets duped in love facing an unjustified ‘Triple Talaq’. She raises her son against all odds only to see him subject her daughter-in-law to the same fate in a most unjustifiable manner. The woman rises to the occasion squarely meeting the daunting challenges of society and clerics to ensure that justice prevails. Directed by Lekh Tandon the film failed to impress at the box office.
The film deals with the theme of loyalty, love and the institution of marriage that is deemed to be pious by society. It is a story of human emotions, which depicts the trials and tribulations that women in our society go through. The film is about a woman whose husband divorces her so that she does not face the ire of his mother. As per the Muslim customs, the woman has to marry again and divorce the second husband if the first husband wants her back.
Directed by National Award Winner Shivaji Lotan Patil, the movie featured Chinmay Deepak Mandlekar, Priyadarshan Jadhav, Pritam Kagne, Vijay Chavan, Vimal Mhatre, Chhaya Kadam, Amol Kagne and Sanjay Sugaokar.
‘Code Blue’ refers to the life-saving emergency code and in this movie it revolves around this girl, whose story is inspired by a real-life incident. The protagonist is pushed to the limits by society’s malpractices and how she comes back and fights those evils, is what Code Blue is all about. The battle of a girl from a dead-end! Made in association with Rahat Kazmi Films, the film features Alok Nath, Rishi Bhutani, Sushmita Mukerji and Khan in lead roles.
Khan wants to use the medium of movies to bring to light the lives of women who find their lives shattered with this instant divorce practice. She says, she felt traumatised when she encountered cases of women having to endure the mistreatment and misuse of the oral talaq system. For more Bollywood news and updates, stay tuned with CineBlitz.
Katrina Kaif, Priyanka Chopra, Ranveer Singh – 5 stars who’ve been teased by Arjun Kapoor on social media
Post Arjun Kapoor’s funny comment on Anil Kapoor’s recent post, here’s taking a look at the top 5 funny comments that the young star made on his B-Town friends’ social media posts
Arjun Kapoor is often seen headlining news and it’s not just for his films. The actor is a master of trolling. Well, sort of and his fans enjoy the friendly banter that he has on social media with his friends. His recent comment on Anil Kapoor’s latest picture brought him in the limelight again. Anil had posted a picture with the caption saying, “I could add some deep quote here but let’s be honest I just wanted to post some good looking pictures of myself.” And Arjun had something interesting to say. He wrote, “& u say I ruin ur reputation….just see this post.” Well this made us take a look at the other times he has teased his friends on their social media. Check it out:
Katrina Kaif is one of Arjun’s favourite when it comes to making funny remarks. Recently, when Katrina posted a picture from her Mexico vacation, Arjun had a rather hilarious take on the photo. He commented, “Watch where you going, girl! Hope you didn’t walk into the pillar while posing,” as Katrina was posing next to a pillar.
Arjun did not spare his Gunday co-star and best friend Ranveer Singh as well. The Gully Boy actor is known for his outlandish style and when had posted a photo wearing a colourful outfit, Arjun didn’t miss the opportunity to comment on the same. He said, ”Narangi Mausambi wala.”
The Ishqzaade jodi is known for their online banter and Arjun is forever ready to tease Pari. So during the shooting of their film Namaste England, Arjun made sure he did it again. He posted a video where he can be seen teasing Parineeti and just because she wore a green dress, Arjun captioned the video as, “Presenting Hari – Pari the tourist photography expert !!!”
Priyanka Chopra Jonas
Remember Priyanka Chopra’s all-white Cannes 2019 dress. Priyanka definitely killed the look but Arjun yet again had a fun take on it. When PeeCee posted that picture on social media, Arjun couldnt resist commenting, “Surf Excel vibes.”
Aditya Roy Kapur
When Aditya Roy Kapur claimed that he is single through an Instagram post, he also was obliged with a funny comment from Arjun Kapoor. Arjun said, “Chal Jhoota.” and hinted that Aditya might actually be in a relationship.
These were some instances that we feel Arjun was bang on with his hilarious comments. Which one was your favourite? Let us know in the comments section below. Also, stay tuned to CineBlitz for more such interesting features.
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Since 1944, Iowans Have Enjoyed Delicious Pizza From The Airliner
Way back in 1944, a small pub opened up in Iowa City and it quickly became famous for friendly service, a welcoming atmosphere, and outrageously tasty food. Now, more than 75 years later, you’re sure to find plenty of people who agree that the legendary Airliner serves the best pizza in Iowa City.
The Airliner is the oldest bar in Iowa City. This family-owned establishment opened its doors in 1944 and has since earned a legendary reputation.
You'll find a variety of comfort food bar bites here, including wings, burgers, salads, sandwiches and more.
If you're a big fan of wings, you'll be happy to hear there are half a dozen sauce choices, ranging from mild to blazin' hot.
With at least seven different burgers on the menu at any given time, The Airliner is a great place for carnivores, too.
Each burger is named after a plane, so try the Cessna or the F-16 for a treat. Enjoy yours served with fresh cut fries, salad, sweet potato fries, or even waffle fries.
The Airliner is most famous for their outrageously tasty pizza. In fact, pretty much everyone will tell you they make the best pizza in Iowa City!
With at least 17 traditional and specialty pizzas on the menu, you're sure to find a pie to please even the pickiest foodie.
Like any good Iowa pizzeria, The Airliner makes a delicious taco pizza. Try it for a new twist on taco Tuesday.
You can also build your own pizza by choosing from four different crust styles and more than 20 toppings.
Stop in to the Airliner to enjoy the best pizza in Iowa City, and you'll soon understand why this legendary bar has been a local favorite for more than 75 years.
Stop by The Airliner to try the best pizza in Iowa City! Whether you like Chicago Deep Dish or NY-Style thin crust, you’ll find the pie of your dreams here in the heart of the Hawkeye State.
OnlyInYourState may earn compensation through affiliate links in this article. As an Amazon Associate, we earn from qualifying purchases.
22 S Clinton St, Iowa City, IA 52240, USA

domain: food


text:
Vaccinating your dog at home can save you money and be a less stressful experience than a trip to the vet. Check your state and local laws before giving vaccines. Some states require your dog to receive his rabies vaccination from a licensed veterinarian.
Video of the Day
Vaccinations come in a standard dose for all sizes and types of dogs. Purchasing a single dose vaccine is easier and has less risk of contamination than purchasing a multidose vial. Read the instructions on the vaccine to ensure you are administering it in the correct location.
Subcutaneous Injection Sites
Most vaccines that you will give your dog at home are administered subcutaneously, or under the skin. Inject these vaccines under the loose skin of the dog's shoulder. Lift the skin of either shoulder, inject the needle at a 45-degree angle and administer the entire contents of the syringe. Before injecting the vaccine, ensure that the tip of the needle did not come through the skin on the other side.
Intramuscular Injection Sites
Some vaccines are injected into your dog's muscle. Ask your veterinarian to teach you to administer these shots before attempting it on your own. Intramuscular injections may be made into your dog's lumbar muscles along his back, about 2 inches away from the spine. The quadriceps muscle at the front of your dog's thigh or the triceps muscle behind the bone of the front leg are also good locations to administer these vaccinations.
Inject the needle into the muscle at a 90-degree angle. Before injecting the vaccine, pull back slightly on the syringe to make sure no blood flows into the needle. If you do see blood, remove the needle and use a different injection site.
Intranasal vaccines are administered into your dog's nostril. These vaccines may be administered with a syringe or with a dropper. Administer half of the dose into each nostril. It is normal for your dog to sneeze or shake his head after you administer these vaccines.
Cautions and Warnings
Check the instructions on the vaccine to determine how the vaccine should be administered. Administering a vaccine incorrectly may result in ineffective immunity or cause serious medical side effects. For example, injecting the intranasal Bordetella vaccine may result in liver failure.
Keep vaccines refrigerated at 35 to 45 degrees Fahrenheit until you are ready to administer them. Failure to do so may reduce the effectiveness of the vaccine. When preparing the vaccination, ensure that the needle is securely attached to the syringe. Withdraw the liquid into the syringe and inject any air bubbles back into the vial. After giving the vaccine, place the cover back on the syringe and turn the used needles over to your veterinarian for proper disposal.
Watch your dog for any reactions for at least two to three hours after giving the vaccine. Some side effects you might see include lethargy, hives, vomiting or difficulty breathing. Contact your vet immediately if your dog has a reaction to the shot.
Always check with your veterinarian before changing your pet’s diet, medication, or physical activity routines. This information is not a substitute for a vet’s opinion.
- Doctors Foster and Smith: How to Vaccinate Your Dog at Home
- Maddie's Fund: Proper Handling and Use of Vaccines in Animal Shelters
- Doctors Foster and Smith: Vaccinate Your Dog at Home
- American Veterinary Medical Association: Administration of Rabies Vaccination State Laws
- Cold River Veterinary Center: How To Administer an Intramuscular Injection
- Watkins and Tasker Veterinary Group: Injecting your dog
- PetMD: Does a Smaller Dog Need a Smaller Vaccine?

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