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A novel role for heparanase in the onset of liver fibrosis establishment
Full text linkHeparan sulfate proteoglycans are important structural and functional components of basal membranes composed of a core protein (soluble or transmembrane) covalently linked to highly sulfated chains of glycosaminoglycans called heparan sulfate. Heparanase is the only endoglucuronidase capable of cleaving heparan sulfate chains of heparan sulfate proteoglycans. It exerts its enzymatic activity by catalyzing the cleavage of the β(1,4)-glycoside bond between glucuronic acid and glucosamine residues, generating fragments of about 5–7kDa. At intracellular level (endosomal and lysosomal), heparanase participates in the turnover of membrane-associated heparan sulfate proteoglycans, while secreted enzyme is involved in the remodeling and degradation of extracellular matrix. Given the electrostatic interaction of heparan sulfate with growth factors, cytokines and enzymes, heparanase cleavage indirectly facilitates the release and diffusion of these molecules. Heparanase exerts also non-enzymatic functions since it regulates gene expression by the activation of specific signaling pathways. Through degradation of heparan sulfate chains and heparan sulfate-independent functions, HPSE regulates several physiological and pathological processes. In particular, heparanase has a significant role in tumor progression and in renal glomerular diseases. In addition, it was recently shown its involvement also in bowel and kidney chronic inflammation as well as in tubulo-interstitial fibrosis. In general, fibrosis is an unregulated process of tissue repair that occurs in response to persistent damage and chronic inflammation. In the liver, the progressive accumulation of extracellular matrix can lead to cirrhosis and organ failure. In this process, activated Kupffer cells and hepatic stellate cells (HSCs) play a fundamental role, the first in the inflammatory response, the latter in fibrogenesis.
The involvement of heparanase in the development of chronic liver disease has not been demonstrated so far. Given the reproducibility of the mechanisms that contribute to the development of chronic diseases, this study was aimed to: i) investigate whether heparanase is up-regulated during chronic liver disease, ii) study the possible regulation of its expression and iii) study the possible effects on the development of the disease.
The tempo-spatial expression of heparanase was studied in mice with chronic hepatic damage induced by carbon tetrachloride (CCl4) administration for 1, 2, 8 and 12 weeks. The progression of chronic injury and fibrosis was assessed by Azan-Mallory and Hematoxylin-Eosin histological stainings. Extensive centrilobular areas with necro-inflammatory activity and fibrosis were observed after 1 and 2 weeks of treatment that progressively developed fibrotic septa and micronodular cirrhosis observed after 8 and 12 weeks of treatment. Analyses of gene expression (by real time RT-PCR) and protein expression (by western blot and immunofluorescence), showed a significant increase of heparanase expression in liver tissue after 1 and 2 weeks of treatment but not after 8 and 12 weeks suggesting a possible role in the early stages of chronic damage. Immunohistochemical analyses revealed the localization of heparanase in the centrilobular areas with necro-inflammatory damage and fibrosis. To identify the cellular source responsible for heparanase increase in tissue, in vitro analyses on cell cultures and co-immunofluorescence analyses on sections from 1 and 2 week-treated livers were performed. Given heparanase localization in fibrotic areas and the fundamental role of the HSCs in chronic liver disease, we wondered if the expression of heparanase increases in HSC during their activation. For this purpose, primary HSCs were isolated from rat livers and induced to activate through culture on plastic dishes. After 15 days of isolation, the levels of heparanase and transdifferentiation markers (α-SMA, fibronectin, TGF-β and collagen I) expression increased significantly compared to cells cultured for 7 days. However, despite immunofluorescence analyses on liver sections revealed the expression of heparanase by in vivo activated HSCs at 1 and 2 weeks of treatment with CCl4, a more significant degree of co-localization was observed with macrophages labeled with F4/80 and CD68.
Given the main involvement of macrophages in increasing hepatic heparanase in the sites of inflammation, an analysis of the possible mechanisms of heparanase up-regulation by inflammatory macrophages was then conducted. To this purpose, primary Kupffer cells were isolated from rat livers and treated with LPS and TNF-α, two important pro-inflammatory stimuli. In contrast to LPS, that did not alter the expression of heparanase, TNF-α induced a significant increase of heparanase expression. Also human U937 macrophages, treated with increasing concentrations of TNF-α, increased the heparanase gene and protein levels, in a dose-dependent mechanism. By Western blot on the conditioned media from cells treated or not with TNF-α, we also showed an increase of extracellular enzyme in the presence of TNF-α, indicating that this factor stimulates also heparanase secretion. In addition, two observations provided further evidence on the possible role of TNF-α as a regulator of heparanase expression in chronic liver disease: first, the significant increase in TNF-α expression in the liver tissue only at 1 and 2 weeks of intoxication by CCl4 and, secondly, its co-localization with heparanase at the same weeks of treatment. Among the other pro-inflammatory molecules tested, while IFN-γ stimulated heparanase gene transcription, IL-4 reduced its expression thus suggesting a different regulation of heparanase by macrophages depending on their state of M1 or M2 polarization.
The observation of enhanced heparanase expression in the early stages of chronic liver disease led to wonder what it could be its role in the process of fibrogenesis. Given the involvement of Kupffer cells in the activation of HSC through the release of pro-fibrotic stimuli, we examined whether a mechanism of regulation through the release of heparanase was also possible. For this purpose, LX-2 stellate cells were treated with the conditioned media of U937 cells that were previously induced to produce heparanase by stimulation with TNF-α. The involvement of heparanase in the activation of LX-2 has been verified using an heparanase inhibitor during treatment. The results showed that heparanase is able to regulate the expression of α-SMA and fibronectin by LX-2 cells.
Besides extracellular matrix degradation, the promotion of macrophage activation by heparanase is already known. In this study, using an in vitro migration assay, we demonstrated that heparanase is also able to stimulate the migration of macrophages.
Finally, to verify the involvement of heparanase also in human liver fibrosis, the levels of heparanase activity were measured in the plasma of healthy subjects and patients with chronic liver disease, of viral or autoimmune etiology and at different stages of fibrosis. Accordingly to the animal model, we showed that, regardless of the etiology of hepatic disease, heparanase plasma activity increased in patients with mild and moderate fibrosis compared to healthy subjects, but returned to baseline in patients with cirrhosis. In addition, in patients, plasma heparanase activity negatively correlated with the degree of liver stiffness.
Overall, our results indicate the involvement of heparanase in chronic liver disease but only in its early stages. Inflammatory macrophages and, to a lesser extent, activated HSCs are an important source of heparanase. In this context, secreted heparanase in the extracellular environment may play a role in the macrophage-mediated activation of HSCs and in the migration of macrophages themselves
Extrahepatic autoimmunity in autoimmune liver disease
Full text linkThe most important autoimmune liver disease include: autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. In general, about one in three patients with an autoimmune liver disease have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary or dermatological conditions. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, extrahepatic autoimmunity represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues. This review aims to focus the clinical and pathophysiological aspects of extrahepatic autoimmunity associated to autoimmune liver diseases
Heparanase and macrophage interplay in the onset of liver fibrosis
Full text linkAbstractThe heparan sulfate endoglycosidase heparanase (HPSE) is involved in tumor growth, chronic inflammation and fibrosis. Since a role for HPSE in chronic liver disease has not been demonstrated to date, the current study was aimed at investigating the involvement of HPSE in the pathogenesis of chronic liver injury. Herein, we revealed that HPSE expression increased in mouse livers after carbon tetrachloride (CCl4)-mediated chronic induction of fibrosis, but with a trend to decline during progression of the disease. In mouse fibrotic liver tissues HPSE immunostaining was restricted in necro-inflammatory areas, co-localizing with F4/80 macrophage marker and TNF-α. TNF-α treatment induced HPSE expression as well as HPSE secretion in U937 macrophages. Moreover, macrophage-secreted HPSE regulated the expression of α-SMA and fibronectin in hepatic stellate LX-2 cells. Finally, HPSE activity increased in the plasma of patients with liver fibrosis but it inversely correlated with liver stiffness. Our results suggest the involvement of HPSE in early phases of reaction to liver damage and inflammatory macrophages as an important source of HPSE. HPSE seems to play a key role in the macrophage-mediated activation of hepatic stellate cells (HSCs), thus suggesting that HPSE targeting could be a new therapeutic option in the treatment of liver fibrosis.</jats:p
The Close Relationship between Large Bowel and Heart: When a Colonic Perforation Mimics an Acute Myocardial Infarction
Full text linkColonoscopic perforation is a serious and potentially life-threatening complication of colonoscopy. Its incidence varies in frequency from 0.016% to 0.21% for diagnostic procedures, but may be seen in up to 5% of therapeutic colonoscopies. In case of extraperitoneal perforation, atypical signs and symptoms may develop. The aim of this report is to raise the awareness on the likelihood of rare clinical features of colonoscopic perforation. A 72-year-old male patient with a past medical history of myocardial infarction presented to the emergency department four hours after a screening colonoscopy with polypectomy, complaining of neck pain, retrosternal oppressive chest pain, dyspnea, and rhinolalia. Right chest wall and cervical subcutaneous emphysema, pneumomediastinum, pneumoretroperitoneum, and bilateral subdiaphragmatic free air were reported on the chest and abdominal X-rays. The patient was treated conservatively, with absolute bowel rest, total parental nutrition, and broad-spectrum intravenous antibiotics. Awareness of the potentially unusual clinical manifestations of retroperitoneal perforation following colonoscopy is crucial for the correct diagnosis and prompt management of colonoscopic perforation. Conservative treatment may be appropriate in patients with a properly prepared bowel, hemodynamic stability, and no evidence of peritonitis. Surgical treatment should be considered when abdominal or chest pain worsens, and when a systemic inflammatory response arises during the conservative treatment period
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Recent data concerning heparanase: Focus on fibrosis, inflammation and cancer
No full textHeparanase (HPSE) is a multitasking protein characterized by enzymatic and non-enzymatic activities. By means of its enzymatic activity, HPSE catalyzes the cutting of the side chains of heparan sulfate (HS) proteoglycans, thereby inducing the remodeling of the extracellular matrix and basement membranes. Thanks to the cleavage of HS, HPSE also promotes the release and diffusion of several HS-linked molecules such as growth factors, cytokines and enzymes. In addition to degrading HS chains, HPSE has non-enzymatic functions that trigger several signaling pathways. This signaling activity is achieved by interacting with transmembrane proteins, activating kinases such as Akt and Src, or modulating the activity of factors such as FGF-2 and TGF-β. Several studies have recently highlighted a possible intracellular activity for HPSE, particularly at nuclear level. While HPSE activity is quite limited in physiological conditions, its demonstrated increasing involvement in various pathological conditions, such as in tumor progression and renal disease, have attracted the attention of a growing number of researchers. The fact that no other molecule is capable of performing the same function as HPSE makes this enzyme an attractive potential target of medical treatment. With this short conceptual overview, we aim to provide an update on current knowledge concerning the HPSE protein in the experimental and clinical settings, paying particular attention to its role in fibrosis, inflammation and cancer
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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