RESUMEN
Heparanase (HPSE) is part of the biologic network triggered by ischemia/reperfusion (I/R) injury, a complication of renal transplantation and acute kidney injury. During this period, the kidney or graft undergoes a process of macrophages recruitment and activation. HPSE may therefore control these biologic effects. We measured the ability of HPSE and its inhibitor, SST0001, to regulate macrophage polarization and the crosstalk between macrophages and HK-2 renal tubular cells during in vitro hypoxia/reoxygenation (H/R). Furthermore, we evaluated in vivo renal inflammation, macrophage polarization, and histologic changes in mice subjected to monolateral I/R and treated with SST0001 for 2 or 7 d. The in vitro experiments showed that HPSE sustained M1 macrophage polarization and modulated apoptosis, the release of damage associated molecular patterns in post-H/R tubular cells, the synthesis of proinflammatory cytokines, and the up-regulation of TLRs on both epithelial cells and macrophages. HPSE also regulated M1 polarization induced by H/R-injured tubular cells and the partial epithelial-mesenchymal transition of these epithelial cells by M1 macrophages. All these effects were prevented by inhibiting HPSE. Furthermore, the inhibition of HPSE in vivo reduced inflammation and M1 polarization in mice undergoing I/R injury, partially restored renal function and normal histology, and reduced apoptosis. These results show for the first time that HPSE regulates macrophage polarization as well as renal damage and repair after I/R. HPSE inhibitors could therefore provide a new pharmacologic approach to minimize acute kidney injury and to prevent the chronic profibrotic damages induced by I/R.-Masola, V., Zaza, G., Bellin, G., Dall'Olmo, L., Granata, S., Vischini, G., Secchi, M. F., Lupo, A., Gambaro, G., Onisto, M. Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.
Asunto(s)
Células Epiteliales/enzimología , Glucuronidasa/metabolismo , Enfermedades Renales/enzimología , Túbulos Renales/enzimología , Macrófagos/enzimología , Daño por Reperfusión/enzimología , Animales , Células Epiteliales/patología , Enfermedades Renales/patología , Túbulos Renales/lesiones , Túbulos Renales/patología , Macrófagos/patología , Ratones , Daño por Reperfusión/patologíaRESUMEN
Autoimmune hepatitis is a chronic inflammatory liver disease characterized by hypergammaglobulinemia, the presence of autoantibodies, and inflammation within the liver, including lymphocytic infiltrates and interface hepatitis. Autoimmune hepatitis shows a female predominance and can present at any age and in any ethnicity. The disease is thought to be a consequence of a break of immune tolerance leading to an autoimmune process that induces liver injury. The self-attack is triggered by T-helper cell-mediated liver autoantigen recognition and B-cell production of autoantibodies, and is sustained by impaired regulatory T cells number and function. Superimposed on a genetic predisposition, infections and environmental factors have been studied as triggering factors for the disease. Allelic variants in the HLA locus have been associated with susceptibility; associations with single nucleotide polymorphisms within non-HLA genes have also been assessed. Several factors have been described as triggers of autoimmune responses in predisposed individuals, including infections, alcohol, vitamin D deficiency, and an altered composition of the intestinal microbiome. Importantly, drugs and herbal agents may trigger classical autoimmune hepatitis, or may induce a liver disease with autoimmune features. Interactions between female hormones and genetic factors have been hypothesized to play a role in autoimmunity, although the exact role for these factors has not been fully established. Herein we present a review of the etiology of autoimmune hepatitis including de novo autoimmune hepatitis post-liver transplantation as well as animal models for its study.
Asunto(s)
Alcoholismo/inmunología , Enfermedades Transmisibles/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Hígado/inmunología , Deficiencia de Vitamina D/inmunología , Alcoholismo/complicaciones , Alcoholismo/diagnóstico , Alcoholismo/genética , Animales , Autoanticuerpos/biosíntesis , Autoantígenos/genética , Autoantígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Enfermedades Transmisibles/complicaciones , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA/inmunología , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/etiología , Hepatitis Autoinmune/genética , Humanos , Hígado/patología , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/etiología , Cirrosis Hepática Biliar/genética , Trasplante de Hígado/efectos adversos , Factores Sexuales , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/diagnóstico , Deficiencia de Vitamina D/genéticaRESUMEN
Epithelial-mesenchymal transition (EMT) of tubular cells is one of the mechanisms which contribute to renal fibrosis and transforming growth factor-ß (TGF-ß) is one of the main triggers. Heparanase (HPSE) is an endo-ß-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-ß). HPSE controls FGF-2-induced EMT in tubular cells and is necessary for the development of diabetic nephropathy in mice. The aim of this study was to investigate whether HPSE can modulate the expression and the effects of TGF-ß in tubular cells. First we proved that the lack of HPSE or its inhibition prevents the increased synthesis of TGF-ß by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products (AGE) and albumin overload. Second, since TGF-ß may derive from sources different from tubular cells, we investigated whether HPSE modulates tubular cell response to exogenous TGF-ß. HPSE does not prevent EMT induced by TGF-ß although it slows its onset; indeed in HPSE-silenced cells the acquisition of a mesenchymal phenotype does not develop as quickly as in wt cells. Additionally, TGF-ß induces an autocrine loop to sustain its signal, whereas the lack of HPSE partially interferes with this autocrine loop. Overall these data confirm that HPSE is a key player in renal fibrosis since it interacts with the regulation and the effects of TGF-ß. HPSE is needed for pathological TGF-ß overexpression in response to pro-fibrotic factors. Furthermore, HPSE modulates TGF-ß-induced EMT: the lack of HPSE delays tubular cell transdifferentiation, and impairs the TGF-ß autocrine loop.
Asunto(s)
Glucuronidasa/metabolismo , Riñón/metabolismo , Riñón/patología , Factor de Crecimiento Transformador beta/genética , Actinas/genética , Actinas/metabolismo , Animales , Comunicación Autocrina , Biomarcadores/metabolismo , Línea Celular , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis , Regulación de la Expresión Génica , Glucuronidasa/genética , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Mesodermo/metabolismo , Mesodermo/patología , Ratones , Factor de Crecimiento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMEN
The 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.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Autoinmunidad , Colangitis Esclerosante/complicaciones , Hepatitis Autoinmune/complicaciones , Cirrosis Hepática Biliar/complicaciones , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/inmunología , Humanos , Hígado/patología , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/inmunologíaRESUMEN
Colonoscopic 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.
RESUMEN
The 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.
Asunto(s)
Glucuronidasa/análisis , Cirrosis Hepática/patología , Hígado/patología , Macrófagos/patología , Animales , Tetracloruro de Carbono , Línea Celular , Glucuronidasa/inmunología , Células Estrelladas Hepáticas/inmunología , Células Estrelladas Hepáticas/patología , Humanos , Hígado/inmunología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/inmunología , Macrófagos/inmunología , Masculino , Ratones Endogámicos BALB CRESUMEN
Heparanase (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-ß. 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.
Asunto(s)
Glucuronidasa/metabolismo , Heparitina Sulfato/metabolismo , Inflamación/enzimología , Neoplasias/enzimología , Transducción de Señal , Transición Epitelial-Mesenquimal , Fibrosis/enzimología , Humanos , Riñón/enzimología , Riñón/patología , Modelos BiológicosRESUMEN
Heparanase is the unique and specific functional endoglycosidase capable of cleaving heparan sulfate (HS) chains. It exerts its enzymatic activity catalyzing the cleavage of the ß (1,4)-glycosidic bond between glucuronic acid and glucosamine residue. HS cleavage results in remodelling of the extracellular matrix as well as in regulating the release of many HS-linked molecules such as growth factors, cytokines and enzymes involved in inflammation, wound healing and tumour invasion. A pro-metastatic and pro-angiogenic role for this enzyme has been widely demonstrated in many primary human tumours since high levels of heparanase correlate with lymph node and distant metastasis, elevated micro vessel density and reduced survival of cancer patients. Recently, data have been reported that heparanase regulates heparan sulfate proteoglycan syndecan-1 and promotes its shedding from the cell surface. Shed syndecan-1 in turn controls tumour growth, metastasis and neo-angiogenesis mainly by promoting growth-factor signaling in the tumour milieu. Considering that, once inactivated, there are no other molecules capable of performing the same function, it is evident how this enzyme may be an effective and attractive drug target. Several heparanase inhibitors have been developed and some of them have undergone clinical trials showing efficacy against tumours. In this mini-review we will discuss current knowledge of heparanase involvement in cancer as well as its targeted inhibition as a promising therapeutic option in tumour treatment.