How tubular epithelial cells dictate the rate of renal fibrogenesis?

The main threat to a kidney injury,whatever its cause and regardless of whether it is acute or chronic,is the initiation of a process of renal fibrogenesis,since fibrosis can auto-perpetuate and is of high prognostic significance in individual patients.In the clinic,a decrease in glomerular filtration rate correlates better with tubulointerstitial damage than with glomerular injury.Accumulation of the extracellular matrix should not be isolated from other significant cellular changes occurring in the kidney,such as infiltration by inflammatory cells,proliferation of myofibroblasts,obliteration of peritubular capillaries and atrophy of tubules.The aim of this review is to focus on tubular epithelial cells(TEC),which,necessarily involved in the repair process,eventually contribute to accelerating fibrogenesis.In the context of injury,TEC rapidly exhibit phenotypic and functional changes that recall their mesenchymal origin,and produce several growth factors known to activate myofibroblasts.Because they are high-demanding energy cells,TEC will subsequently suffer from the local hypoxia that progressively arises in a microenvironment where the matrix increases and capillaries become rarified.The combination of hypoxia and metabolic acidosis may induce a vicious cycle of sustained inflammation,at the center of which TEC dictate the rate of renal fibrogenesis.     

Changes of shear-wave velocity by interferon-based therapy in chronic hepatitis C

AIM: To evaluate the changes of shear-wave velocity(Vs) by acoustic radiation force impulse after treatment in chronic hepatitis C.METHODS: Eighty-seven patients with chronic hepatitis C were consecutively treated with combinations of interferon(IFN) plus ribavirin(RBV). Vs value(m/s) was measured with acoustic radiation force impulse before treatment, at end of treatment(EOT), 1 year after EOT, and 2 years after EOT.RESULTS: In patients with a sustained virological response(SVR)(n = 41), Vs significantly decreased at EOT [1.19(1.07-1.37), P = 0.0004], 1 year after EOT [1.10(1.00-1.22), P = 0.0001], and 2 years after EOT [1.05(0.95-1.16), P 0.0001] compared with baseline [1.27(1.11-1.49)]. In patients with a relapse(n = 26), Vs did not significantly decrease at EOT [1.23(1.12-1.55)], 1 year after EOT [1.20(1.12-1.80)], and 2 years after EOT [1.41(1.08-2.01)] compared with baseline [1.39(1.15-1.57)]. In patients with a nonvirological response(n = 20), Vs did not significantly decrease at EOT [1.64(1.43-2.06)], 1 year after EOT [1.66(1.30-1.95)], and 2 years after EOT [1.61(1.36-2.37)] compared with baseline [1.80(1.54-2.01)]. Among genotype 1 patients, baseline Vs was significantly lower in SVR patients [1.28(1.04-1.40)] than in non-SVR patients [1.56(1.20-1.83)](P = 0.0142).CONCLUSION: Reduction of Vs values was shown in SVR patients after IFN-plus-RBV therapy by acoustic radiation force impulse.     

Cross talk of the immune system in the adipose tissue and the liver in non-alcoholic steatohepatitis: Pathology and beyond

Non-alcoholic steatohepatitis(NASH) is considered to be the hepatic manifestation of the metabolic syndrome, thus has a tight correlation with systemic metabolic impairment. The complex mechanisms underlying the pathogenesis of NASH involve different organs and systems that cross talk together contributing to the onset of NASH. A crucial role is played by inflammatory mediators, especially those deriving from the adipose tissue and the liver, which are involved in the cascade of inflammation, fibrosis and eventually tumorigenesis. In this setting cytokines and adipokines as well as immunity are emerging drivers of the key features of NASH. The immune system participates in this process with disturbances of the cells constituting both the innate and the adaptive immune systems that have been reported in different organs, such as in the liver and in the adipose tissue, in clinical and preclinical studies. The role of the immune system in NASH is increasingly studied, not only because of its contribution to the pathogenetic mechanisms of NASH but also because of the new potential therapeutic options it offers in this setting. Indeed, novel treatments acting on the immune system could offer new options in the management of NASH and the correlated clinical consequences.     

In Vitro and In Vivo Protection of Stellate Cells from Apoptosis by Leptin

Hepatic fibrogenesis is reduced in the absence of leptin. We hypothesized that leptin protects hepatic stellate cells (HSCs) from apoptosis and tested this in in vitro and in vivo systems. (i) Fas ligand (fas-L)-mediated apoptosis was induced in vitro in activated HSCs in the absence and presence of leptin. (ii) HSC apoptosis was also induced by UV irradiation in the absence and presence of leptin. (iii) Fas-L-mediated apoptosis was induced in vitro in HSCs from db/db mice in the absence and presence of leptin. (iv) Liver fibrosis was induced in wt and db/db mice. (v) Liver fibrosis was induced in wild-type mice with TAA, and mice received additional leptin or a control solution. HSC apoptosis was assessed by TUNEL staining. Western blot for α-SMA was used to determine differences in HSC activation. Results were as follows. (i) Fas-L induced significant apoptosis of HSC, and preincubation with leptin reduced this approximately threefold. (ii) Leptin provided no protection from UV-induced apoptosis. (iii) HSCs from db/db mice were not protected by leptin against fas-L-induced apoptosis. (iv) TAA-induced fibrosis was significantly less in db/db mice compared to wild type. (v) Wild-type mice receiving leptin had less apoptosis and more α-SMA than controls. We conclude that leptin protects HSC from in vitro and in vivo apoptosis. The antiapoptotic effect of leptin requires the long form of the leptin receptor and interacts with the apoptotic pathway proximal to mitochondrial activation.     

Novel CFTR Mutations in a Korean Infant with Cystic Fibrosis and Pancreatic Insufficiency

Cystic fibrosis (CF) is an autosomal recessive disease that is very rare in Asians: only a few cases have been reported in Korea. We treated a female infant with CF who had steatorrhea and failure to thrive. Her sweat chloride concentration was 102.0 mM/L. Genetic analysis identified two novel mutations including a splice site mutation (c.1766+2T>C) and a frameshift mutation (c.3908dupA; Asn1303LysfsX6). Pancreatic enzyme replacement and fat-soluble vitamin supplementation enabled the patient to get a catch-up growth. This is the first report of a Korean patient with CF demonstrating pancreatic insufficiency. CF should therefore be considered in the differential diagnosis of infants with steatorrhea and failure to thrive.     

Responsibility of hepatitis C virus in the development of hepatocellular carcinoma: From molecular alterations to possible solutions

There are several causes of hepatocellular carcinoma(HCC), but certainly the hepatitis C virus(HCV) is one of the most common. The HCV is able to contribute, both directly and indirectly, to the development of HCC. Determining early HCV clearance before an advanced liver disease develops, is absolutely necessary as this prevents the initiation of the cascade of events induced by HCV that may result in the development of HCC. The early treatment of the infection and the clearance of HCV represents today, in the age of the direct antiviral agents(DAAs), an extraordinary opportunity for true prevention of the development of HCV-related HCC.     

Established and novel pathophysiological mechanisms of pericardial injury and constrictive pericarditis

This review article aims to:(1) discern from the literature the immune and inflammatory processes occurring in the pericardium following injury; and(2) to delve into the molecular mechanisms which may play a role in the progression to constrictive pericarditis. Pericarditis arises as a result of a wide spectrum of pathologies of both infectious and non-infectious aetiology, which lead to various degrees of fibrogenesis. Current understanding of the sequence of molecular events leading to pathological manifestations of constrictive pericarditis is poor. The identification of key mechanisms and pathways common to most fibrotic events in the pericardium can aid in the design and development of novel interventions for the prevention and management of constriction. We have identified through this review various cellular events and signalling cascades which are likely to contribute to the pathological fibrotic phenotype. An initial classical pattern of inflammation arises as a result of insult to the pericardium and can exacerbate into an exaggerated or prolonged inflammatory state. Whilst the implication of major drivers of inflammation and fibrosis such as tumour necrosis factor and transforming growth factor β were foreseeable, the identification of pericardial deregulation of other mediators(basic fibroblast growth factor, galectin-3 and the tetrapeptide Ac-SDKP) provides important avenues for further research.