[Show abstract][Hide abstract] ABSTRACT: Elafin, a natural protease inhibitor expressed in healthy intestinal mucosa, has pleiotropic anti-inflammatory properties in vitro and in animal models. We found that mucosal expression of Elafin is diminished in patients with inflammatory bowel disease (IBD). This defect is associated with increased elastolytic activity (elastase-like proteolysis) in colon tissue. We engineered two food-grade strains of lactic acid bacteria (LAB) to express and deliver Elafin to the site of inflammation in the colon to assess the potential therapeutic benefits of the Elafin-expressing LAB. In mouse models of acute and chronic colitis, oral administration of Elafin-expressing LAB decreased elastolytic activity and inflammation and restored intestinal homeostasis. Furthermore, when cultures of human intestinal epithelial cells were treated with LAB secreting Elafin, the inflamed epithelium was protected from increased intestinal permeability and from the release of cytokines and chemokines, both of which are characteristic of intestinal dysfunction associated with IBD. Together, these results suggest that oral delivery of LAB secreting Elafin may be useful for treating IBD in humans.
Science translational medicine 10/2012; 4(158):158ra144. · 14.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transjugular liver biopsy (TJLB) is usually performed when a percutaneous liver biopsy (PLB) is contraindicated. TJLB is an invasive procedure and the patient's tolerance may be variable.
To compare patient tolerance and quality of the biopsy sample between PLB and TJLB.
A total of 143 patients underwent a liver biopsy; of these, 75 underwent TJLB and 68 underwent PLB. To evaluate patient tolerance, we used a visual analog scale that scored the intensity of the symptoms. The length of the biopsy sample and the total number of portal tracts per biopsy were also determined for assessment of biopsy quality.
The biopsy sample length was similar in both groups (18.88±8.83 mm on PLB vs. 18.26±10.30 mm on TJLB). No differences were found in the number of portal tracts between the two groups (10.43±8.25 on TJLB vs. 12±10.09 on PLB). Fewer complications were observed in the TJLB group compared with the PLB group (P=0.002).Further, higher degree of pain was reported by patients who underwent PLB compared with patients who underwent TJLB (3.18±3.17 vs. 1.19±2.07); as such, there was a greater need for analgesics on PLB.
TJLB and PLB techniques provide similar quality of tissue samples; however, TJLB is less painful and therefore better tolerated by patients.
European journal of gastroenterology & hepatology 06/2012; 24(10):1209-13. · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Depletion of CD4+ T cells from the gut occurs rapidly during acute HIV-1 infection. This has been linked to systemic inflammation and disease progression as a result of translocation of microbial products from the gut lumen into the bloodstream. Combined antiretroviral therapy (cART) substantially restores CD4+ T cell numbers in peripheral blood, but the gut compartment remains largely depleted of such cells for poorly understood reasons. Here, we show that a lack of recruitment of CD4+ T cells to the gut could be involved in the incomplete mucosal immune reconstitution of cART-treated HIV-infected individuals. We investigated the trafficking of CD4+ T cells expressing the gut-homing receptors CCR9 and integrin α4β7 and found that many of these T cells remained in the circulation rather than repopulating the mucosa of the small intestine. This is likely because expression of the CCR9 ligand CCL25 was lower in the small intestine of HIV-infected individuals. The defective gut homing of CCR9+β7+ CD4+ T cells - a population that we found included most gut-homing Th17 cells, which have a critical role in mucosal immune defense - correlated with high plasma concentrations of markers of mucosal damage, microbial translocation, and systemic T cell activation. Our results thus describe alterations in CD4+ T cell homing to the gut that could prevent efficient mucosal immune reconstitution in HIV-infected individuals despite effective cART.
The Journal of clinical investigation 12/2011; 122(1):62-9. · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND & AIMS:: Colon tissues of patients with inflammatory bowel disease (IBD) have been reported to have increased proteolytic activity, but no studies have clearly addressed the protease to anti-protease balance in the pathogenesis of colitis. We investigated the role of Elafin, a serine protease inhibitor expressed by skin and mucosal surfaces in human inflammatory conditions, and the proteases neutrophil elastase (NE) and proteinase-3 (PR-3), in mice with colitis. METHODS:: We studied mice with heterozygous disruptions in NE and PR-3and 2 strains of mice that express transgenic human elafin (an inhibitor of NE and PR-3). Trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulphate (DSS) was used to induce colitis. Protease and cytokine levels were measured in colonic tissues collected from the mice. CaCO(2) and HT29 cells were studied in assays for cytokine expression and permeability. RESULTS:: Mice that expressed transgenic elafin developed less colitis and had reduced levels of proteases than wild-type mice following administration of TNBS or DSS. Expression of elafin did not modify activities of elastase or PR-3, but inhibited their increase upon the induction of colitis. Mice that expressed reduced levels of NE and PR-3 were protected against DSS-induced colitis. Elafin expression altered the patterns of inflammatory mediators and strengthened intestinal epithelial barrier functions in cells and colonic tissues from mice. CONCLUSIONS:: The protease inhibitor Elafin prevents intestinal inflammation in a mouse model of colitis and might be developed as a therapeutic agent for IBD.
[Show abstract][Hide abstract] ABSTRACT: Colonic tissues of patients with inflammatory bowel disease have been reported to have increased proteolytic activity, but no studies have clearly addressed the role of the balance between proteases and antiproteases in the pathogenesis of colitis. We investigated the role of Elafin, a serine protease inhibitor expressed by skin and mucosal surfaces in human inflammatory conditions, and the proteases neutrophil elastase (NE) and proteinase-3 (PR-3) in mice with colitis.
We studied mice with heterozygous disruptions in NE and PR-3, mice that express human elafin (an inhibitor of NE and PR-3), and naïve mice that received intracolonic adenoviral vectors that express elafin. Trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulphate (DSS) was used to induce colitis. Protease, cytokine levels, and NF-κB activity were measured in colons of mice. Caco-2 and HT29 cells were studied in assays for cytokine expression, permeability, and NF-κB activity.
Elafin expression or delivery re-equilibrated the proteolytic balance in inflamed colons of mice. In mice given TNBS or DSS, transgenic expression of elafin or disruption of NE and PR-3 protected against the development of colitis. Similarly, adenoviral delivery of Elafin significantly inhibited inflammatory parameters. Elafin modulated a variety of inflammatory mediators in vitro and in vivo and strengthened intestinal epithelial barrier functions.
The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease.
[Show abstract][Hide abstract] ABSTRACT: Interventional radiology techniques, namely embolization and shunting, were developed mainly to deal with the failures of
drug and/or endoscopic treatments. Among those techniques, the transjugular intrahepatic portosystemic shunt (TIPS) is the
only that aims to normalize portal pressure and is therefore able to treat both refractory bleeding and intractable ascites.
Embolization of esophago-gastric or ectopic varices, balloon occluded retrograde transvenous obliteration of varices, or partial
splenic embolization have been poorly evaluated. Severe complications may be observed and since portal hypertension is maintained
or even increased, these procedures have only a transient effect with a high rebleeding rate. Their role should be explored
in patients with uncontrolled variceal hemorrhage who have a contraindication for TIPS, such as pulmonary arterial hypertension,
congestive heart failure, liver failure, or severe or recurrent encephalopathy. Nowadays, TIPS should be performed using PTFE-covered
prostheses, which were shown to decrease the rate of shunt dysfunction and improve clinical outcomes. TIPS has been found
more effective than drug and/or endoscopic treatments in controlling active variceal bleeding as well as in preventing rebleeding,
though survival was not improved and encephalopathy was more frequent. It can also be used for gastric or ectopic varices.
In refractory ascites, TIPS was shown to be more effective than large volume paracenteses. It has also been successfully
used in hydrothorax.
KeywordsInterventional radiology-Embolization-TIPS-Variceal bleeding-Refractory ascites-Cirrhosis-Portal-hypertension
[Show abstract][Hide abstract] ABSTRACT: KLF6 protein is a transcription factor that plays important functions in hepatocellular carcinoma (HCC), which is one of the leading causes of death by cancer worldwide. Previous studies showed the existence of three splice variants of KLF6, termed SV1, SV2, and SV3. An increased SV1/KLF6 mRNA ratio in HCC was already described. In this study, we aimed to investigate the expression of the SV2 variant in HCC samples and its role in hepatic cells.
We measured the expression of the SV2 variant in HCC and adjacent tissue samples by q-RT-PCR. We established IHH and HepG2 stable cell lines over-expressing the SV2 variant and measured cell growth and apoptotic rate.
We observed a reduced expression of the SV2 variant in HCC samples versus surrounding tissues and normal liver. Interestingly, our findings demonstrate that the over-expression of the SV2 variant in IHH and HepG2 cells leads to a significant reduction of proliferation associated with cell death by apoptosis. We further demonstrate that the SV2 expression leads to an induction of the cell-cycle-controlling p21(CIP/WAF1) and the pro-apoptotic Bax genes, mediated by the p53 protein. We show further that the SV2 expression in IHH and HepG2 cells induces their sensitivity to the anti-cancer drug, gemcitabine.
We reveal a reduced expression of the SV2 variant of KLF6 in HCC samples and describe anti-proliferative and pro-apoptotic functions for this variant in hepatic cells.
Journal of Hepatology 11/2010; 53(5):880-8. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis E virus (HEV) is transmitted via the fecal-oral route and locally acquired sporadic hepatitis E can occur in Western countries. Chronic hepatitis E virus infections have been recently described in solid organ transplant recipients. There is little data on the evolution of hepatitis E in patients immunocompromised for other reasons.
The aim of this study was to evaluate the clinical course of hepatitis E in patients immunocompromised because of hematological malignancies.
Starting on November 2003, all patients in the Toulouse University Hospital Hematology Department with unexplained elevated transaminases were tested for hepatitis E using viral RNA detection in serum or stools and serology.
Acute hepatitis E was diagnosed in six middle-aged hematology patients. All cases were autochthonous. HEV strains were genotype 3. All patients had a significant increase of transaminases (6-95 upper limit normal) and only two had HEV IgG. Five patients were asymptomatic and one had jaundice. Transmission of HEV occurred between two patients who had overlapping stays in the hematology ward. All five evaluable patients ultimately cleared their HEV but viremia was prolonged over 6 months in three patients and specific treatment had to be postponed in two patients.
Screening for HEV should be carried out routinely in hematology patients with elevated transaminases, and patient-to-patient transmission is a concern. Further studies are required to determine whether management of malignancy, particularly stem-cell transplantation should be adapted to HEV status.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2010; 49(2):141-4. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ligand-gated calcium channels have been reported to be involved in the pathogenesis of inflammatory bowel disease. One family member, transient receptor potential vanilloid 4 (TRPV4), is activated by arachidonic acid derivatives that might be released on inflammation, yet its role in gastrointestinal inflammation has not been characterized. We investigated whether TRPV4 activation participates in intestinal inflammation and its expression and functions in the gastrointestinal tract.
TRPV4 expression was studied in human colon samples, human intestinal epithelial cell lines (Caco-2 and T84), and inflamed colons of mice. Calcium mobilization and cytokine release were analyzed in intestinal epithelial cells exposed to the selective TRPV4 agonist 4α-phorbol-12,13-didecanoate (4αPDD). Mice were killed 3, 6, or 24 hours after intracolonic administration of 4αPDD; inflammatory parameters were measured in their colon tissues, and paracellular colonic permeability was measured by the passage of (51)Cr-EDTA from the colon lumen to the blood.
High levels of TRPV4 were detected in Caco-2 cells and in epithelial cells of human colon tissue samples; its expression was up-regulated in colons from inflamed mice compared with noninflamed control mice. Administration of 4αPDD to Caco-2 and T84 cells caused a dose-dependent increase in intracellular calcium concentration and chemokine release. In mice, intracolonic administration of 4αPDD caused colitis to develop 3 to 6 hours later; inflammation resolved by 24 hours. Increased colonic permeability was observed in vivo 3 hours after intracolonic administration of 4αPDD.
TRPV4 is expressed and functional in intestinal epithelial cells; its activation in the gastrointestinal tract causes increases in intracellular calcium concentrations, chemokine release, and colitis.
[Show abstract][Hide abstract] ABSTRACT: Krüppel-like factor (KLF) family members share a three C2H2 zinc finger DNA binding domain, and are involved in cell proliferation and differentiation control in normal as in pathological situations. Studies over the past several years support a significant role for this family of transcription factors in carcinogenesis. KLFs can both activate and repress genes that participate in cell-cycle regulation. Among them, many up-regulated genes are inhibitors of proliferation, whereas genes that promote cell proliferation are repressed. However, several studies do present KLFs as positive regulator of cell proliferation. KLFs can be deregulated in multiple cancers either by loss of heterozygosity (LOH), somatic mutation or transcriptional silencing by promoter hypermethylation. Accordingly, KLF expression was shown to mediate growth inhibition when ectopically expressed in multiple cancer-derived cell lines through the inhibition of a number of key oncogenic signaling pathways, and to revert the tumorogenic phenotype in vivo. Taken together, these observations suggest that KLFs act as tumor suppressor. However, in some occasion, KLFs could act as tumor promoters, depending on "cellular context". Thus, this review will discuss the roles and the functions of KLF family members in carcinogenesis, with a special focus on cancers from epithelial origin.
Current Genomics 08/2009; 10(5):353-60. · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
New England Journal of Medicine 03/2008; 358(8):811-7. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatitis E virus is a ribonucleic acid (RNA) enterically transmitted virus that causes both epidemics and sporadic cases of acute hepatitis E in many countries of Asia and Africa. Domestically acquired (non-travel-associated) hepatitis E has been reported recently in many industrialized countries including the USA, Europe, and Japan. There is little information available on liver histology in these patients. We report a series of 11 patients with sporadic acute hepatitis E and needle liver histology in South-West France. Hepatitis E was diagnosed based on elevated transaminases (>10 upper limit normal) and the presence of specific serum antibodies (immunoglobulin-G class, present in all 11 patients) and/or viral RNA detection in serum and/or stools. Acute hepatitis lesions were observed in all cases with marked necro-inflammatory activity in nine patients. Confluent necrosis was present in five cases. Anisocaryosis and Kupffer's cell aggregates with siderosis were observed in most of the 11 patients. Cholangitis was frequent (9/11 cases). Cholestasis was observed in eight cases. Pseudo-glandular pattern was present in only one case but without zonal repartition. Characteristic pathological signs of acute hepatitis E were severe intralobular necrosis, polymorph inflammation, and acute cholangitis with numerous neutrophils.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2007; 450(4):405-10. · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Codification of variant forms between Primary Biliary Cirrhosis (PBC) and Autoimmune Hepatitis (AIH) has not been definitively standardized. The aim of this study was to compare among 102 consecutive patients, 2 subsets of overlap syndrome (OS, N=21) with and without antimitochondrial antibody (AMA) to two groups of patients with typical PBC (N=43) or AIH (N=38).
OS was defined by the presence in the same patient of at least 2 of 3 accepted criteria of PBC and AIH. Twelve patients with OS were AMA negative and 9 were AMA positive.
A lower level of alanine transaminase (139+/-48 vs 269+/-154 IU/L, P<0.05) and a trend towards a higher level of alkaline phosphatase or gamma-glutamyl transpeptidase was observed in OS without AMA than in OS with AMA (693+/-200 vs 544+/-124 IU/L; 370+/-66 vs 241+/-77 IU/L, respectively). All AMA-negative patients with OS had antinuclear and/or anti-smooth muscle antibodies. OS without AMA differed from those with AMA in that they had more severe bile duct damage including destructive cholangitis (P<0.05), ductopenia (P<0.05), ductular hyperplasia (P<0.05) and a higher METAVIR fibrosis score (2.5+/-0.3 vs 1.3+/-0.3, P<0.05). The response to therapy was not different between PBC, AIH and OS.
According to the presence of AMA, 2 homogeneous subgroups of patients with overlap syndrome between PBC and AIH may be identified. AMA status affects clinical presentation and liver disease severity of OS.
Gastroentérologie Clinique et Biologique 01/2007; 31(1):11-6. · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of pegylated interferons (PEG-IFN) has significantly improved the eradication rates in patients with chronic hepatitis C. Two forms of PEG-IFN have been developed, based on two pegylation chemistries: the 12-kDa linear PEG-IFN-alpha2b and the 40-kDa branched PEG-IFN-alpha2a. We compared the in vitro antiviral activity of linear and branched PEG-IFN using the vesicular stomatitis virus (VSV) cytopathic effect (CPE) reduction assay. The specific antiviral activity of branched PEG-IFN was 7% of that of linear PEG-IFN. A given quantity of linear and of branched PEG-IFN does not represent the same biologic activity. A bioassay could give new insights to compare the pharmacokinetic profile of linear PEG-IFN and of branched PEG-IFN.
Journal of Interferon & Cytokine Research 01/2007; 26(12):849-53. · 3.90 Impact Factor