Biomedical subjects

Jean-Paul Galmiche

Publications and source records attributed to Jean-Paul Galmiche.

At least 19 recordsLinked to original sources

PubMed2007

Value of wireless capsule endoscopy in patients with indeterminate colitis (inflammatory bowel disease type unclassified).

BACKGROUND: Wireless capsule endoscopy (WCE) can identify small bowel mucosal lesions not seen with other imaging modalities. This technique can therefore play an important diagnostic role in the evaluation of patients with inflammatory bowel disease type unclassified (IBDU). We report on a multicentric study whose objective was to evaluate the value of WCE to increase diagnostic accuracy in categorizing IBDU. METHODS: Thirty patients with IBDU and negative serology were included. WCE was performed with a standard Pillcam capsule. Outcome measures were classified as suggestive of Crohn's disease (CD) when -3 ulcerations were present. RESULTS: WCE displayed endoscopic features suggestive for CD in 5 patients. In 6 other patients, WCE was negative, but repeated ileocolonoscopy with biopsies performed during follow-up evaluation revealed CD in 5 and ulcerative colitis (UC) in 1 patient. UC was found in a seventh case at colectomy performed just after WCE. Eighteen patients remained with a diagnosis of IBDU 16 months on average after WCE. CONCLUSIONS: WCE is a potentially clinically useful technique for categorizing a subgroup of patients with IBDU, although negative WCE does not exclude further diagnosis of CD. Patients with negative WCE who remain IBDU at follow-up evaluation may belong to an original subgroup of IBD.

Adolescent↗

PubMed2006

Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy.

INTRODUCTION: Combined esophageal pH-impedance monitoring allows detection of nearly all gastroesophageal reflux episodes, acid as well as nonacid. However, the role of nonacid reflux in the pathogenesis of symptoms is poorly known. The aim of this study was to evaluate the diagnostic yield of this technique in patients with suspected reflux symptoms while on or off PPI therapy. PATIENTS AND METHODS: The recordings of 150 patients recruited at seven academic centers with symptoms possibly related to gastroesophageal reflux were analyzed. Reflux events were detected visually using impedance (Sandhill, CO) and then characterized by pHmetry as acid or nonacid reflux. The temporal relationship between symptoms and reflux episodes was analyzed: a symptom association probability (SAP) > or =95% was considered indicative of a positive association. RESULTS: One hundred fifty patients were included, 102 women (mean age 52 +/- 14 yr, range 16-84). Among the 79 patients off PPI, five did not report any symptom during the recording period. A positive SAP was found in 41 of the 74 symptomatic patients (55.4%), including acid reflux in 23 (31.1%), nonacid reflux in three (4.1%), and acid and nonacid in 15 (20.3%). In the group of patients on PPI (N = 71, 46 women, mean age 51 +/- 15 yr), 11 were asymptomatic during the study, SAP was positive in 22 of the 60 symptomatic patients (36.7%), including acid reflux in three (5.0%), nonacid reflux in 10 (16.7%), and acid and nonacid in nine (15.0%). The symptoms most frequently associated with nonacid reflux were regurgitation and cough. CONCLUSION: Adding impedance to pH monitoring improves the diagnostic yield and allows better symptom analysis than pHmetry alone, mainly in patients on PPI therapy. The impact of this improved diagnostic value on gastroesophageal reflux disease management remains to be investigated by outcome studies.

Adolescent↗

PubMed2006

Acidity induces c-Fos expression in a subpopulation of human colonic submucosal neurons.

Enteric neurons responding to chemical challenge of the mucosa have been characterized in animal models mainly in the myenteric plexus. However, in humans, the existence of enteric neurons responding to chemical stimulation of the mucosa remains currently unknown. Therefore, the aim of our study was to identify and characterize human submucosal neurons activated by mucosal challenge with butyrate or hydrochloric acid. Segments of human colon were placed in a modified Ussing chamber and incubated on the mucosal side with butyric acid (20 mM, pH 6.5), sodium butyrate (20 mM, pH 7.5), hydrochloric acid (10 mM, pH 6.5) or culture medium (pH 7.5). After 90 min of culture, tissues were fixed and microdissected to obtain whole mount preparation of submucosa containing the Meissner's plexus. Neuron specific enolase (NSE), c-Fos, vasoactive intestinal peptide (VIP) and substance P (SP) were detected using immunohistochemical methods. Tetrodotoxin (TTX, 1 microM) was used to inhibit neuronal activity. After 90 min of culture, butyric acid induced a significant 5.6-fold increase in the proportion of c-Fos-immunoreactive neurons compared to control (19 +/- 4% versus 4 +/- 1%, respectively, p < 0.001). 41 +/- 5% of c-Fos-immunoreactive neurons were VIP-immunoreactive and 3 +/- 2% were SP-immunoreactive. Butyric acid did not modify the proportion of VIP-immunoreactive neurons. The increase in c-Fos-immunoreactive neurons induced by butyric acid was reproduced with hydrochloric acid at the same pH but not with sodium butyrate. Finally, preincubation of the tissue with TTX prevented the effect of butyric acid. In conclusion, our results demonstrate that acidic mucosal challenge induced the activation of a population of human submucosal neurons with a specific neurochemical coding.

Butyrates↗

PubMed2006

Intestinal neuro-epithelial interactions modulate neuronal chemokines production.

Human enteric neurons have recently been shown to produce chemokines during intestinal inflammation. However, whether (1) neuro-epithelial interactions modulate neuronal chemokines production and (2) neurons can induce the chemotaxis of immune cells remain unknown. Neuro-epithelial interactions were studied using a coculture model composed of human neurons (NT2-N) and intestinal epithelial cells (Caco-2). IL-8 or MIP-1beta expression was analyzed by quantitative-PCR, ELISA or immunohistochemistry. Neuronally induced chemotaxis was studied using a coculture model composed of NT2-N and human peripheral blood mononuclear cells (PBMC). Following Caco-2 inflammation with IFNgamma/TNFalpha, neuronal IL-8 and MIP-1beta mRNA expression was significantly increased compared to control. This increase was significantly reduced by IL-1 receptor antagonist. IL-1beta-pretreated NT2-N induced the chemotaxis of PBMC, which was significantly reduced by anti-IL-8, but not by anti-MIP-1beta neutralizing antibody. Our results demonstrate that, under inflammatory conditions, neuro-epithelial interactions can modulate neuronal chemokines production through IL-1beta-dependent pathways. Furthermore, neuronal IL-1beta-induced chemotactic properties could favor the development of immune cells infiltrates within the enteric nervous system, as is observed during intestinal inflammation.

Cell Communication↗

PubMed2006

High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study.

BACKGROUND & AIMS: High-resolution colonoscopy with chromoscopy (HRC) is a technique designed to improve the detection of colonic neoplasias. We prospectively compared standard colonoscopy (SC) and HRC in a randomized multicenter trial. METHODS: Patients (n = 203; age, 58 +/- 10 years; sex ratio, 1) were recruited according to the following criteria: (1) a history of either familial or personal colonic neoplasia or (2) alarm symptoms after the age of 60 years. After randomization, an SC was performed in 100 patients (resolution, < or = 410,000 pixels) and a HRC in 103 patients (Fujinon EC485ZW, 850,000 pixels). In the HRC group, each colonic segment was examined before and after spraying with indigo carmine 0.4%. RESULTS: Two hundred seventy-six polyps were detected in 198 patients. One hundred sixty of them were hyperplastic polyps, 116 were adenomas, and 2 were carcinomas. The numbers of hyperplastic polyps and purely flat adenomas were significantly higher in the HRC group than in the SC group (1.1 +/- 1.6 vs 0.5 +/- 1.4 and 0.22 +/- 0.68 vs 0.07 +/- 0.29, respectively; P = .01 and P = .04), but there was no significant difference in the total number of adenomas per patient (primary end point) detected between the HRC and the SC groups (0.6 +/- 1.0 vs 0.5 +/- 0.9, respectively). CONCLUSIONS: Although HRC improves detection of purely flat adenomas and hyperplastic polyps, the overall detection of colonic adenomas in a population at increased risk of neoplasia is not significantly improved. These findings do not support the routine use of HRC in clinical practice.

Adenoma↗

PubMed2006

Altered lipid, apolipoprotein, and lipoprotein profiles in inflammatory bowel disease: consequences on the cholesterol efflux capacity of serum using Fu5AH cell system.

Epidemiological data suggest a link between chronic inflammation condition and atherosclerosis. Infection and inflammation can also impair lipoprotein metabolism and produce a wide variety of changes in plasma concentrations of lipids and lipoproteins. Twenty-one patients with inflammatory bowel diseases (IBDs) and 28 healthy subjects were recruited. Serum concentrations of lipids, lipoproteins, apolipoproteins, leptin, ghrelin, and inflammation markers (C-reactive protein and serum amyloid A) were measured, and subjects' lipoproteins were characterized. The ability of patients with serum IBD to efflux free cell cholesterol was measured. Serum cholesterol, high-density lipoprotein cholesterol, apolipoprotein (apo) A-I, apoC-II, apoC-III bound to apoB, phospholipid, and phospholipids not bound to apoB levels were significantly lower, whereas serum triglyceride, serum amyloid A, and C-reactive protein levels were significantly higher in patients with active IBD. Apolipoprotein A-I immunoreactivity (pre-beta small particles and small alpha-high-density lipoprotein particles) is decreased in patients with IBD. In contrast, apoE immunoreactivity (slow/small apoE containing lipoprotein particles [LpE particle]) increased in these patients. The efflux capacity of serum from patients with IBD using [(3)H]-cholesterol-labeled Fu5AH cells was reduced (P < .005). Our results demonstrate that, in subjects with active IBD, inflammation leads to alterations in lipid, apolipoprotein, and lipoprotein profiles and reduced cholesterol efflux. These changes are similar to those proposed to promote atherogenesis and may contribute to the development of cardiovascular events.

Adult↗

PubMed2006

Novel developments in non-erosive and erosive gastroesophageal reflux disease.

PURPOSE OF REVIEW: Despite being clinically important and highly prevalent, several aspects of gastroesophageal reflux disease are incompletely understood. Research activity remains high, however, and we shall review some highlights from last year's publications. RECENT FINDINGS: Community based epidemiological studies have elucidated the risk factors for gastroesophageal reflux disease and demonstrated a significant risk for developing complications over time. New histological parameters such as distended intercellular spaces in the epithelium will detect minor signs of reflux damage. The esophageal endoscopic capsule has been studied as a way of screening for esophageal disease. Wireless pH-metry and impedance-pH-metry have increased our insight into the pathophysiology and improved the diagnostic work-up in atypical and therapy resistant cases. At the molecular level, the role of cytokines has been elucidated and there is increased support for the nitrosative stress theory for epithelial damage at the cardia. Endoscopic therapies have shown disappointing long-term results or safety concerns, leading to withdrawal of several methods. SUMMARY: The last year has brought significant development in diagnostic modalities, and increased our insight in the molecular events involved in the pathogenesis of gastroesophageal reflux disease. Ultimately, this may and must lead to new therapeutic modalities which will supplement proton pump inhibitors in medical therapy for gastroesophageal reflux disease.

Endoscopy, Gastrointestinal↗

PubMed2005

Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids.

OBJECTIVE: The efficacy of intravenous cyclosporin (CSA) in acute severe ulcerative colitis (UC) is well established. The aim of this study was to evaluate its efficacy in moderately severe colitis refractory to steroids. METHODS: Twenty-six patients (17 men, mean age 41 +/- 14 yr) with UC refractory to steroids treated with CSA were included in this study. Severity was defined according to Truelove criteria. A clinical activity score below 10 during 2 consecutive days defined clinical response. RESULTS: According to Truelove criteria, all patients had moderate UC. CSA was administered IV at a mean daily dose of 3.7 +/- 0,5 mg/kg until response and then orally for 3.5 +/- 2.6 months. A clinical response was achieved in 20/26 patients (76,9%) within 5.7 +/- 2.8 days (5/6 failures were treated by proctocolectomy). During a follow-up of 27.8 +/- 20.8 months, relapse rate was 60% (12/20): 7 patients underwent proctocolectomy and 5 had clinical remission with CSA retreatment (N=4) and steroids (N=1). At the end of follow-up, 12 patients (46%) were in clinical remission, 12 (46%) required colectomy, 1 had chronic active UC and 1 was lost of follow-up. The probability to avoid surgery was 52% at 78 months. The only factor associated with avoidance of surgery was concomitant treatment with azathioprine (P=0.007). Ten reversible adverse events occurred in 9 patients. CONCLUSION: This study shows that CSA is safe and effective in moderately severe steroid resistant UC. Concomitant treatment with azathioprine significantly decreases the rate of subsequent surgery. CSA may act as a "bridge" until the therapeutic action of azathioprine is achieved for maintenance treatment. These results should be further confirmed by a prospective controlled study.

Administration, Oral↗

PubMed2005

Human mucosa/submucosa interactions during intestinal inflammation: involvement of the enteric nervous system in interleukin-8 secretion.

Interleukin-8 (IL-8) is a key chemokine upregulated in various forms of intestinal inflammation, especially those induced by bacteria such as Clostridium difficile (C. difficile). Although interactions between different mucosal and submucosal cellular components have been reported, whether such interactions are involved in the regulation of IL-8 secretion during C. difficile infection is unknown. Moreover, whether the enteric nervous system, a major component of the submucosa, is involved in IL-8 secretion during an inflammatory challenge remains to be determined. In order to investigate mucosa/submucosa interactions that regulate IL-8 secretion, we co-cultured human intestinal mucosa and submucosa. In control condition, IL-8 secretion in co-culture was lower than the sum of the IL-8 secretion of both tissue layers cultured alone. Contrastingly, IL-8 secretion increased in co-culture after mucosal challenge with toxin B of C. difficile through an IL-1 beta-dependent pathway. Moreover, we observed that toxin B of C. difficile increased IL-8 immunoreactivity in submucosal enteric neurones in co-culture and in intact preparations of mucosa/submucosa, through an IL-1 beta-dependent pathway. IL-1 beta also increased IL-8 secretion and IL-8 mRNA expression in human neuronal cell lines (NT2-N and SH-SY5Y), through p38 and ERK1/2 MAP kinase-dependent pathways. Our results demonstrate that mucosa/submucosa interactions regulate IL-8 secretion during inflammatory processes in human through IL-1 beta-dependent pathways. Finally we observed that human submucosal neurones synthesize IL-8, whose production in neurones is induced by IL-1 beta via MAPK-dependent pathways.

Aged↗

PubMed2005

Search for localized dysbiosis in Crohn's disease ulcerations by temporal temperature gradient gel electrophoresis of 16S rRNA.

The mucosa-associated microbiota lining the gut epithelium might play a central role in the activation and/or perpetuation of mucosal inflammation in Crohn's disease (CD). We sought for localized dysbiosis by comparing the biodiversity and composition of the microbiotas in ulcerated and nonulcerated mucosal samples from patients with CD. Biopsy samples (n = 75) of ulcerated and adjacent nonulcerated mucosa were collected during colonoscopy from 15 patients, from the ileum, right colon, left colon, and rectum. Temporal temperature gradient gel electrophoresis (TTGE) of bacterial 16S rRNAs was used to evaluate the dominant bacterial species. TTGE profiles were compared using software that calculates similarity percentages. For a given patient, average similarity indexes between ulcerated and nonulcerated mucosal TTGE profiles ranged from 95.2% +/- 4.2% to 97.9% +/- 1.7% (means +/- standard deviations) for the different segments. The mean values did not differ significantly. Average interindividual similarity indexes for a given segment among the different patients ranged from 33.6% +/- 15.5% to 42.0% +/- 25.6%. In CD, the dominant microbiotas do not differ qualitatively between ulcerated and nonulcerated mucosae. Biodiversity remains high in ulcerated mucosa. This argues against a pathogenic role of localized qualitative dysbiosis in CD-associated ulceration.

Colon↗

PubMed2004

Early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of Clostridium.

Necrotizing enterocolitis (NEC) is among the most severe conditions that can affect preterm infants. Although the etiology of NEC remains unknown, initial bacterial colonization could play a pivotal role in the development of NEC. To further explore the putative relationship between pathogen microorganisms and NEC, we conducted a prospective case-control study in 12 preterm infants with a new approach based on molecular techniques. Over an inclusion period of 24 mo, 12 neonates of <34 wk gestational age admitted to the neonatal unit were enrolled. The group included three cases of NEC, and nine control infants without evidence of NEC who were matched for gestational age and birth weight. Stool samples were collected at weekly intervals from all infants. PCR and temporal temperature gradient gel electrophoresis of 16S ribosomal DNA were used to detect the establishment of bacterial communities in the digestive tract. A salient feature of the bacteriological pattern was observed only in the three infants who later developed NEC: A band corresponding to the Clostridium perfringens subgroup could be detected in early samples, before diagnosis. There was no evidence for this specific band in any of the nine controls. To our knowledge, the current report is the first to demonstrate that the use of molecular techniques based on the study of bacterial 16S rRNA genes allowed the recognition of C. perfringens species in the first 2 wk of life of three infants who later displayed symptoms of NEC. A significant temporal relationship was thus established between early colonization by Clostridium and the later development of NEC. Compared with conventional bacteriological culturing methods, the use of this new molecular approach to analyze the gastrointestinal ecosystem should therefore allow a more complete and rapid assessment of intestinal flora. Although the current data do not constitute definitive proof that the identified bacterial species was a causative agent in the development of NEC, they outline the promise of this new technique based on molecular biology, and suggest that large-scale studies on a much wider population at high risk for NEC may be warranted.

Birth Weight↗

PubMed2004

Vasoactive intestinal peptide induces IL-8 production in human colonic epithelial cells via MAP kinase-dependent and PKA-independent pathways.

Vasoactive intestinal peptide (VIP) has been shown to be a key regulator of intestinal epithelial functions such as mucus and chloride secretion, paracellular permeability, and cell proliferation. However, its regulatory role in intestinal epithelial chemokine production remains unknown. The aim of this study was (1) to determine whether VIP can modulate intestinal epithelial interleukin-8 (IL-8) production and (2) to identify intracellular mediators responsible for this effect. In the human colonic epithelial cell line HT29-Cl.16E, VIP stimulates IL-8 secretion dose-dependently and IL-8 mRNA level at 10(-9) M. The protein kinase A (PKA) inhibitor PKI did not abolish the effect of VIP. However, inhibition of the ERK1/2 and p38 MAPK pathways reduced the VIP-stimulated IL-8 secretion and mRNA level. Together, our results showed that VIP stimulates IL-8 production in intestinal epithelial cells via PKA-independent and MAPK-dependent pathways. These data suggest that VIPergic pathways can play an immunomodulatory role in intestinal epithelial cells, by regulating epithelial IL-8 secretion.

Cell Polarity↗

PubMed2004

Glutamine metabolism in Crohn's disease: a stable isotope study.

AIMS: To determine whether chronic intestinal inflammation alters glutamine utilization, six 31 +/- 6 yr-old patients with Crohn's disease and an age-matched group of 6 healthy subjects received 7-h intravenous infusions of L-[5,5,5-2H3]leucine, along with an infusion of L-[1-13C]glutamine delivered intravenously for the first 3.5 h, and via a nasogastric tube for the subsequent 3.5 hrs. None of the patients was receiving any nutritional supplement or antiinflammatory drug. All were in remission (Crohn's disease activity index < 150) and in a near-normal nutritional status. METHODS: We used plasma 2H3-alpha-ketoisocaproate to determine leucine appearance rate (Ra), and plasma 13C-glutamine and breath 13CO2 to determine glutamine Ra and oxidation, respectively. The fraction of enteral glutamine undergoing uptake in the splanchnic bed was determined from the difference in plasma 13C-glutamine enrichments between the intravenous and nasogastric 13C-glutamine infusion periods. RESULTS: Neither leucine Ra, nor plasma glutamine concentration (526 +/- 40 vs. 530 +/- 50 micromol/l), glutamine Ra (364 +/- 19 vs. 355 +/- 24 micromol kg(-1) h(-1)), or splanchnic glutamine uptake (61 +/- 5 vs. 65 +/- 2%) differed between groups. In both groups, glutamine oxidation rose when the glutamine tracer was supplied enterally, compared with the intravenous route (70 +/- 6 vs. 39 +/- 2% in patients; 69 +/- 2 vs. 38 +/- 1% in controls), but did not differ between groups. CONCLUSION: When in remission, patients with Crohn's disease have normal rates of proteolysis, and glutamine production, utilization, oxidation, and splanchnic uptake. The data suggest there is no obvious requirement for glutamine in patients with quiescent Crohn's disease.

Adult↗

PubMed2004

Push enteroscopy for gastrointestinal bleeding: diagnostic yield and long-term follow-up.

AIM: Little is known about the long-term course of patients explored by push enteroscopy for gastrointestinal bleeding of obscure origin. This study aimed to determine the diagnostic yield and the therapeutic impact of enteroscopy, the rate of rebleeding and predictive factors of rebleeding in these patients. PATIENTS AND METHODS: One hundred nineteen patients underwent push enteroscopy for overt bleeding (N=66) or anemia (N=53). RESULTS: Enteroscopy was positive in 42% of patients (colon 17%, stomach 13%, small bowel 12%) and diagnosed arteriovenous malformations in two-thirds of patients. Twenty-five additional diagnoses were established during the 2-month follow-up. Treatment was definitive in 13% of patients, without recurrent bleeding. Rebleeding occurred in 45% of patients, and was more frequent when a lesion was visualized (73% vs 28% after 5 years, P=0.02). In multivariate analysis, a lesion visualized by enteroscopy was the only independent predictive factor. CONCLUSION: Enteroscopy is not a high-performance diagnostic tool for obscure gastrointestinal bleeding and enables definitive treatment in less than 15% of patients.

Adolescent↗

PubMed2003

Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways.

Although the enteric nervous system (ENS) has been shown to regulate various mucosal functions, its role in the physiological control of the human intestinal epithelial barrier is unknown. The aim of this study was to investigate whether the ENS is able to modulate epithelial barrier permeability and a key tight junction-associated protein, zonula occludens-1 (ZO-1). Therefore, we developed a co-culture model, consisting of human submucosa containing the submucosal neuronal network and human polarized colonic epithelial monolayers (HT29-Cl.16E or Caco-2). Submucosal neurons were activated by electrical field stimulation (EFS). Permeability was assessed by measuring the flux of paracellular permeability markers (FITC-dextran or FITC-inulin) across epithelial monolayers. Expression of ZO-1 was determined by immunofluorescence, quantitative immunoblot analysis, and real time RT-PCR. Using the coculture model, we showed that EFS of submucosal neurons resulted in a reduction in FITC-dextran or FITC-inulin fluxes, which was blocked by TTX. In HT29-Cl.16E, the effect of submucosal neuron activation was blocked by a VIP receptor antagonist (VIPra) and reproduced by VIP. Furthermore, ZO-1 expression (mRNA, protein) assessed in HT29-Cl.16E, was significantly increased after submucosal neuron activation by EFS. These effects on ZO-1 expression were blocked by TTX and VIPra and reproduced by VIP. In conclusion, our results strongly suggest a modulatory role of VIPergic submucosal neuronal pathways on intestinal epithelial barrier permeability and ZO-1 expression.

Adult↗

PubMed2003

Adaptation to low-protein diet increases inhibition of gastric emptying by CCK.

Chronic nutritional disorders such as protein malnutrition are associated with delayed gastric emptying and increased postprandial cholecystokinin (CCK) levels. This study investigated the mechanisms involved in gastric emptying adaptation to low-protein diet. Two groups of 12 rats were adapted to a low-protein (LPD) or standard diet (SD) for 3 weeks. As compared to rats fed a SD, in rats adapted to a LPD gastric emptying was delayed, whereas postprandial CCK levels were increased. LPD enhanced antral muscle contractile response to CCK and cerulein without altering response to acetylcholine. This increased contractility was associated with up-regulation of CCK-A receptor mRNA levels in antral muscle. Our data suggest that modulation of gastric emptying after adaptation to a low-protein diet involves up-regulation of both CCK-A receptors and CCK-induced contraction of antral smooth muscle.

Adaptation, Physiological↗

PubMed2003

Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis.

BACKGROUND & AIMS: Rho proteins are involved in the regulation of several cellular functions. Data from in vitro studies suggest that RhoA could be involved in the inflammatory response. We investigated the role of RhoA and its downstream effector Rho kinase in intestinal inflammation. METHODS: Activation of RhoA was assessed by pull-down assays. A specific inhibitor of Rho kinase, Y-27632, was used to examine the role of Rho kinase in inflammatory response in vivo and in vitro by molecular biology and by immunological and biochemical approaches. RESULTS: Increased activation of RhoA was found in inflamed intestinal mucosa of patients with Crohn's disease and of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Oral administration of Y-27632 in rats significantly reduced the colonic inflammation. In vitro, activation of RhoA alone was sufficient to induce tumor necrosis factor production. Y-27632 inhibited production of tumor necrosis factor-alpha and interleukin-1 beta by lamina propria and peripheral blood mononuclear cells. Rho kinase inhibition prevented nuclear factor kappa B activation and I-kappa B phosphorylation and degradation. We showed that Rho kinase associates with and activates I-kappa B kinase alpha and that Y-27632 prevents I-kappa B kinase activation. CONCLUSIONS: Our study provides the first evidence that Rho kinase activates I-kappa B kinase and, thus, nuclear factor kappa B, suggesting a key role of Rho kinase in inflammatory responses and intestinal inflammation. Specific inhibition of Rho kinase may be a promising approach for the treatment of patients with Crohn's disease.

Adolescent↗

PubMed2003

Molecular analysis of the effect of short-chain fatty acids on intestinal cell proliferation.

Short-chain fatty acids (SCFA), particularly butyrate, were shown to regulate cell proliferation in vitro and in vivo. Indeed, butyrate is the major fuel for colonic epithelial cells, and it can influence cell proliferation through the release of growth factors or gastrointestinal peptides such as gastrin, or through modulation of mucosal blood flow. Lastly, SCFA can act directly on genes regulating cell proliferation, and butyrate is the main SCFA to display such an effect. Butyrate inhibits histone deacetylase, which will allow histone hyperacetylation. Such hyperacetylation leads to transcription of several genes, including p21/Cip1. Moreover, it will allow cyclin D3 hyper-expression by inhibiting its degradation. The induction of the cyclin-dependent kinase inhibitory protein p21/Cip1 accounts for cell arrest in the G1 phase of the cell cycle. However, in the absence of p21 other mechanisms are initiated, leading to inhibition of cell proliferation.

Acetylation↗