Melatonin-Activated Receptor Signaling Pathways Mediate Protective Effects on Surfactant-Induced Increase in Jejunal Mucosal Permeability in Rats.

A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of 51Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated.

Probiotics for Preventing and Treating Small Intestinal Bacterial Overgrowth: A Meta-Analysis and Systematic Review of Current Evidence.

The present study conducted a meta-analysis and systematic review of current evidence to assess the efficacy of probiotics in preventing or treating small intestinal bacterial overgrowth (SIBO). Relevant studies from PubMed, Embase, and the Cochrane Central Register of Controlled Trials, until May 2016, were assimilated. The prevention efficacy was assessed by the incidence of SIBO in the probiotic group, and the treatment efficacy by the SIBO decontamination rate, reduction in H2 concentration, and symptom improvement. The relative risk (RR) and weighted mean difference (WMD) were used as effect measures and the random-effects model used for meta-analysis. A total of 14 full-text articles and 8 abstracts were included for the systematic review, and 18 studies were eligible for data synthesis. Patients on probiotic usage showed an insignificant trend toward low SIBO incidence [RR=0.54; 95% confidence intervals (CI), 0.19-1.52; P=0.24]. The pooled SIBO decontamination rate was 62.8% (51.5% to 72.8%). The probiotics group showed a significantly higher SIBO decontamination rate than the nonprobiotic group (RR=1.61; 95% CI, 1.19-2.17; P<0.05). Also, the H2 concentration was significantly reduced among probiotic users (WMD=-36.35 ppm; 95% CI, -44.23 to -28.47 ppm; P<0.05). Although probiotics produced a marked decrease in the abdominal pain scores (WMD=-1.17; 95% CI, -2.30 to -0.04; P<0.05), it did not significantly reduce the daily stool frequency (WMD=-0.09; 95% CI, -0.47 to 0.29). Therefore, the present findings indicated that probiotics supplementation could effectively decontaminate SIBO, decrease H2 concentration, and relieve abdominal pain, but were ineffective in preventing SIBO.

Protective Effects of Vitamin E on Methotrexate-Induced Jejunal Mucosal Damage in Rats.

OBJECTIVE: To investigate the possible protective effects of Vitamin E (Vit E) on oxidative stress and jejunal damage in the rat intestinal mucosa after methotrexate (MTX)-induced enterotoxicity. STUDY DESIGN: Rats were divided into 3 groups: control, MTX, and MTX+ Vit E; each group contained 8 animals. The control group was given physiological serum in addition to sunflower oil for 3 days. The second group was given sunflower oil with intragastric tube daily, followed by MTX injection (20 mg/kg intraperitoneally). To the third group, starting 3 days before injection, Vit E was given dissolved in sunflower oil (600 mg/kg orally) in addition to MTX injection. Four days after MTX injection the anesthetized rats were sacrificed, and the tissue samples obtained from their jejunums were investigated for histological and biochemical analysis. RESULTS: Vit E treatment significantly decreased the elevated tissue malondialdehyde levels and increased the reduced glutathione peroxidase and superoxide dismutase activities in comparison to the MTX-treated group. MTX treatment caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Vit E treatment significantly attenuated the severity of intestinal injury caused by MTX via inhibiting induced nitric oxide synthase levels and NF-κB p65 activation. CONCLUSION: Because of its reconstructing and antioxidant effects, Vit E pretreatment may have protective effects in the intestinal tissue of MTX-treated rats.

Protective effects of ß-casofensin, a bioactive peptide from bovine ß-casein, against indomethacin-induced intestinal lesions in rats.

SCOPE: ß-casofensin, also known as peptide ß-CN(94-123), is a milk bioactive peptide that modulates the intestinal barrier through its action on goblet cells. Here, we evaluated whether oral administration of ß-casofensin can prevent indomethacin-induced injury of the jejunum in rats. METHODS AND RESULTS: Rats received ß-casofensin (0.01-100 µM) or tap water by daily gavage (4 µL/g) for eight days, then two subcutaneous injections of indomethacin (10 mg/kg, days 9 and 10) and were euthanized on day 12. In vitro, we investigated the effects of ß-casofensin on the restitution of a wounded monolayer. Preventive administration of ß-casofensin (100 µM) reduced intestinal macroscopic and microscopic damage induced by indomethacin. ß-casofensin also prevented the depletion of goblet cells and increased myeloperoxidase activity, as well as tumor necrosis factor-ɑ (TNF-ɑ) expression and immunostaining of active caspase-3 in the jejunum of rats treated with indomethacin. In wound healing experiments, ß-casofensin promoted epithelial restitution with no effect on cell proliferation. This effect was inhibited by pre-incubation with an anti-CC chemokine receptor 6 (CCR6) neutralizing antibody. CONCLUSIONS: ß-casofensin exerts protective effects in indomethacin-induced enteritis through preservation of goblet cells and improvement in wound healing. ß-casofensin could therefore become vital in nutritional programs for the prevention of intestinal diseases.

Serum-derived bovine immunoglobulin/protein isolate in the alleviation of chemotherapy-induced mucositis.

BACKGROUND: Gastrointestinal (GI) mucositis caused by chemotherapy is associated with diarrhoea and intestinal barrier disruption caused by apoptosis, immune dysfunction and microbiome alterations. Serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown to manage HIV-associated enteropathy and irritable bowel syndrome with diarrhoea (IBS-D). We investigated in a rat model whether SBI was effective in alleviating symptoms of irinotecan-induced GI mucositis. METHODS: Animals were gavaged with 250 or 500 mg/kg of SBI twice daily for 4 days, before intraperitoneal administration of 200 mg/kg irinotecan. Twice daily gavaging of SBI continued for 6 days post-irinotecan. Animals were monitored for bodyweight changes and incidence of diarrhoea and clinical symptoms of stress. Tissues and blood samples were collected at necropsy 6 h, and 2, 4 and 6 days post-irinotecan. H&E-stained colon and jejunum were analysed for histological damage. RESULTS: The overall incidence, severity and duration of diarrhoea, and clinical symptoms of mucositis were decreased in irinotecan-treated animals that had received SBI. Animals receiving 500 mg/kg SBI also tended to lose less bodyweight than animals treated only with irinotecan (P > 0.10). SBI-gavaged animals had less pronounced irinotecan-induced changes in neutrophil (P = 0.04959) and lymphocyte (P = 0.0035) levels, and lower tissue damage scores than those receiving irinotecan alone (P < 0.0001). CONCLUSIONS: Twice daily oral gavage of SBI was well-tolerated and reduced the incidence, severity and duration of irinotecan-induced mucositis. SBI was associated with less pronounced changes in inflammatory cell levels and tissue damage to colon and jejunum. Ongoing experiments aim to investigate the mechanisms of SBI-associated gastrointestinal protection.

Glutamine ameliorates intestinal ischemia-reperfusion Injury in rats by activating the Nrf2/Are signaling pathway.

Ischemia-reperfusion (I/R)-mediated intestinal mucosal injury is usually induced by oxygen-derived toxic free radicals from the xanthine oxidase system after reperfusion, but the detailed molecular mechanisms underlying glutamine protection is still unclear. This study aims to elucidate whether glutamine prevents damage to the intestinal mucosa after I/R in rats and to investigate signaling by the Nrf2/ARE pathway induced by GLN in a rat model. Our results revealed that Glutamine pretreatment reduced jejunum injury and microvascular hyper-permeability induced by I/R. MDA level significantly increased while the SOD and GSH-Px levels decreased in the I/R group compared to the sham group and the GLN-I/R group. Both the mRNA and protein levels of the Nrf2 and HO-1 were significantly elevated by GLN pretreatment when compared to the I/R group. GLN treatment also elevated Bcl-2 levels, and accordingly suppressed apoptotic damage in the jejunum cells shown by decreased cleaved caspase-3 level. Mechanistic investigation revealed that GLN treatment augmented binding of Nrf2 onto Bcl2 gene promoter. These results indicate that glutamine has protective effects on I/R in vivo by activating the Nrf2/ARE signaling pathway to inhibit ROS production and reduce intestinal apoptosis.

An evidence-based algorithm for the management of marginal ulcers following Roux-en-Y gastric bypass.

As the demand for obesity surgery grows, Roux-en-Y gastric bypass remains the most commonly performed procedure associated with low complication rates and good long-term co-morbidity resolution and weight loss. Marginal ulcers remain a cause of significant morbidity in medium and long term and are reported in every large series of this operation. Marginal ulceration is a complex problem with unclear aetiology and lack of clear consensus on its prevention and management. A clearer understanding of the available evidence regarding the prevention and treatment of marginal ulcers is needed to improve patient care. We propose an algorithm for management of patients with marginal ulcers based on the best available evidence in the literature.

Understanding jejunal hemorrhage syndrome.

Jejunal hemorrhage syndrome (JHS) is an acute, highly fatal enterotoxemic disorder in dairy cattle that has been reported during the last few decades. No specific cause of this syndrome has been identified; however, several studies have revealed a strong association between JHS and infection with Clostridium perfringens type A. A common mold, Aspergillus fumigatus, has also been implicated as a potential causative agent in this disease syndrome. Clinical signs of JHS (including sudden decreases in feed intake and milk production, rapid loss of condition, a right-sided ping audible during simultaneous auscultation and percussion of the abdomen, abdominal distension, and melena or bloody feces) usually develop early during lactation when cattle receive rations that are high in energy and low in fiber. Appropriate preventive strategies have not yet been determined, and intensive medical management with or without surgical intervention is rarely successful. The use of commercially available vaccines that are directed against C perfringens types C and D is of questionable efficacy and not likely to be helpful as a preventative measure. This article highlights the potential etiologic and risk factors, describes common clinical signs, outlines relevant diagnostic testing, and summarizes treatment options and their outcomes.

[Involvement of endogenous tachykinins in the development of jejunal mucosa injury induced by on-steroidal anti-inflammatory drugs]. / Udzial endogennych tachykinin w powstawaniu uszkodzen blony sluzowej jelita czczego wywolanych niesterydowymi lekami przeciwzapalnymi.

UNLABELLED: Previous studies have shown that tachykinins, the largest family of neuropeptides, affect the development of mucosal damage in the stomach and colon. The aim of the study was to assess the influence of tachykinins receptors antagonists on the development of the mucosa injury in the proximal and distal jejunum. MATERIAL AND METHODS: Mucosal damage was induced by administration of non-steroidal anti inflammatory drugs (NSAIDs), indomethacin, celecoxib or combination of indomethacin plus celecoxib given intragastrically. NK-1 receptor antagonist (SR 140333), NK-2 receptor antagonist (SR 48968) and NK-3 receptor antagonist (SR 142801) were administered intraperitoneally twice, 30 min before treatment with NSAID and again 24 h later, 30 min before the end of the experiment. RESULTS: Administration of indomethacin, a relatively selective inhibitor for cyclooxygenase-1 (COX-1), induced mucosal lesions in the jejunum. Lesions area in the distal jejunum was 8-fold bigger than in the proximal jejunum. This effect was associated with a significant reduction in mucosal blood flow and an increase in mucosal concentration of pro-inflammatory interleukin-1beta (IL-1beta). Celecoxib, selective inhibitor for COX-2 failed to induce mucosal lesions and did not affect the mucosal blood flow and IL-1beta concentration in the proximal and distal jejunum. In rats treated with a combination of indomethacin plus celecoxib, ulcers reached maximal area. This effect was associated with the highest concentration of mucosal IL-1beta and maximal reduction in mucosal blood flow. Administration of NK-1 receptor antagonist, SR 140333 reduced jejunal damage induced by indomethacin given alone or in combination with celecoxib. This effect was associated with significant reduction in mucosal concentration of IL-1beta. Effect of SR 140333 on mucosal blood flow was statistically insignificant. Neither NK-2 nor NK-3 receptor inhibitor affected mucosal blood flow, IL-1beta concentration area of NSAIDs-induced mucosal damage in the jejunum. CONCLUSIONS: Blockade of NK-1 receptor protects the jejunum against NSAIDs-induced mucosal injury and reduces local inflammation. This observation indicates the involvement of endogenous tachykinins in deleterious effects of NSAID.

Risk of adhesive obstruction after colorectal surgery: the benefits of the minimally invasive approach may extend well beyond the perioperative period.

BACKGROUND: Risk of adhesive small-bowel obstruction (SBO) is high following open colorectal surgery. Laparoscopic surgery may induce fewer adhesions; however, the translation of this advantage to a reduced rate of bowel obstruction has not been well demonstrated. This study evaluates whether SBO is lower after laparoscopic compared with open colorectal surgery. METHODS: Patients who underwent laparoscopic abdominal colorectal surgery, without any previous history of open surgery, from 1998 to 2010 were identified from a prospective laparoscopic database. Details regarding occurrence of symptoms of SBO (colicky abdominal pain; nausea and/or vomiting; constipation; abdominal distension not due to infection or gastroenteritis), admissions to hospital with radiological findings confirming SBO, and surgery for obstruction after the laparoscopic colectomy were obtained by contacting patients and mailed questionnaires. Patients undergoing open colorectal surgery for similar operations during the same period and without a history of previous open surgery also were contacted and compared with the laparoscopic group for risk of obstruction. RESULTS: Information pertaining to SBO was available for 205 patients who underwent an elective laparoscopic procedure and 205 similar open operations. The two groups had similar age, gender, and sufficiently long duration of follow-up. Despite a significantly longer duration of follow-up for the laparoscopic group, admission to hospital for SBO was similar between groups. Patients who underwent laparoscopic surgery also had significantly lower operative intervention for SBO (8% vs. 2%, p = 0.006). CONCLUSIONS: Although the rate of SBO was similar after laparoscopic and open colorectal surgery, the need for operative intervention for SBO was significantly lower after laparoscopic operations. These findings especially in the context of the longer follow-up for laparoscopic patients suggests that the lower incidence of adhesions expected after laparoscopic surgery likely translates into long-term benefits in terms of reduced SBO.

Exogenous carbon monoxide attenuates inflammatory responses in the small intestine of septic mice.

AIM: To determine whether the carbon monoxide (CO)-releasing molecules (CORM)-liberated CO suppress inflammatory responses in the small intestine of septic mice. METHODS: The C57BL/6 mice (male, n = 36; weight 20 ± 2 g) were assigned to four groups in three respective experiments. Sepsis in mice was induced by cecal ligation and puncture (CLP) (24 h). Tricarbonyldichlororuthenium (II) dimer (CORM-2) (8 mg/kg, i.v.) was administrated immediately after induction of CLP. The levels of inflammatory cytokines [interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)] in tissue homogenates were measured with enzyme-linked immunosorbent assay. The levels of malondialdehyde (MDA) in the tissues were determined. The levels of nitric oxide (NO) in tissue homogenate were measured and the expression levels of intercellular adhesion molecule 1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in the small intestine were also assessed. NO and IL-8 levels in the supernatants were determined after the human adenocarcinoma cell line Caco-2 was stimulated by lipopolysaccharide (LPS) (10 g/mL) for 4 h in vitro. RESULTS: At 24 h after CLP, histological analysis showed that the ileum and jejunum from CLP mice induced severe edema and sloughing of the villous tips, as well as infiltration of inflammatory cells into the mucosa. Semi-quantitative analysis of histological samples of ileum and jejunum showed that granulocyte infiltration in the septic mice was significantly increased compared to that in the sham group. Administration of CORM-2 significantly decreased granulocyte infiltration. At 24 h after CLP, the tissue MDA levels in the mid-ileum and mid-jejunum significantly increased compared to the sham animals (103.68 ± 23.88 nmol/mL vs 39.66 ± 8.23 nmol/mL, 89.66 ± 9.98 nmol/mL vs 32.32 ± 7.43 nmol/mL, P < 0.01). In vitro administration of CORM-2, tissue MDA levels were significantly decreased (50.65 ± 11.46 nmol/mL, 59.32 ± 6.62 nmol/mL, P < 0.05). Meanwhile, the tissue IL-1ß and TNF-α levels in the mid-ileum significantly increased compared to the sham animals (6.66 ± 1.09 pg/mL vs 1.67 ± 0.45 pg/mL, 19.34 ± 3.99 pg/mL vs 3.98 ± 0.87 pg/mL, P < 0.01). In vitro administration of CORM-2, tissue IL-1ß and TNF-α levels were significantly decreased (3.87 ± 1.08 pg/mL, 10.45 ± 2.48 pg/mL, P < 0.05). The levels of NO in mid-ileum and mid-jejunum tissue homogenate were also decreased (14.69 ± 2.45 nmol/mL vs 24.36 ± 2.97 nmol/mL, 18.47 ± 2.47 nmol/mL vs 27.33 ± 3.87 nmol/mL, P < 0.05). The expression of iNOS and ICAM-1 in the mid-ileum of septic mice at 24 h after CLP induction significantly increased compared to the sham animals. In vitro administration of CORM-2, expression of iNOS and ICAM-1 were significantly decreased. In parallel, the levels of NO and IL-8 in the supernatants of Caco-2 stimulated by LPS was markedly decreased in CORM-2-treated Caco-2 cells (2.22 ± 0.12 nmol/mL vs 6.25 ± 1.69 nmol/mL, 24.97 ± 3.01 pg/mL vs 49.45 ± 5.11 pg/mL, P < 0.05). CONCLUSION: CORM-released CO attenuates the inflammatory cytokine production (IL-1ß and TNF-α), and suppress the oxidative stress in the small intestine during sepsis by interfering with protein expression of ICAM-1 and iNOS.

Preoperative determination of appropriate cutting line for proximal gastrectomy to avoid postoperative jejunal ulcer.

BACKGROUND/AIMS: Although proximal gastrectomy has become a procedure of choice for patients' early cancer in the upper third of stomach, no clinical guide for optimal gastric resection in order to avoid postoperative jejunal ulcer is available. The aim of this study was to investigate whether determining the distribution of parietal and chief cells of the stomach using Congo red test is clinically relevant. METHODOLOGY: The F-line was defined as a boundary line between fundic and intermediate area of the stomach according to the pathological findings in 29 patients who underwent total gastrectomy for early gastric cancer, whereas the f-line was regarded as a boundary line between intermediate and pyloric area. In the additional 6 patients undergoing vagus-preserving proximal gastrectomy with jejunal pouch interposition, endoscopic Congo red test was preoperatively performed to determine the F-f-line. RESULTS: The distances from the pyloric ring to f-line on the lesser and greater curvatures were variable. Long-term outcomes of proximal gastrectomy guided by preoperative endoscopic Congo red test were favorable. CONCLUSIONS: It is suggested that preoperative endoscopic Congo red test is useful to determine the appropriate cutting line in order to avoid postoperative jejunal ulcer after proximal gastrectomy.

Ischemic postconditioning does not attenuate ischemia-reperfusion injury of rabbit small intestine.

OBJECTIVE: To determine whether ischemic postconditioning can attenuate intestinal ischemia-reperfusion (I-R) injury and has a beneficial effect on tissue blood flow during reperfusion. STUDY DESIGN: In vivo experimental study. ANIMALS: New Zealand White rabbits (n=6). METHODS: Rabbits were anesthetized with pentobarbital, to avoid the preconditioning effects of volatile anesthetics, and ventilated with room air. Rectal temperature, hemodynamics, and normocapnia were maintained. After celiotomy, 3 jejunal segments were isolated in each rabbit for the following groups: (1) control, (2) I-R, and (3) I-R with postconditioning. I-R was induced by a 45-minute occlusion of the segment jejunal artery followed by 2-hour reperfusion. The postconditioning segment had 4 cycles of 30-second reperfusion and 30-second reocclusion during the initial 4 minutes of reperfusion. Stable isotope-labeled microspheres were used to measure intestinal blood flow at baseline, end occlusion, and end reperfusion. At the end of reperfusion, intestine segments were harvested and the rabbits euthanatized. A semiquantitative histopathologic evaluation (0-5) was conducted by a single, blinded observer. Wet-to-dry weight ratios were calculated to assess intestinal edema. RESULTS: There was no significant difference in grade of necrosis, tissue wet-to-dry weight ratios, or blood flow at any time point between ischemic and postconditioning groups. CONCLUSIONS: Ischemic postconditioning was ineffective in this model of intestinal I-R. CLINICAL RELEVANCE: Further experimental studies will need to be performed before clinical application of postconditioning for intestinal ischemia.

Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice.

BACKGROUND & AIMS: Postoperative ileus, an iatrogenic complication of abdominal surgery, is mediated by severe inflammation of the tunica muscularis. Macrophages that reside in the muscularis have important roles in initiating the inflammation. We investigated whether activation of the p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase is involved in the genesis of postoperative ileus, and whether p38-MAPK inhibition by the macrophage-specific inhibitor semapimod prevents intestinal dysmotility. METHODS: Postoperative ileus was induced by intestinal manipulation of the small bowel in mice. Protein kinase phosphorylation was assessed by immunoblotting of muscularis externa preparations. Proinflammatory gene expression was quantified by real-time polymerase chain reaction. Myeloperoxidase histochemistry for neutrophils was performed in jejunal segments. Nitric oxide production was measured by Griess reaction in smooth-muscle organ culture supernatants. Jejunal contractility was assessed within an organ bath setup. Intestinal motility was analyzed by gastrointestinal and colonic transit measurements. RESULTS: High levels of p38-MAPK and stress-activated protein kinase phosphorylation were observed immediately after intestinal manipulation. Semapimod treatment led to a significant decrease of p38-MAPK phosphorylation in macrophages; proinflammatory gene expression of macrophage inflammatory protein-1alpha, interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; and neutrophil infiltration. Furthermore, semapimod completely abrogated nitric oxide production within the tunica muscularis. Subsequently, semapimod prevented the suppression of smooth muscle contractility and small intestinal and colonic motility after intestinal manipulation. CONCLUSION: A single preoperative semapimod administration prevents intestinal macrophage activation and subsequent gastrointestinal dysmotility induced by abdominal surgery. Semapimod inhibits p38-MAPK and nitric oxide production in macrophages, making it a promising strategy for prophylaxis of postoperative ileus.

Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice.

BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). It plays an important role in the feedback regulation of HO-1 expression, which protects cells from various insults including oxidative stress and inflammatory cytokines. However, the role of Bach1 in intestinal inflammation remains unclear. In this study, the role of Bach1 in intestinal mucosal injury was elucidated using 8-week-old female C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice. Intestinal mucosal injuries induced by a single subcutaneous administration of indomethacin were evaluated macroscopically, histologically, and biochemically. Mucosal protein content and chemokine mRNA levels were determined by real-time PCR. Our results showed that the indomethacin-induced intestinal injury was remarkably improved in Bach1-deficient mice. Histological examination showed that the area of injured lesion was decreased in Bach1-deficient mice compared to wild-type mice. Administration of indomethacin induced expression of inflammatory chemokines such as KC, MIP1alpha and MCP1, which was suppressed in Bach1-deficient mice. Myeloperoxidase activity in the intestinal mucosa was also significantly decreased in Bach1-deficient mice. Additionally, Bach1 deficiency enhanced immunopositivity of HO-1 in the intestinal mucosa after indomethacin administration. Disruption of the Bach1 gene thus caused inhibition of mucosal injury, indicating that inhibition of Bach1 may be a novel therapeutic strategy for treating indomethacin-induced intestinal injury.

Prophylactic effect of irsogladine maleate against indomethacin-induced small intestinal lesions in rats.

The effect of irsogladine maleate, a widely used antiulcer drug in Japan, on indomethacin-induced small intestinal lesions was examined in rats. Animals without fasting were given indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Irsogladine (1-10 mg/kg) or 16,16-dimethyl prostaglandin E2 (dmPGE2 0.03 mg/kg) was given p.o. twice, 0.5 before and 6 h after indomethacin, while ampicillin (800 mg/kg) was given twice, 18 and 0.5 h before. Indomethacin caused severe lesions in the small intestine, mainly the jejunum and ileum, accompanied by intestinal hypermotility, the up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of myeloperoxidase (MPO) activity as well as enterobacterial invasion in the mucosa. These events were all prevented by both dmPGE2 and ampicillin, except the intestinal hypermotility which was only prevented by dmPGE2. Likewise, irsogladine also significantly and dose-dependently prevented these lesions at > 1 mg/kg. This agent alone increased mucus secretion and significantly suppressed the decreased mucus response to indomethacin, resulting in a suppression of the bacterial invasion as well as the increase in MPO activity and iNOS expression. The protective effect of irsogladine was mimicked by isobutylmethylxanthine, a nonselective inhibitor of phosphodiesterase (PDE), as well as rolipram, a selective PDE4 inhibitor. These results suggest that irsogladine protects the small intestine against indomethacin-induced lesions, and this effect may be associated with the increased mucus secretion, probably due to the inhibitory actions of PDE, resulting in suppression of enterobacterial invasion and iNOS expression.

The effects of combined liquid and membrane barriers in prevention of post-operative intra-abdominal adhesions after experimental jejunal anastomosis in dogs.

The study was carried out on 40 apparently clinical healthy dogs classified into 5 groups of 8 dogs each. Adhesion was experimentally induced by transsection and reanastomosis of jejunum. In the control group the site of anastomosis and abdominal cavity was lavaged with 250 ml saline solution. In group two lavage was done with 250 ml of a liquid barrier composed of a combination of high molecular weight solution (1% sodium carboxymethylcellulose) as a carrier, non-steroidal anti-inflammatory drug (Piroxecam), broad spectrum antibiotic (Cephalosporin), anticoagulant (Heparin) and antioxidant (0.5% methylene blue). In group three the anastomosis site was covered with a sodium hyalouronate/carboxymethylcellulose bioresorbable membrane (Seprafilm). In group four a natural biocompatible collagen sheet (VET BIO SIS T) was applied on the anastomosis site. In group five the abdominal cavity was lavaged with 250 ml liquid barrier and the anastomosis site was covered by either Seprafilm membrane or VET BIO SIS T sheet. At the fourteen day after operation, adhesion was assessed by ultrasonography after instillation of 1000 ml of physiological saline solution into the abdominal cavity. The dogs were sacrificed and an autopsy examination was carried out with the attention to the number, density and site of the adhesion formation. The results revealed that all the control dogs and some dogs in the treatment groups had positive ultrasonographic findings. Transabdominal sonogram clearly showed echogenic bands floating in the abdominal cavity and echogenic masses in more serious subjects. Necropsy examination showed that all the control dogs had intra-abdominal adhesions (8 of 8 dogs) and treatment with liquid barrier (4 of 8 dogs), seprafilm membrane barrier (3 of 8 dogs), VET BIO SIS T sheet barrier (4 of 8 dogs) and combination of fluid and membrane barrier groups (4 of 8 dogs) significantly (p < 0.05) reduced the incidence of adhesion formation. The adhesion severity in the four treated groups was significantly (p < 0.05) decreased compared with the control group as shown by both ultrasonography and necropsy examination scores. In conclusion the suggested hypothesis is more or less positive and the combined liquid and membrane barriers might be an effective way to decrease intra-abdominal adhesion formation, and the ultrasonography is a useful tool to diagnose intra-abdominal adhesion, and their applications might be valuable to the clinical settings.