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PubMed1995

Diaspirin crosslinked hemoglobin (DCLHb) attenuates bacterial translocation in rats.

Intestinal barrier function is compromised following severe hemorrhage which may allow bacterial translocation (BT) to occur and subsequently initiate a systemic response leading to multiple system organ failure (MSOF). This study compared BT following hemorrhage and resuscitation with lactated Ringer's solution (LR) or diaspirin crosslinked hemoglobin solution (DCLHb). Rats (250-350 grams) were hemorrhaged to a base deficit of 15 +/- 2 mmol/L and immediately resuscitated with either 3:1 LR or 1:1 DCLHb based on shed blood volume. Four hours following resuscitation, the mesenteric lymph node complex was harvested, homogenized and plated onto MacConkey and Columbia CNA agar culture media. Facultative anaerobic and obligate aerobic bacteria were identified 48 hours later in 11/22 (50%) LR-treated rats and in 4/21 (19%) DCLHb-treated rats (p < or = 0.05). Following resuscitation, base excess (BE) and central venous oxygen saturation (SvO2) were not only restored to baseline but were significantly greater (p < or = 0.05) in DCLHb-treated rats than in LR-treated rats. In a separate group of rats subjected to the same hemorrhage and resuscitation protocol, mean arterial pressure in DCLHb-treated rats, but not LR-treated rats, was restored to baseline by 15 minutes and remained at or above baseline for up to 4 hrs. Twenty-four hour survival was 50% in LR-treated rats and 77% in DCLHb-treated rats (p > 0.05). These data suggest that DCLHb is superior to LR in restoring tissue oxygen delivery, as judged by BE and SvO2. Furthermore, since DCLHb restores oxygen delivery and attenuates BT, early resuscitation with DCLHb may limit gut ischemia and subsequent gut barrier failure and hence prevent the development of sepsis, MSOF and subsequent death.

Animals↗

PubMed1999

Does glutamine reduce bacterial translocation? A study in two animal models with impaired gut barrier.

Failure of intestinal barrier function and subsequent translocation of bacteria from the gut are believed to play a decisive role in the development of systemic septic complications, for example, following major trauma or major abdominal surgery. This study evaluated: (a) the effect of glutamine on colonic microcirculation and electrophysiological parameters reflecting gut barrier function, (b) the translocation of live bacteria to extraintestinal organs, and (c) disease outcome in two animal models with impaired gut barrier function. Severe acute pancreatitis or colitis was induced in rats randomized for therapy with or without glutamine (0.5 g/kg daily). After 48 h one animal group was prepared for intravital microscopy of colonic capillary blood flow and electrophysiological measurement of gut permeability; another was killed after 96 h for histological and microbiological examination. In animals with pancreatitis, glutamine (Gln) supplementation significantly improved gut permeability, i.e., Gln increased colonic transmucosal resistance from 67+/-7 to 92+/-3 Omega/cm(2) and decreased mannitol flux through the epithelium by 53%. Capillary blood flow in the colonic mucosa was improved by 25%. The prevalence of pancreatic infections was reduced from 86% in animals on standard parenteral nutrition to 33% in animals given the Gln-enriched diet (P<0.05); mortality decreased by 32%. In colitis, Gln had no significant effect on these parameters except for improving colonic capillary blood flow in colon segments not adjacent to the major injury site. Glutamine supplementation improves colonic capillary blood flow, stabilizes gut permeability, and reduces secondary pancreatic infections and mortality in severe rodent pancreatitis, but it is not helpful in colitis. This confirms previous reports that glutamine stabilizes gut barrier function only in certain diseases. Our experimental data strongly suggest that acute pancreatitis (rather than colitis) is one of the diseases with gut barrier dysfunction in which glutamine substitution may be helpful to reduce bacterial translocation and should therefore be tested in a controlled clinical trial.

Animals↗

PubMed2004

Clinical endocrinology and metabolism. Glucagon-like peptide-1 and glucagon-like peptide-2.

The glucagon-like peptides (glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)) are released from enteroendocrine cells in response to nutrient ingestion. GLP-1 enhances glucose-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying and feeding. GLP-1 also has proliferative, neogenic and antiapoptotic effects on pancreatic beta-cells. More recent studies illustrate a potential protective role for GLP-1 in the cardiovascular and central nervous systems. GLP-2 is an intestinal trophic peptide that stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment. GLP-2 also regulates intestinal glucose transport, food intake and gastric acid secretion and emptying, and improves intestinal barrier function. Thus, GLP-1 and GLP-2 exhibit a diverse array of metabolic, proliferative and cytoprotective actions with important clinical implications for the treatment of diabetes and gastrointestinal disease, respectively. This review will highlight our current understanding of the biology of GLP-1 and GLP-2, with an emphasis on both well-characterized and more novel therapeutic applications of these peptides.

Animals↗

PubMed2004

Intestinal injury after thoracic aortic cross-clamping in the pig.

BACKGROUND: The mucosal surface epithelium is an essential part of the functional intestinal barrier, but its structural response to ischemia/reperfusion is only partly characterized. The purpose of this study was to provide a detailed morphological evaluation of intestinal surface epithelium after aortic cross-clamping. MATERIAL AND METHODS: Pigs were subjected to thoracic aortic cross-clamping for 60 min and subsequent reperfusion for 120 min. Tissue blood flow and high-energy phosphates were measured with microspheres and HPLC, respectively. Urinary excretion of (14)C polyethylene glycol (MW 4000 Da) (PEG-4000), loaded into an intestinal loop, provided an index of intestinal permeability. RESULTS: Jejunal blood flow was restored at 10 min after aortic declamping. Denudation of the basement membrane of the intestinal villi tips, as a consequence of epithelial shedding, increased markedly during the initial 60 min of reperfusion (P = 0.002). During the following 45 min, the denuded basement membrane was partly covered with low cuboidal and squamous-shaped cells extending lamellipodia over a wavy basement membrane. Restoration of ATP at 60 min after aortic declamping correlated inversely to the extent of denuded basement membrane (r = 0.75, P = 0.032). Permeability of PEG-4000 increased markedly after aortic declamping and was linearly correlated to the area of denuded basement membrane (r = 0.87, P = 0.01). CONCLUSIONS: Reperfusion for 2 h after aortic cross-clamping is associated with initial aggravation of ischemia-induced injury in the porcine jejunum, but thereafter with restitution of the surface epithelium. Restoration of ATP may be important to avoid intestinal injury after ischemia. Increased permeability of a macromolecule in response to reperfusion is closely correlated to injury of the surface epithelium.

Adenosine Diphosphate↗

PubMed2004

Gut regulatory peptides bombesin and neurotensin reduce hepatic oxidative stress and histological alterations in bile duct ligated rats.

Gut regulatory peptides bombesin (BBS) and neurotensin (NT) exert a wide spectrum of biological actions on gastrointestinal tissues and we have previously shown that they improve intestinal barrier function and oxidative stress in experimentally jaundiced rats. In the present study, we explored their potential action on liver histology and oxidative status in bile duct ligated rats. Seventy male Wistar rats were randomly divided into five groups: controls, sham operated, bile duct ligated (BDL), BDL + BBS (10 microg/kg, s.c. x3), BDL + NT (300 microg/kg, i.p.). At the end of the experiment, on day 10, serum total bilirubin and alanine aminotransferase (ALT) levels were determined and endotoxin was measured in portal and aortic blood. Liver tissue samples were examined histologically for evaluation of the ratio of portal tracts presenting changes of obstructive cholangiopathy and neutrophils' number in portal tracts. In addition, hepatic oxidative status was estimated on liver homogenates by measurements of lipid peroxidation (malondialdehyde), protein oxidation (protein carbonyl groups) and thiol redox state [reduced glutathione (GSH), oxidized glutathione (GSSG), total non-protein mixed disulfides (NPSSR) and protein thiols (PSH)]. Administration of BBS or NT significantly reduced portal and aortic endotoxaemia observed in obstructive jaundice. Both agents significantly ameliorated liver injury, as demonstrated by improvement of obstructive cholangiopathy and reduction of ALT. This effect was accompanied by prevention of lipid peroxidation, protein oxidation and decrease of the oxidized forms GSSG and NPSSR. Moreover, neutrophil accumulation in portal tracts was significantly decreased. In conclusion, this study shows that gut regulatory peptides BBS and NT reduce cholestatic liver injury, exerting protective effects on portal tract architecture, neutrophil infiltration and hepatic oxidative stress in bile duct ligated rats.

Alanine Transaminase↗

PubMed2002

The effect of chitosan and other polycations on tight junction permeability in the human intestinal Caco-2 cell line(1).

Chitosan is a polycationic compound widely employed as dietary supplement and also present in pharmaceutical preparations. Although it has been approved for human consumption, its possible side effects have not been widely investigated and the available data in the literature are still controversial. Several polycationic substances have been shown to affect tight junction permeability in epithelial cell models in vitro. In this study we have compared the effects of chitosan and other polycations (polyethylenimine, poly-L-lysines of different molecular weights) on the integrity of tight junctions and of the actin cytoskeleton in the human intestinal Caco-2 cell line. We have measured trans-epithelial electrical resistance and paracellular passage of the extracellular marker inulin, and we have localized F-actin and tight junctional proteins (ZO1 and occludin) in cell monolayers treated with various concentrations of each polycation. Fluorescent poly-L-lysines were also employed to determine their association with the cell monolayer. Our results indicate that all polycations investigated are able to induce a reversible increase in tight junction permeability. This effect is concentration and energy dependent, affected by the extracellular concentration of divalent cations (calcium, magnesium and manganese) and it is associated with morphological changes in the F-actin cytoskeleton, as well as in the localization of tight junctional proteins. Chitosan, in particular, was the only cationic polymer that displayed an irreversible effect on tight junctions at the highest concentration tested (0.01%). These results indicate that oral ingestion of chitosan may have more widespread health effects by altering intestinal barrier function, thus allowing the entrance into the circulation of potentially toxic and/or allergenic substances.

Journal Article↗

PubMed2002

Anabolic strategies in critical illness.

Critical illness precipitates a marked catabolic response, with protein wasting and loss of lean body mass. Prolongation of this response leads to impaired immunity, poor wound healing, loss of intestinal barrier function and muscle weakness, thereby increasing morbidity and perhaps mortality. Conventional nutritional support only partially ameliorates this process. Disappointingly, specific anabolic and anticatabolic strategies have so far met with only limited success, although recent findings, in particular studies demonstrating the potential value of aggressive insulin therapy and the administration of growth hormone secretagogues, have been encouraging.

Adrenergic Agents↗

PubMed2001

Smectite in the treatment of acute diarrhea: a nationwide randomized controlled study of the Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP) in collaboration with primary care pediatricians. SIGEP Study Group for Smectite in Acute Diarrhea.

BACKGROUND: Childhood gastroenteritis is associated with considerable health costs. The natural clay dioctahedral smectite increases intestinal barrier function and is effective against infectious diarrhea in children in developing countries. The purpose of this work was to investigate the efficacy of smectite in Italian children with acute diarrhea of mild to moderate severity. METHODS: A national, prospective, randomized, case-controlled study was performed in collaboration with primary care pediatricians. Children seen by pediatricians for acute gastroenteritis were treated with oral rehydration solution (ORS) alone or ORS with smectite. Parents returned a form in which total duration of diarrhea, incidence of vomiting and fever, persistence of diarrhea for more than 7 days and hospital admissions were recorded. RESULTS: Eight hundred four children with acute diarrhea were randomly assigned to treated or control groups. Administration of smectite was associated with significant reduction of the duration of diarrhea, as judged by stool frequency and consistency. The incidence and duration of vomiting and fever were not different. Diarrhea lasted more than 7 days in 10% of treated and in 18% of control children (P < 0.01). Hospital admission was necessary in seven treated and six control children. No side effects were observed. CONCLUSIONS: Smectite reduces the duration of diarrhea and prevents a prolonged course. It may therefore consistently reduce the costs of gastroenteritis.

Acute Disease↗

PubMed2002

Management of Lithuanian children's acute diarrhoea with Gastrolit solution and dioctahedral smectite.

OBJECTIVE: Acute gastroenteritis represents a major cause of morbidity and mortality worldwide among children, and rehydration treatment has been one of the cornerstones in the management strategy. The natural clay dioctahedral smectite (Smecta) increases intestinal barrier function and is effective against infectious diarrhoea in children. The purpose of this work was to compare the efficacy and tolerance of Lithuanian children's diarrhoea treatment with dioctahedral smectite combined with hypotonic oral rehydration solution (ORS)--Gastrolit--versus Gastrolit alone to establish the influence of Smecta on serum electrolyte balance in young children with diarrhoea and mild or moderate dehydration. METHODS: Smecta combined with ORS (study group) and ORS alone (control group) were evaluated in a multicentre, open, randomized trial in 54 children aged 6-48 months hospitalized for acute diarrhoea (mostly rotavirus aetiology) and signs of mild and moderate dehydration. The main outcomes examined were duration of diarrhoea, fever, number of vomiting episodes, and serum electrolyte balance before and after treatment. RESULTS: The mean duration of diarrhoea was significantly shorter in the study group (42.3 +/- 24.7 h) than in the control group (61.8 +/- 33.9 h). No side effects of Smecta were observed. The changes of sodium, potassium, chloride and calcium concentrations after treatment were minimal and in the normal range. CONCLUSIONS: Smecta significantly reduced the duration of diarrhoea, was safe and well tolerated, and had no impact on the adsorption of electrolytes. Smecta could be used together with ORS in children suffering from acute gastroenteritis (without uncontrollable vomiting) with mild and moderate dehydration.

Antidiarrheals↗

PubMed2006

Systemic autoimmune disorders in celiac disease.

PURPOSE OF REVIEW: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established. RECENT FINDINGS: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease. SUMMARY: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

Animals↗

PubMed2007

Heat shock stress ameliorates cytokine mixture-induced permeability by downregulating the nitric oxide and signal transducer and activator of transcription pathways in Caco-2 cells.

Proinflammatory cytokines are known to impair intestinal barrier function and to activate signaling pathways, whereas heat shock responses prevent cytokine-induced mucosal damage. We hypothesized that heat shock response blocks the effects of proinflammatory cytokines by regulating nitric oxide (NO) production and the activities of the Janus kinase/signal transducer and activator of transcription (STAT) pathway. A monolayer of Caco-2 cells were pretreated with sodium arsenite (SA, 500 micromol/L) for 1 h, followed by a 1-h recovery, and then stimulated with a cytokine mixture (cytomix: tumor necrosis factor alpha [10 ng/mL], interferon beta [1000 U/mL], and interleukin [IL] 1beta [1 ng/mL]) for 24 h. The permeability of horseradish peroxidase and fluorescein isothiocyanate-conjugated Dextran and transepithelial resistance and potential difference were measured in Ussing chambers. Interleukin-6, IL-8, NO, inducible NO synthase mRNA, STAT activity, and suppressor of cytokine signaling (SOCS) expression were measured in medium or cell lysates. Cytomix resulted in increased epithelial permeability of both fluorescein isothiocyanate-conjugated Dextran and horseradish peroxidase; whereas treatment of Caco-2 cells with SA 500 micromol/L blocked the cytomix-induced permeability changes. In addition, SA treatment decreased cytomix-induced NO production and inducible NO synthase mRNA expression and decreased the levels of STAT1, STAT3, SOCS1, and SOCS3. The SA treatment also decreased cytomix-induced IL-6 and IL-8 production in a dose-dependent manner. In conclusion, cytomix increased epithelial permeability, which is associated with increased NO and STAT activities. The SA treatment ameliorated cytomix-induced permeability, possibly through the downregulation of the NO and Janus kinase/STAT pathways.

Caco-2 Cells↗

PubMed2004

Enteropathogenic Escherichia coli EspF is targeted to mitochondria and is required to initiate the mitochondrial death pathway.

Enteropathogenic Escherichia coli (EPEC) is a causative agent of infant diarrhoea in developing countries. The EspF protein is the product of the espF gene found on the locus of enterocyte effacement, the key pathogenicity island carried by EPEC and enterohemorrhagic E. coli. EspF is injected from adherent EPEC into host cells via a type III secretion system and was previously shown to induce apoptotic cell death and to be required for disruption of host intestinal barrier function. In this work, we show by immunofluorescence and fractionation studies that EspF is targeted to host mitochondria. The N-terminal region of EspF serves as a mitochondrial import signal and, when expressed within cells, can target hybrid green fluorescent protein to mitochondria. Assessment of mitochondrial membrane potential in infected epithelial cells indicated that EspF plays a role in the mitochondrial membrane permeabilization induced by EPEC infection. Furthermore, EspF was associated with the release of cytochrome c from mitochondria into the cytoplasm and with caspase-9 and caspase-3 cleavage. These findings indicate a role for EspF in initiating the mitochondrial death pathway.

Caspase 3↗

PubMed2006

Enteropathogenic Escherichia coli effector EspF interacts with host protein Abcf2.

Enteropathogenic Escherichia coli (EPEC) is a major causative agent of infant diarrhoea in developing countries. The EspF effector protein is injected from EPEC into host cells via a type III secretion system and is involved in the disruption of host intestinal barrier function. In addition, EspF is sorted to mitochondria and has a role in initiating the mitochondrial death pathway. To clarify the manner in which EspF affects host cells, we sought to identify eukaryotic EspF-binding proteins using affinity purification. Abcf2, a protein of unknown function and member of the ABC-transporter family, bound EspF in this assay. An interaction between EspF and Abcf2 was confirmed in a yeast two-hybrid system, by colocalization and by co-immunoprecipitation from EPEC-infected cells. Levels of Abcf2 were decreased in cells infected with EPEC in an EspF dose-dependent manner. Knock-down of Abcf2 expression by RNA interference increased EspF-induced caspase 9 and caspase 3 cleavage. In addition, Abcf2-knocked down cells showed increased caspase 3 cleavage upon treatment with the apoptosis inducing agent staurosporine. These results indicate that EspF induces or facilitates host cell death by targeting and interfering with the putative protective function of Abcf2.

ATP-Binding Cassette Transporters↗

PubMed1999

Normal human colonic subepithelial myofibroblasts enhance epithelial migration (restitution) via TGF-beta3.

After injury and loss of epithelial cells, intestinal barrier function is reestablished by migration of viable epithelial cells from the wound edge (restitution). Myofibroblasts are located close to the basal surface of epithelial cells. This study aimed to investigate the role of human colonic subepithelial myofibroblasts in epithelial restitution. Primary cultures of subepithelial myofibroblasts were established. Monolayers of the epithelial cell lines IEC-6 and T84 were "wounded" in a standard manner to create an in vitro model of restitution. Migration of epithelial cells across the wound edge was assessed following culture in myofibroblast-conditioned medium. Myofibroblast expression of transforming growth factor (TGF)-beta isoforms was examined using RT-PCR, and TGF-beta isoform bioactivity was assessed using Mv 1 Lu bioassay. Myofibroblast-conditioned medium, via a TGF-beta-dependent pathway, significantly enhanced migration of epithelial cells across the wound edge and significantly inhibited cell proliferation in wounded monolayers. Messenger RNA for TGF-beta1, -beta2, and -beta3 was detected in the myofibroblasts, and Mv 1 Lu bioassay showed the presence of predominantly bioactive TGF-beta3. This study shows that human colonic subepithelial myofibroblasts secrete predominantly bioactive TGF-beta3 and enhance restitution in wounded epithelial monolayers via a TGF-beta-dependent pathway.

Animals↗

PubMed2006

The effects of Saccharomyces boulardii on bacterial translocation in rats with obstructive jaundice.

INTRODUCTION: The aim of this study was to investigate the effect of Saccharomyces boulardii treatment on preventing bacterial translocation in an obstructive jaundice animal model. MATERIALS AND METHODS: Sixty adult rats were divided into five groups: group 1 - the sham-operated group; group 2 - the common bile duct ligation group; group 3 - the S. boulardii group; group 4 - the ampicillin-sulbaktam group; and group 5 - the S. boulardii plus ampicillin-sulbaktam group. The saline, antibiotics and S. boulardii were given, respectively, for a 7-day period as a single dose per day via temporary orogastric intubation. Seven days following the obstructive jaundice, the animal had laparatomy under sterile conditions. Segments of ileum were removed for histopathological examination. Blood, liver, spleen and mesenteric lymph nodes were taken for microbiological culture. RESULTS: Bacterial translocation rates were 0% in the sham-operated group, 83% in group 2, 42% in group 3, 42% in group 4 and 33% in group 5. Bacterial translocation significantly increased in group 2 compared to groups 3, 4 and 5 (P = 0.001). The bacterial counts (CFU/g) of group 2 were significantly higher than those of groups 3, 4 and 5 (P = 0.001). Histopathological examination of ileum specimens revealed a significant decrease in the heights of villi in groups 2-5 compared to the sham-operated group (P = 0.001). The mean villus height in groups 3 and 5 was significantly higher than that of group 4 (P = 0.001). CONCLUSIONS: S. boulardii was found to be effective in the successful control of translocation and improvement of intestinal barrier function.

Animals↗

PubMed2006

TH1-dominant granulomatous pathology does not inhibit fibrosis or cause lethality during murine schistosomiasis.

Schistosoma mansoni egg-induced inflammation is accompanied by TH2 cell polarization and development of fibrotic granulomas in host tissue. The interleukin (IL)-4 receptor alpha (IL-4Ralpha), which mediates IL-4 and IL-13 signaling, is essential for granulomatous pathology through a putative CD4+ T-cell-dependent mechanism. In this study, we asked whether CD4+ T-cell-specific IL-4Ralpha-deficient mice (Lck(Cre)IL-4Ralpha(-/lox)) developed granulomas and egg-driven collagen production. Although eosinophilia and goblet cell hyperplasia were impaired in Lck(Cre)IL-4Ralpha(-/lox) mice, there was no reduction in size or collagen content of lung and liver granulomas. The lack of CD4+ T-cell IL-4Ralpha expression caused significant increases in interferon-gamma-producing cells, inducible nitric-oxide synthetase production, and hepatic damage, compared with similarly infected wild-type mice. Interestingly, this TH1-associated liver injury did not lead to premature mortality in this strain. Instead, lower levels of serum endotoxin in Lck(Cre)IL-4Ralpha(-/lox) mice suggest that intestinal barrier function may be the dominant factor for survival during natural infection.

Animals↗

PubMed2004

Effects of ischemia and the cyclooxygenase inhibitor flunixin on in vitro passage of lipopolysaccharide across equine jejunum.

OBJECTIVE: To determine whether ischemia and flunixin affect in vitro lipopolysaccharide (LPS) absorption in samples of the jejunum of horses. ANIMALS: 12 horses. PROCEDURE: Horses were anesthetized, a midline celiotomy was performed, and the jejunum was located. Two 30-cm sections of jejunum (60 cm apart) were selected. One segment was designated as control tissue; ischemia was induced in the other segment for 120 minutes. Horses were then euthanatized. Mucosa from each jejunal segment was mounted on Ussing chambers and treated with or without flunixin. Tissues from 6 horses were used to assess permeability to radiolabeled LPS; mucosal samples from the remaining 6 horses were incubated with fluorescent-labeled LPS (FITC-LPS) and examined histologically. Production of tumor necrosis factor-alpha (TNF-alpha) and production of LPS-binding protein (LBP) were assessed as indicators of mucosal response to LPS. RESULTS: Ischemia significantly increased mucosal permeability to LPS, but by 180 minutes, the mucosa was not more permeable than control tissue. Flunixin treatment adversely affected intestinal barrier function throughout the experiment but did not result in increased mucosal permeability to LPS. Compared with control tissues, LBP production was increased by ischemia and reduced by exposure to LPS. In ischemic tissue, FITC-LPS entered the lamina propria but TNF-alpha was produced on the mucosal side only, indicating little response to the absorbed LPS. CONCLUSIONS AND CLINICAL RELEVANCE: Ischemia increased LPS passage across equine jejunal mucosa. Flunixin delayed mucosal recovery but did not exacerbate LPS absorption. Evaluation of the clinical importance of flunixin-associated delayed mucosal recovery requires further in vivo investigation.

Acute-Phase Proteins↗

PubMed2004

Effects of flunixin meglumine or etodolac treatment on mucosal recovery of equine jejunum after ischemia.

OBJECTIVE: To examine the effects of flunixin meglumine and etodolac treatment on recovery of ischemic-injured equine jejunal mucosa after 18 hours of reperfusion. ANIMALS: 24 horses. PROCEDURE: Jejunum was exposed to 2 hours of ischemia during anesthesia. Horses received saline (0.9% NaCl) solution (12 mL, i.v., q 12 h), flunixin meglumine (1.1 mg/kg, i.v., q 12 h), or etodolac (23 mg/kg, i.v., q 12 h). Tissue specimens were obtained from ischemic-injured and nonischemic jejunum immediately after ischemia and 18 hours after recovery from ischemia. Transepithelial electric resistance (TER) and transepithelial flux of tritium-labeled mannitol measured mucosal permeability. Denuded villous surface area and mean epithelial neutrophil count per mm2 were calculated. Western blot analysis for cyclooxygenase (COX)-1 and -2 was performed. Pharmacokinetics of flunixin and etodolac and eicosanoid concentrations were determined. RESULTS: Ischemic-injured tissue from horses treated with flunixin and etodolac had significantly lower TER and increased permeability to mannitol, compared with that from horses treated with saline solution. Epithelial denudation after ischemia and 18 hours after recovery was not significantly different among treatments. Both COX-1 and -2 were expressed in ischemic-injured and nonischemic tissues. Ischemia caused significant upregulation of both COX isoforms. Eicosanoid concentrations were significantly lower in tissues from flunixin and etodolac-treated horses, compared with that from horses treated with saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Flunixin and etodolac treatment retarded recovery of intestinal barrier function in jejunal mucosa after 18 hours of reperfusion, whereas tissues from horses treated with saline solution recovered baseline values of TER and permeability to mannitol.

Animals↗