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Opgenorth J, Mayorga EJ, Abeyta MA, Goetz BM, Rodriguez-Jimenez S, Freestone A, Stahl CH, Baumgard LH. Calcium trafficking and gastrointestinal physiology following an acute lipopolysaccharide challenge in pigs. J Anim Sci 2024; 102:skae073. [PMID: 38483214 PMCID: PMC11034434 DOI: 10.1093/jas/skae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/13/2024] [Indexed: 04/23/2024] Open
Abstract
The influence of systemic immune activation on whole-body calcium (Ca) trafficking and gastrointestinal tract (GIT) physiology is not clear. Thus, the study objectives were to characterize the effects of lipopolysaccharide (LPS) on Ca pools and GIT dynamics to increase understanding of immune-induced hypocalcemia, ileus, and stomach hemorrhaging. Twelve crossbred pigs [44 ± 3 kg body weight (BW)] were randomly assigned to 1 of 2 intramuscular treatments: (1) control (CON; 2 mL saline; n = 6) or (2) LPS (40 µg LPS/kg BW; n = 6). Pigs were housed in metabolism stalls to collect total urine and feces for 6 h after treatment administration, at which point they were euthanized, and various tissues, organs, fluids, and digesta were weighed, and analyzed for Ca content. Data were analyzed with the MIXED procedure in SAS 9.4. Rectal temperature and respiration rate increased in LPS relative to CON pigs (1.4 °C and 32%, respectively; P ≤ 0.05). Inflammatory biomarkers such as circulating alkaline phosphatase, aspartate aminotransferase, and total bilirubin increased in LPS compared with CON pigs whereas albumin decreased (P ≤ 0.02). Plasma glucose and urea nitrogen decreased and increased, respectively, after LPS (43% and 80%, respectively; P < 0.01). Pigs administered LPS had reduced circulating ionized calcium (iCa) compared to CON (15%; P < 0.01). Considering estimations of total blood volume, LPS caused an iCa deficit of 23 mg relative to CON (P < 0.01). Adipose tissue and urine from LPS pigs had reduced Ca compared to CON (39% and 77%, respectively; P ≤ 0.05). There did not appear to be increased Ca efflux into GIT contents and no detectable increases in other organ or tissue Ca concentrations were identified. Thus, while LPS caused hypocalcemia, we were unable to determine where circulating Ca was trafficked. LPS administration markedly altered GIT dynamics including stomach hemorrhaging, diarrhea (increased fecal output and moisture), and reduced small intestine and fecal pH (P ≤ 0.06). Taken together, changes in GIT physiology suggested dyshomeostasis and alimentary pathology. Future research is required to fully elucidate the etiology of immune activation-induced hypocalcemia and GIT pathophysiology.
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Affiliation(s)
- Julie Opgenorth
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Edith J Mayorga
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Megan A Abeyta
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Brady M Goetz
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | | | - Alyssa D Freestone
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Chad H Stahl
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Lance H Baumgard
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
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Castro M, Valero MS, López-Tofiño Y, López-Gómez L, Girón R, Martín-Fontelles MI, Uranga JA, Abalo R. Radiographic and histopathological study of gastrointestinal dysmotility in lipopolysaccharide-induced sepsis in the rat. Neurogastroenterol Motil 2023; 35:e14639. [PMID: 37417393 DOI: 10.1111/nmo.14639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 05/03/2023] [Accepted: 06/20/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Sepsis is a highly incident condition in which a cascade of proinflammatory cytokines is involved. One of its most frequent consequences is ileus, which can increase mortality. Animal models such as that induced by systemic administration of lipopolysaccharide (LPS) are useful to deeply evaluate this condition. The effects of sepsis on the gastrointestinal (GI) tract have been explored but, to our knowledge, in vivo studies showing the motor and histopathological consequences of endotoxemia in an integrated way are lacking. Our aim was to study in rats the effects of sepsis on GI motility, using radiographic methods, and to assess histological damage in several organs. METHODS Male rats were intraperitoneally injected with saline or E. coli LPS at 0.1, 1, or 5 mg kg-1 . Barium sulfate was intragastrically administered, and X-rays were performed 0-24 h afterwards. Several organs were collected for organography, histopathology, and immunohistochemistry studies. KEY RESULTS All LPS doses caused gastroparesia, whereas changes in intestinal motility were dose-and time-dependent, with an initial phase of hypermotility followed by paralytic ileus. Lung, liver, stomach, ileum, and colon (but not spleen or kidneys) were damaged, and density of neutrophils and activated M2 macrophages and expression of cyclooxygenase 2 were increased in the colon 24 h after LPS 5 mg kg-1 . CONCLUSIONS AND INFERENCES Using radiographic, noninvasive methods for the first time, we show that systemic LPS causes dose-, time-, and organ-dependent GI motor effects. Sepsis-induced GI dysmotility is a complex condition whose management needs to take its time-dependent changes into account.
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Affiliation(s)
- Marta Castro
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Universidad de Zaragoza, Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza-CITA, Zaragoza, Spain
| | - Marta Sofía Valero
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Universidad de Zaragoza, Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
- Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza-CITA, Zaragoza, Spain
| | - Yolanda López-Tofiño
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
- High-Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), Alcorcón, Spain
| | - Laura López-Gómez
- High-Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), Alcorcón, Spain
- Área de Histología Humana y Anatomía Patológica, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
| | - Rocío Girón
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
- High-Performance Research Group in Experimental Pharmacology (PHARMAKOM-URJC), Alcorcón, Spain
- Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - María Isabel Martín-Fontelles
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
- Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- Grupo de Trabajo de Ciencias Básicas en Dolor y Analgesia de la Sociedad Española del Dolor, Madrid, Spain
| | - José A Uranga
- High-Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), Alcorcón, Spain
- Área de Histología Humana y Anatomía Patológica, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
| | - Raquel Abalo
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain
- High-Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), Alcorcón, Spain
- Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- Grupo de Trabajo de Ciencias Básicas en Dolor y Analgesia de la Sociedad Española del Dolor, Madrid, Spain
- Grupo de Trabajo de Cannabinoides de la Sociedad Española del Dolor, Madrid, Spain
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Role of nitric oxide on zymosan-induced inhibition of crop emptying in chicks. Comp Biochem Physiol A Mol Integr Physiol 2021; 261:111057. [PMID: 34419574 DOI: 10.1016/j.cbpa.2021.111057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 01/03/2023]
Abstract
Zymosan, a component of yeast cell walls, reduces feed passage through the digestive tract in chicks (Gallus gallus), although the mechanism mediating this effect is poorly understood. Nitric oxide (NO) is associated with a variety of biological actions including effects on the immune system. In addition, it has been suggested that NO is involved in relaxation of the digestive tract and affects feed passage in mammals. It is therefore possible that NO might be related to zymosan-induced reduction of feed passage in chicks. However, the role of NO on the effect of zymosan feed passage has not been clarified yet. Thus, the purpose of the present study was to investigate whether NO is associated with zymosan-induced alteration of feed passage in chicks. Intraperitoneal (IP) injection of zymosan significantly increased plasma nitrate and nitrite (NOx) concentrations at 6 h after injection. Zymosan-induced elevation of plasma NOx concentration was abolished by co-injection of S-methylisothiourea (SMT), a selective inhibitor for inducible NO synthase (iNOS), indicating that zymosan facilitated the induction of iNOS. Furthermore, because zymosan increased iNOS mRNA expression in the digestive tract, NO is likely associated with the effect of zymosan on the digestive tract. IP injection of NO donors significantly decreased crop emptying rate, suggesting that NO functions as an inhibitor of crop emptying. This result implied that zymosan stimulates NO production by the induction of iNOS in the digestive tract and thereby inhibits crop emptying rate. However, the co-injection of SMT did not attenuate the inhibitory effect of zymosan on crop emptying. The present study provides evidence that some changes in the digestive tract caused by zymosan are mediated by iNOS-induced NO in chicks, but NO does not mediate the effect of zymosan on feed passage through the crop.
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Tachibana T, Takahashi M, Takeda K, Ogino M, Khan MSI, Makino R, Cline MA. Effect of zymosan on feed passage in the digestive tract in chicks. Br Poult Sci 2020; 62:414-423. [PMID: 33314959 DOI: 10.1080/00071668.2020.1863336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
1. The purpose of the present study was to examine whether zymosan, which is a component of fungi, affects feed passage through the digestive tract in chicks (Gallus gallus).2. Intraperitoneal (IP) injection of 2.5 mg zymosan significantly reduced the crop-emptying rate and this effect was similar to that of 100 µg lipopolysaccharide (LPS). Zymosan affected phenol red transit from the proventriculus.3. Zymosan significantly affected the gene expression of interleukin-1β (IL-1β), IL-6, IL-8 and histidine decarboxylase in various regions of the digestive tract.4. The present study suggested that zymosan retarded feed passage through the digestive tract in chick and interleukins and histamine may be participating in this process.
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Affiliation(s)
- T Tachibana
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama, Japan
| | - M Takahashi
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama, Japan
| | - K Takeda
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama, Japan
| | - M Ogino
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama, Japan
| | - M S I Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Toon, Japan
| | - R Makino
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama, Japan
| | - M A Cline
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
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Tachibana T, Ueoka W, Khan MSI, Makino R, Cline MA. Compound 48/80 reduces the crop-emptying rate, likely through a histamine-associated pathway in chicks. Domest Anim Endocrinol 2019; 66:57-63. [PMID: 30472035 DOI: 10.1016/j.domaniend.2018.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/31/2018] [Accepted: 10/11/2018] [Indexed: 11/15/2022]
Abstract
Infectious conditions are associated with reduced food passage through the digestive tract in both mammals and chicks; however, the precise mechanism mediating this response in chicks remains unclear. The purpose of the present study was to determine if mast cells, a blood cell type which plays an important role in the immune system, might affect food passage through the digestive tract in chicks. Specifically, we performed intraperitoneal (IP) injections of compound 48/80, an inducer of mast cell degranulation, and measured crop emptying. The IP injection of compound 48/80 significantly reduced the crop-emptying rate, but it did not affect the proventriculus to small intestine transit rate or the number of defecations. We also found that IP-injected histamine, which is secreted by mast cells, also reduced the crop-emptying rate. In addition, IP injection of 2-pyridylethylamine (histamine H1 receptor agonist), but not dimaprit, (R)-(-)-α-methylhistamine, and VUF8430 (histamine H2, H3, and H4 receptor agonists, respectively), reduced the crop-emptying rate, implying that histamine reduces the crop emptying rate via the histamine H1 receptor. Finally, we found that IP injection of compound 48/80 reduced mRNA expression of histidine decarboxylase, a rate-limiting enzyme for histamine synthesis, in the esophagus and proventriculus at 1 h and the proventriculus and duodenum at 3 h after the injection. In sum, the present study suggests that the degranulation of mast cells causes a reduction in the crop-emptying rate, possibly via the histamine pathway in chicks.
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Affiliation(s)
- Tetsuya Tachibana
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan.
| | - Wataru Ueoka
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan
| | - Md Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University, Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Ryosuke Makino
- Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan
| | - Mark A Cline
- Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
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Li H, Qu Y, Zhang J, Zhang J, Gao W. Spasmolytic activity of Aquilariae Lignum Resinatum extract on gastrointestinal motility involves muscarinic receptors, calcium channels and NO release. PHARMACEUTICAL BIOLOGY 2018; 56:559-566. [PMID: 31070538 PMCID: PMC6292371 DOI: 10.1080/13880209.2018.1492000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
CONTEXT Aquilariae Lignum Resinatum (ALR), the dry rhizome of Aquilaria agallocha R. (Thymelaeaeeae), has been widely used to treat emesis, stomachache and gastrointestinal dysfunction. OBJECTIVE This study evaluates the effects of ALR methanol extract on gastrointestinal motility (GIM) and possible mechanisms of the action involved. MATERIALS AND METHODS In vivo, the study evaluated the effects of ALR (200-800 mg/kg) on gastric emptying and small intestinal motility in normal and neostigmine-induced adult KM mice. The in vitro effects of ALR (0.2-1.6 mg/mL) on GIM were performed on isolated jejunum of Wistar rats, pretreated with acetylcholine (ACh), KCl, CaCl2, and pre-incubation with l-NAME (a selective inhibitor of the nitric oxide synthase). RESULTS In vivo, ALR (800 mg/kg) decreased gastric emptying (70.82 ± 9.81%, p < 0.01, compared with neostigmine group 91.40 ± 7.81%), small intestinal transit (42.82 ± 3.82%, p < 0.01, compared with neostigmine group 85.53 ± 5.57%). In vitro, ALR concentration dependently decreased the contractions induced by ACh (10-5 M) and KCl (60 mM) with respective EC50 values of 0.35 and 0.32 mg/mL. The Ca2+ concentration-response curves were shifted by ALR to the right, similar to that caused by verapamil (the positive). The spasmolytic activity of ALR was inhibited by pre-incubation with l-NAME. DISCUSSION AND CONCLUSIONS ALR played a spasmolytic role in GIM, which is probably mediated through inhibition of muscarinic receptors, blockade of Ca2+ influx and NO release. This is the first study presenting a comprehensive description of the effects of ALR on GIM.
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Affiliation(s)
- Huimin Li
- Department of Pharmacy, Special Drugs R&D Center of People’s Armed Police Forces, Logistics University of Chinese People’s Armed Police Forces, Tianjin, China
| | - Yanfei Qu
- Department of Pharmacy, Special Drugs R&D Center of People’s Armed Police Forces, Logistics University of Chinese People’s Armed Police Forces, Tianjin, China
| | - Jiawei Zhang
- Department of Pharmacy, Special Drugs R&D Center of People’s Armed Police Forces, Logistics University of Chinese People’s Armed Police Forces, Tianjin, China
| | - Jingze Zhang
- Department of Pharmacy, Special Drugs R&D Center of People’s Armed Police Forces, Logistics University of Chinese People’s Armed Police Forces, Tianjin, China
- CONTACT Jingze Zhang Department of Pharmacy, Logistics College of Chinese People’s Armed Police Forces, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Tianjin300162, China; Wenyuan Gao School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin300072, China
| | - Wenyuan Gao
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- CONTACT Jingze Zhang Department of Pharmacy, Logistics College of Chinese People’s Armed Police Forces, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Tianjin300162, China; Wenyuan Gao School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin300072, China
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Bannert E, Tesch T, Kluess J, Winkler J, Frahm J, Kersten S, Kahlert S, Renner L, Rothkötter HJ, Dänicke S. On the distribution and metabolism of Fusarium-toxins along the gastrointestinal tract of endotoxaemic pigs. Arch Anim Nutr 2018; 72:163-177. [PMID: 29741131 DOI: 10.1080/1745039x.2018.1465261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
The aim of this study was to investigate the potential modulatory effect of E. coli lipopolysaccharides (LPS) on residues of deoxynivalenol (DON), de-epoxy-deoxynivalenol (DOM-1), zearalenone (ZEN) and its metabolites α-zearalenol (α-ZEL), β-zearalenol (β-ZEL), zearalanone (ZAN), α-zearalanol (α-ZAL) and β-zearalanol (β-ZAL) after pre- or post-hepatic administration along the gastrointestinal axis. Fifteen barrows were exposed to a naturally mycotoxin contaminated diet (4.59 mg DON/kg feed and 0.22 mg ZEN/kg feed) and equipped with jugular (ju) and portal (po) catheters. On sampling day (day 29), the barrows were infused with LPS or a control fluid (LPS, 7.5 µg/kg body weight; control, 0.9% NaCl) either pre- or post-hepatically, resulting in three infusion groups: CONju-CONpo, CONju-LPSpo and LPSju-CONpo. At 195 min relative to infusion start (210 min post-feeding), pigs were sacrificed and content of stomach and small intestine (proximal, medial and distal part) as well as faeces were collected. In all LPS-infused animals, higher amounts of dry matter were recovered irrespective of LPS entry site suggesting a reduced gastric emptying and a decreased gastrointestinal motility under endotoxaemic conditions. DON metabolism in the gastrointestinal tract (GIT) remained unaltered by treatments and included an increase in the proportion of DOM-1 along the GIT, particularly from distal small intestine to faeces. Variables describing ZEN metabolism suggest a stimulated biliary release of ZEN and its metabolites in LPS-infused groups, particularly in the LPSju-CONpo group. In conclusion, the GIT metabolism of ZEN was markedly influenced in endotoxaemic pigs whereby a jugular induction of an acute phase reaction was more effective than portal LPS infusion hinting at a strong hepatic first-pass effect.
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Affiliation(s)
- Erik Bannert
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Tanja Tesch
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Jeannette Kluess
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Janine Winkler
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Jana Frahm
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Susanne Kersten
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
| | - Stefan Kahlert
- b Medical Faculty, Institute of Anatomy , Otto-von-Guericke University Magdeburg , Magdeburg , Germany
| | - Lydia Renner
- b Medical Faculty, Institute of Anatomy , Otto-von-Guericke University Magdeburg , Magdeburg , Germany
| | - Hermann-Josef Rothkötter
- b Medical Faculty, Institute of Anatomy , Otto-von-Guericke University Magdeburg , Magdeburg , Germany
| | - Sven Dänicke
- a Institute of Animal Nutrition, Friedrich-Loeffler Institute (FLI), Federal Research Institute for Animal Health , Braunschweig , Germany
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Nakato J, Ho YY, Omae R, Mizushige T, Uchida K, Tominaga M, Kim M, Goto T, Takahashi N, Kawada T, Akiduki S, Kanamoto R, Ohinata K. l-Ornithine and l-lysine stimulate gastrointestinal motility via transient receptor potential vanilloid 1. Mol Nutr Food Res 2017; 61. [PMID: 28722259 DOI: 10.1002/mnfr.201700230] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/15/2017] [Accepted: 07/04/2017] [Indexed: 01/09/2023]
Abstract
SCOPE The gastrointestinal (GI) tract senses and responds to intraluminal nutrients and these interactions often affect GI functions. We found that, among basic amino acids, l-ornithine (Orn) and l-lysine (Lys) stimulated but l-arginine (Arg) suppressed GI motility after oral administration (24 mmol/kg) in mice (Orn and Lys, 14.3 and 26.4% promotion; Arg, 7.7% suppression). We investigated the mechanism of the action of Orn and Lys on GI motility. METHODS AND RESULTS Orn-induced promotion of small intestinal transit was significantly inhibited (p<0.05) by oral administration of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. Moreover, the stimulatory effect of Orn and Lys was abolished in TRPV1-knockout mice. In TRPV1-transfected HEK293 cells, Orn and Lys (10 mM) evoked Ca2+ influx, which was blocked by ruthenium red, a TRP channel antagonist. These results suggest that Orn and Lys promote GI motility via activation of TRPV1. The GI motility stimulation by Orn and Lys was also blocked by atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, or NG -nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. CONCLUSION Orally administered Orn and Lys stimulate GI motility via TRPV1, mAChR and NO synthase in mice.
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Affiliation(s)
- Junya Nakato
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Yee Yin Ho
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Ryo Omae
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Takafumi Mizushige
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Kunitoshi Uchida
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Minji Kim
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Nobuyuki Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Saori Akiduki
- Healthcare Products Development Center, KYOWA HAKKO BIO CO., LTD., Tsukuba, Ibaraki, Japan
| | - Ryuhei Kanamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Kousaku Ohinata
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
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Lai NY, Mills K, Chiu IM. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J Intern Med 2017; 282:5-23. [PMID: 28155242 PMCID: PMC5474171 DOI: 10.1111/joim.12591] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.
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Affiliation(s)
- N Y Lai
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - K Mills
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - I M Chiu
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
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Bannert E, Tesch T, Kluess J, Valenta H, Frahm J, Kersten S, Kahlert S, Renner L, Rothkötter HJ, Dänicke S. Plasma kinetics and matrix residues of deoxynivalenol (DON) and zearalenone (ZEN) are altered in endotoxaemic pigs independent of LPS entry site. Mycotoxin Res 2017; 33:183-195. [DOI: 10.1007/s12550-017-0276-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 04/04/2017] [Accepted: 04/06/2017] [Indexed: 01/29/2023]
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Tachibana T, Ogino M, Makino R, Khan MSI, Cline MA. Lipopolysaccharide reduces food passage rate from the crop by a prostaglandin-independent mechanism in chickens. Br Poult Sci 2016; 58:100-106. [PMID: 27871194 PMCID: PMC5359745 DOI: 10.1080/00071668.2016.1237768] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
1. We examined the effect of lipopolysaccharide (LPS), a component of Gram-negative bacteria, on food passage in the digestive tract of chickens (Gallus gallus) in order to clarify whether bacterial infection affects food passage in birds. 2. Food passage in the crop was significantly reduced by intraperitoneal (IP) injection of LPS while it did not affect the number of defecations, suggesting that LPS may affect food passage only in the upper digestive tract. 3. Similar to LPS, prostaglandin E2 (PGE2), one of the mediators of LPS, also reduced crop-emptying rate in chickens while it had no effect on the number of defecations. 4. Pretreatment with indomethacin, which is an inhibitor of cyclooxygenase (COX), a prostaglandin synthase, had no effect on LPS-induced inhibition of crop emptying. 5. IP injection of LPS did not affect the mRNA expression of COX2 in the upper digestive tract of chickens. 6. It is therefore likely that LPS and PGE2 reduced food passage rate in the crop by a prostaglandin-independent pathway in chickens.
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Affiliation(s)
- T Tachibana
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - M Ogino
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - R Makino
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - M S I Khan
- b Department of Anatomy and Embryology , Ehime University Graduate School of Medicine , Toon , Japan
| | - M A Cline
- c Department of Animal and Poultry Sciences , Virginia Polytechnic Institute and State University , Blacksburg , VA , USA
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Wang S, Zhao Y, Zhang J, Huang X, Wang Y, Xu X, Zheng B, Zhou X, Tian H, Liu L, Mei Q. Antidiarrheal effect of Alpinia oxyphylla Miq. (Zingiberaceae) in experimental mice and its possible mechanism of action. JOURNAL OF ETHNOPHARMACOLOGY 2015; 168:182-190. [PMID: 25861952 DOI: 10.1016/j.jep.2015.03.066] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 02/12/2015] [Accepted: 03/30/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The fructus Alpinia oxyphylla Miq. (AOM) has been used for treating diarrhea with spleen deficiency and gastralgia for thousands of years. A number of traditional Chinese medicine formulae provide AOM as an alternative herbal treatment for diarrhea, but the scientific basis for this usage has not been well defined. AIM OF THE STUDY In this study, we tried to investigate the antidiarrheal activity and possible mechanisms of Fructus AOM, aiming to enrich our understanding to the scientific meanings and theoretical significance of Fructus AOM in clinical practice. MATERIALS AND METHODS The fructus of AOM collected from Hainan province in China were macerated in the 95% ethanol to obtain the crude 95% ethanol extract, followed by subjected to chromatographic separation over a Diaion HP20 column to obtain 90% and 50% ethanol eluted fractions. The activities of the crude extract and fractions on castor oil induced acute diarrhea, rhubarb induced chronic diarrhea, gastrointestinal transit (GIT) in mice, and contractions of isolated guinea-pig ileum were evaluated. Additionally, nitric oxide (NO), gastrointestinal peptides gastrin (GAS), motilin (MTL) and somatostatin (SS) levels that related to gastrointestinal motilities were detected to demonstrate the potential mechanisms. Ultimately, LC-MS/MS method was utilized to ensure the chemical consistency. RESULTS The 95% ethanol extract and 90% ethanol eluted fraction significantly delayed the onset time and decreased the wet faeces proportion compared with control group in the castor oil induced acute diarrhea mice. In terms of further evaluation of antidiarrheal activity, the 95% ethanol extract and 90% ethanol elution displayed significant inhibition of the intestinal propulsion at the two highest oral doses of 20 g crude drug/kg and 1g/kg. Moreover the 95% ethanol extract (10 and 20 g crude drug/kg) and 90% ethanol elution (0.5 and 1g/kg) could significantly inhibit the GIT, which was partially attributed to the increase in NO and SS levels, and the decreased MTL. In vitro spontaneous contractions of the isolated guinea pig ileum induced by carbachol, neostigmine and histamine were attenuated by both the extract and elution. Phytochemical analysis of 95% ethanol extract and its fractions identified the presence of diphenylheptanes, sesquiterpenes, and flavones as the major components. CONCLUSIONS Our in vivo and in vitro data could partly support and justify the traditional usage of Fructus AOM on the treatment of diarrhea in traditional medicine.
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Affiliation(s)
- Sheng Wang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Yang Zhao
- Vascular Biology Program, Centenary Institute, The University of Sydney, Shanghai 2042, NSW, Australia.
| | - Junqing Zhang
- Hainan Provincial Key Laboratory of Research and Development of Tropical Medicinal Plants, Hainan Medical University, Haikou 571199, China.
| | - Xiaoxing Huang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Yifei Wang
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Xiaotao Xu
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Bin Zheng
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Xue Zhou
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Huajie Tian
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Li Liu
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
| | - Qibing Mei
- China State Institute of Pharmaceutical Industry, Shanghai 200040, China; State Key Laboratory of New Drug & Pharmaceutial Process, Shanghai Institute of Pharmaceutial Industry, Shanghai 200437, China.
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Romero R, Yoon BH, Chaemsaithong P, Cortez J, Park CW, Gonzalez R, Behnke E, Hassan SS, Chaiworapongsa T, Yeo L. Bacteria and endotoxin in meconium-stained amniotic fluid at term: could intra-amniotic infection cause meconium passage? J Matern Fetal Neonatal Med 2013; 27:775-88. [PMID: 24028637 DOI: 10.3109/14767058.2013.844124] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Meconium-stained amniotic fluid (MSAF) is a common occurrence among women in spontaneous labor at term, and has been associated with adverse outcomes in both mother and neonate. MSAF is a risk factor for microbial invasion of the amniotic cavity (MIAC) and preterm birth among women with preterm labor and intact membranes. We now report the frequency of MIAC and the presence of bacterial endotoxin in the amniotic fluid of patients with MSAF at term. MATERIALS AND METHODS We conducted a cross-sectional study including women in presumed preterm labor because of uncertain dates who underwent amniocentesis, and were later determined to be at term (n = 108). Patients were allocated into two groups: (1) MSAF (n = 66) and (2) clear amniotic fluid (n = 42). The presence of bacteria was determined by microbiologic techniques, and endotoxin was detected using the Limulus amebocyte lysate (LAL) gel clot assay. Statistical analyses were performed to test for normality and bivariate comparisons. RESULTS Bacteria were more frequently present in patients with MSAF compared to those with clear amniotic fluid [19.6% (13/66) versus 4.7% (2/42); p < 0.05]. The microorganisms were Gram-negative rods (n = 7), Ureaplasma urealyticum (n = 4), Gram-positive rods (n = 2) and Mycoplasma hominis (n = 1). The LAL gel clot assay was positive in 46.9% (31/66) of patients with MSAF, and in 4.7% (2/42) of those with clear amniotic fluid (p < 0.001). After heat treatment, the frequency of a positive LAL gel clot assay remained higher in the MSAF group [18.1% (12/66) versus 2.3% (1/42), p < 0.05]. Median amniotic fluid IL-6 concentration (ng/mL) was higher [1.3 (0.7-1.9) versus 0.6 (0.3-1.2), p = 0.04], and median amniotic fluid glucose concentration (mg/dL) was lower [6 (0-8.9) versus 9 (7.4-12.6), p < 0.001] in the MSAF group, than in those with clear amniotic fluid. CONCLUSION MSAF at term was associated with an increased incidence of MIAC. The index of suspicion for an infection-related process in postpartum women and their neonates should be increased in the presence of MSAF.
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Affiliation(s)
- Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS , Bethesda, MD and Detroit, MI , USA
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Thompson A, Meah D, Ahmed N, Conniff-Jenkins R, Chileshe E, Phillips CO, Claypole TC, Forman DW, Row PE. Comparison of the antibacterial activity of essential oils and extracts of medicinal and culinary herbs to investigate potential new treatments for irritable bowel syndrome. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 13:338. [PMID: 24283351 PMCID: PMC4220539 DOI: 10.1186/1472-6882-13-338] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 11/21/2013] [Indexed: 12/11/2022]
Abstract
Background Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, which may result from alteration of the gastrointestinal microbiota following gastrointestinal infection, or with intestinal dysbiosis or small intestinal bacterial overgrowth. This may be treated with antibiotics, but there is concern that widespread antibiotic use might lead to antibiotic resistance. Some herbal medicines have been shown to be beneficial, but their mechanism(s) of action remain incompletely understood. To try to understand whether antibacterial properties might be involved in the efficacy of these herbal medicines, and to investigate potential new treatments for IBS, we have conducted a preliminary study in vitro to compare the antibacterial activity of the essential oils of culinary and medicinal herbs against the bacterium, Esherichia coli. Methods Essential oils were tested for their ability to inhibit E. coli growth in disc diffusion assays and in liquid culture, and to kill E. coli in a zone of clearance assay. Extracts of coriander, lemon balm and spearmint leaves were tested for their antibacterial activity in the disc diffusion assay. Disc diffusion and zone of clearance assays were analysed by two-tailed t tests whereas ANOVA was performed for the turbidometric assays. Results Most of the oils exhibited antibacterial activity in all three assays, however peppermint, lemon balm and coriander seed oils were most potent, with peppermint and coriander seed oils being more potent than the antibiotic rifaximin in the disc diffusion assay. The compounds present in these oils were identified by gas chromatography mass spectrometry. Finally, extracts were made of spearmint, lemon balm and coriander leaves with various solvents and these were tested for their antibacterial activity against E. coli in the disc diffusion assay. In each case, extracts made with ethanol and methanol exhibited potent antibacterial activity. Conclusions Many of the essential oils had antibacterial activity in the three assays, suggesting that they would be good candidates for testing in clinical trials. The observed antibacterial activity of ethanolic extracts of coriander, lemon balm and spearmint leaves suggests a mechanistic explanation for the efficacy of a mixture of coriander, lemon balm and mint extracts against IBS in a published clinical trial.
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Voinot F, Fischer C, Schmidt C, Ehret-Sabatier L, Angel F. Controlled ingestion of kaolinite (5%) modulates enteric nitrergic innervation in rats. Fundam Clin Pharmacol 2013; 28:405-13. [DOI: 10.1111/fcp.12040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 05/02/2013] [Accepted: 06/04/2013] [Indexed: 11/29/2022]
Affiliation(s)
- Florian Voinot
- Université de Strasbourg; IPHC-DEPE; 23 rue Becquerel 67087 Strasbourg France
- CNRS; UMR7178; 67037 Strasbourg France
| | - Caroline Fischer
- Université de Strasbourg; IPHC-DEPE; 23 rue Becquerel 67087 Strasbourg France
- CNRS; UMR7178; 67037 Strasbourg France
| | - Camille Schmidt
- Université de Strasbourg; IPHC-DEPE; 23 rue Becquerel 67087 Strasbourg France
- CNRS; UMR7178; 67037 Strasbourg France
| | - Laurence Ehret-Sabatier
- CNRS; UMR7178; 67037 Strasbourg France
- Université de Strasbourg; IPHC-DSA; 25 rue Becquerel 67087 Strasbourg France
| | - Fabielle Angel
- Université de Strasbourg; IPHC-DEPE; 23 rue Becquerel 67087 Strasbourg France
- CNRS; UMR7178; 67037 Strasbourg France
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Miao B, Zhang S, Wang H, Yang T, Zhou D, Wang BE. Magnolol Pretreatment Prevents Sepsis-Induced Intestinal Dysmotility by Maintaining Functional Interstitial Cells of Cajal. Inflammation 2013; 36:897-906. [DOI: 10.1007/s10753-013-9617-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Nürnberger S, Miller I, Duvigneau JC, Kavanagh ET, Gupta S, Hartl RT, Hori O, Gesslbauer B, Samali A, Kungl A, Redl H, Kozlov AV. Impairment of endoplasmic reticulum in liver as an early consequence of the systemic inflammatory response in rats. Am J Physiol Gastrointest Liver Physiol 2012; 303:G1373-83. [PMID: 23064756 DOI: 10.1152/ajpgi.00056.2012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
It is well known that systemic inflammatory response (SIR) often causes liver dysfunction. The aim of this study was to identify the intracellular compartment in the liver most susceptible to SIR. We analyzed morphology, ultrastructure, proteome, and expression of relevant genes in livers of rats subjected to endotoxic shock. Histological examination revealed that focal necrosis in liver was insignificant to explain liver dysfunction. Electron microscopy revealed no morphological changes in the mitochondrial structure and in the cytosol, but dilated endoplasmic reticulum (ER) cisterns were frequently observed. Apoptosis was found in white blood cells within liver tissue but not in hepatocytes. Mitochondrial, ER, and cytosolic fractions were subjected to proteome analysis by difference gel electrophoresis, and the protein spots with the highest degree of differential regulation were identified with mass spectrometry. The most pronounced proteome changes appeared in the ER, manifested as a remarkable downregulation of several proteins essential for ER functions, such as protein synthesis and transport, whereas the changes in mitochondrial and cytosolic fractions suggested a compensatory response. ER stress, as an underlying mechanism for ER impairment, was confirmed by analysis of upstream (splicing X-box-binding protein 1 mRNA) and downstream (e.g., 78-kDa glucose-regulated protein mRNA) markers, suggesting ongoing unresolved ER stress as a cause for ER dilation. Because ER is the intracellular compartment responsible for the major liver functions, our data suggest that inflammatory mediators induce unresolved ER stress, resulting in the biochemical, functional, and morphological impairment of ER that in turn causes liver dysfunction. The pathway activating ER stress in response to SIR is not known yet.
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Affiliation(s)
- Sylvia Nürnberger
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Allgemeine Unfallversicherungsanstalt Research Center, Vienna, Austria
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Caddell KA, Martindale R, McClave SA, Miller K. Can the intestinal dysmotility of critical illness be differentiated from postoperative ileus? Curr Gastroenterol Rep 2011; 13:358-367. [PMID: 21626118 DOI: 10.1007/s11894-011-0206-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Gastrointestinal dysmotility is commonly noted in the intensive care unit and postoperative settings. Characterized by delayed passage of stool and flatus, nausea, vomiting, and abdominal distention, the condition is associated with nutritional deficiencies, risk of aspiration, and considerable allocation of health care resources. Knowledge of gastrointestinal function in health and illness continues to expand. While the factors that precipitate ileus differ between postoperative and critically ill patients, the two clinical scenarios seem to have similar mechanisms and share many of the same pathophysiologic patterns. By reviewing and comparing the literature on the respective mechanisms and contributing factors generated in these separate clinical settings, a common more comprehensive management strategy may be derived with the potential for newer innovative therapeutic options.
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Affiliation(s)
- Kirk A Caddell
- Department of Surgery, Oregon Health and Sciences University, Portland, OR 97239-3098, USA
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Fichna J, Dicay M, Hirota SA, Traboulsi D, Macdonald JA, Janecka A, Beck PL, Zjawiony JK, Macnaughton WK, Storr MA. Differential effects of salvinorin A on endotoxin-induced hypermotility and neurogenic ion transport in mouse ileum. Neurogastroenterol Motil 2011; 23:583-e212. [PMID: 21414104 DOI: 10.1111/j.1365-2982.2011.01699.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Salvinorin A (SA) is the principal active ingredient of Salvia divinorum, with an established inhibitory action on gastrointestinal (GI) transit and colonic ion transport in mice. Under normal conditions, the effects of SA are mediated by kappa opioid (KOR) and cannabinoid (CB1 and CB2) receptors. However, the role of SA in pathophysiological conditions remains unresolved. The aim of this study was to characterize the in vitro and in vivo effects of SA on mouse ileum after endotoxin challenge. METHODS Changes in GI motility were studied in vitro, using smooth muscle preparations from the mouse ileum. In vivo, the fecal pellet output and small intestinal fluid content were measured. Neurogenic ion transport and intestinal permeability were examined using Ussing chambers. In addition, Western blot analysis of mucosa was performed and plasma nitrite/nitrate levels were determined. KEY RESULTS Salvinorin A inhibited endotoxin-induced ileal hypercontractility via KOR, CB1, and CB2 receptors. Neurogenic ion transport, which was significantly reduced after endotoxin challenge, was normalized by SA through a nitric oxide synthase (NOS)-dependent mechanism. Western blot analysis and plasma nitrite/nitrate level quantitation confirmed the involvement of NOS in the regulatory action of SA. CONCLUSIONS & INFERENCES This is the first report showing differential effects of SA on motor and secretory activity in mouse GI during endotoxemia. The outcomes of our study imply possible novel applications of SA and its analogs in the treatment of GI disorders.
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Affiliation(s)
- J Fichna
- Division of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III), University of Calgary, Calgary, AB, Canada
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De Winter BY, De Man JG. Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility. World J Gastroenterol 2010; 16:5523-5535. [PMID: 21105185 PMCID: PMC2992670 DOI: 10.3748/wjg.v16.i44.5523] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 07/30/2010] [Accepted: 08/06/2010] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system.
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Ward JL, Delano BA, Adams SD, Mercer EE, Mercer DW. Laparotomy attenuates lipopolysaccharide-induced gastric bleeding in the rat. Dig Dis Sci 2010; 55:902-10. [PMID: 19390968 DOI: 10.1007/s10620-009-0800-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2008] [Accepted: 03/17/2009] [Indexed: 12/16/2022]
Abstract
Lipopolysaccharide (LPS) increases systemic inflammation and causes duodenogastric reflux of bile and gastric bleeding. Laparotomy prevents gastric injury from the luminal irritant bile, but its effects on LPS-induced gastric injury are unknown. We hypothesized that laparotomy would diminish inflammation and attenuate gastric bleeding caused by LPS. In the rat, laparotomy, done either before or after administration of LPS, attenuated LPS-induced bile reflux, gastric bleeding, and cyclooxygenase-2, but not inducible nitric oxide synthase, expression when compared to controls given LPS. Laparotomy also blunted LPS-induced changes in serum cytokine production. These data suggest that laparotomy has gastroprotective effects by preventing LPS-induced bile reflux and gastric bleeding and by a mechanism mediated, at least in part by cyclooxygenase-2.
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Affiliation(s)
- Jeremy L Ward
- Department of Surgery, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite 4.264, Houston, TX, 77030, USA.
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Abstract
BACKGROUND Although ketamine has many beneficial effects in a rat model of noninfectious inflammation with lipopolysaccharide (LPS), its effects on gut ileus are unknown. We hypothesized that ketamine would improve LPS-induced ileus and therefore examined its effects on gastric emptying and intestinal transit as well as duodenogastric bile reflux and associated gastric bleeding. METHODS Male rats received saline or ketamine (7 mg/kg ip) 1 hour before saline or LPS (20 mg/kg ip) for 5 hours. Thirty minutes before killing, rats received orogastric rhodamine B isothiocyanate-labeled dextran and 5 minutes later fluorescein isothiocyanate-labeled dextran via a duodenal catheter. GI contents were collected for dye, bile acid, and hemoglobin (index of bleeding) determinations. RESULTS LPS significantly impaired intestinal transit and increased duodenogastric bile reflux and gastric luminal hemoglobin content. Ketamine improved intestinal transit, prevented LPS-induced bile reflux, and diminished gastric bleeding. In mechanistic studies, ketamine also attenuated LPS-induced upregulation of the proinflammatory genes inducible nitric oxide synthase and cyclo-oxygenase-2 in the stomach but preserved expression of the anti-inflammatory gene heme-oxygenase-1 (Western blot). CONCLUSIONS These data suggest that ketamine may prevent LPS-induced gastric bleeding by decreasing bile reflux through improved intestinal transit or by local changes in nitric oxide, prostaglandin, and carbon monoxide metabolism.
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Overhaus M, Toegel S, Bauer AJ. Interaction of hemorrhagic shock and subsequent polymicrobial sepsis on gastrointestinal motility. Shock 2009; 31:382-9. [PMID: 18791497 PMCID: PMC2966389 DOI: 10.1097/shk.0b013e3181862ea4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Understanding "two-hit" experimental models is crucial for the rational development of therapies for hemorrhagic shock (HS). We modeled the clinical scenario of HS followed by polymicrobial sepsis (cecal ligation and puncture [CLP]) to investigate the molecular and functional alterations that occur within the gastrointestinal tract. Control, HS, CLP, simultaneous HS + CLP, and HS + delayed CLP by 24 h groups of Sprague-Dawley rats were studied for gastrointestinal transit and in vitro colonic circular muscle contractility to bethanechol. Reverse transcription-polymerase chain reaction quantified IL-6, IL-10, and heme oxygenase 1 messenger RNA expression in the isolated colonic muscularis 6 h after insult. Myeloperoxidase-positive neutrophils were quantified in colonic muscularis whole mounts. Mortality at 24 h was significantly increased in simultaneous mild HS + CLP (88%) over control, mild HS, CLP alone, or HS + delayed CLP. Cecal ligation and puncture significantly delayed transit compared with controls and HS alone. Hemorrhagic shock + delayed CLP animals had normal transit. Colonic contractions were suppressed by 50% after CLP compared with controls and HS. In contrast, HS + delayed CLP displayed control levels of contractile responses to bethanechol. Cecal ligation and puncture and simultaneous HS + CLP caused significant inflammatory messenger RNA induction of IL-6, iNOS, IL-10, and heme oxygenase 1 compared with control and HS, and these responses were significantly suppressed in HS + delayed CLP colonic muscularis extracts. Neutrophils were significantly recruited into the colonic muscularis following CLP after 24 h compared with control and HS. This recruitment was significantly less in the HS + delayed CLP animals. These data demonstrate the ability of mild HS to precondition the animal and protect it against a delayed, but not simultaneous, polymicrobial event.
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Affiliation(s)
- Marcus Overhaus
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of General-, Visceral-, Thoracic- and Vascular Surgery, University of Bonn, Bonn, Germany
| | - Sandra Toegel
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anthony J. Bauer
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Yang TC, Zhang SW, Sun LN, Wang H, Ren AM. Magnolol attenuates sepsis-induced gastrointestinal dysmotility in rats by modulating inflammatory mediators. World J Gastroenterol 2008; 14:7353-60. [PMID: 19109869 PMCID: PMC2778119 DOI: 10.3748/wjg.14.7353] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effects of magnolol on sepsis-induced inflammation and intestinal dysmotility.
METHODS: Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS). Male Wistar rats were randomly assigned to one of three treatment groups: magnolol prior to LPS injection (LPS/Mag group); vehicle prior to LPS injection (LPS/Veh group); vehicle prior to injection of saline (Control/Veh). Intestinal transit and circular muscle mechanical activity were assessed 12 h after LPS injection. Tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) mRNA in rat ileum were studied by RT-PCR 2 h after LPS injection. Nuclear factor-κB (NF-κB) activity in the intestine was also investigated at this time using electrophoretic mobility shift assay. In addition, antioxidant activity was determined by measuring malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity in the intestine 2 h after LPS injection.
RESULTS: Magnolol significantly increased intestinal transit and circular muscle mechanical activity in LPS-treated animals. TNF-α, MCP-1 and iNOS mRNA expression in the small intestine were significantly reduced after magnolol treatment in LPS-induced septic animals, compared with untreated septic animals. Additionally, magnolol significantly increased IL-10 mRNA expression in septic rat ileum. Magnolol also significantly suppressed NF-κB activity in septic rat intestine. In addition, magnolol significantly decreased MDA concentration and increased SOD activity in rat ileum.
CONCLUSION: Magnolol prevents sepsis-induced suppression of intestinal motility in rats. The potential mechanism of this benefit of magnolol appears to be modulation of self-amplified inflammatory events and block of oxidative stress in the intestine.
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Pathophysiology of LPS-induced gastrointestinal injury in the rat: role of secretory phospholipase A2. Shock 2008; 30:206-11. [PMID: 18180698 DOI: 10.1097/shk.0b013e318160f47f] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A hydrophobic layer of phosphatidylcholine (PC) overlies and protects the surface of the gastrointestinal (GI) tract, contributing to barrier integrity. During critical illness such as sepsis, gut barrier integrity is compromised, which could be related to degradation of PC. The purpose of this study was to investigate a role for luminal (secretory) phospholipase A2 (sPLA(2)) in LPS-induced GI injury. Rats were treated with LPS (5 mg/kg) or saline for 0.5, 1, 3, and 5 h. The gastric and ileal luminal contents were collected for determination of sPLA(2) activity, and the luminal lipids were analyzed using thin layer chromatography for lyso-PC content. The GI permeability was assessed in vivo with fluorescein-isothiocyanate dextran 4000 and rats were tested with or without a specific sPLA(2) inhibitor. LPS induced significant increases in sPLA(2) activity and lyso-PC content in the gastric and ileal lumens at 5 h. In addition, LPS treated rats showed a significant increase in GI permeability to fluorescein-isothiocyanate dextran in both the stomach and ileum at 5 h, which was prevented by pretreatment with the sPLA(2) inhibitor. In response to LPS, sPLA(2) activity increases in the GI tract lumen where it may degrade the extracellular protective phospholipid layer and membranes, producing injurious lyso-PC and increased GI permeability. Pretreatment with an orally active sPLA(2) inhibitor blocks the LPS-induced increase in GI permeability, and may suggest a new approach to fortify the GI mucosal barrier and prevent complications from endotoxin in trauma and other patients.
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van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, van Roon EN, Zandstra DF, van der Voort PHJ. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med 2007; 35:2726-31. [PMID: 17893628 DOI: 10.1097/01.ccm.0000287526.08794.29] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To study whether lactulose or polyethylene glycol is effective to promote defecation in critically ill patients, whether either of the two is superior, and whether the use of enteral laxatives is related to clinical outcome. DESIGN Double-blind, placebo-controlled, randomized study. SETTING Two tertiary intensive care units. PATIENTS Three hundred and eight consecutive patients with multiple organ failure were included when receiving mechanical ventilation and intravenous circulatory support and when defecation did not occur on day 3 after admission. INTERVENTIONS Thrice daily administration of lactulose, polyethylene glycol, or placebo until defecation occurred, to a maximum of 4 days. MEASUREMENTS AND MAIN RESULTS The number of patients with defecation during the study period was 32 of 103 (31%) for placebo, 76 of 110 (69%) for lactulose, and 70 of 95 (74%) for polyethylene glycol (p = .001 for lactulose and polyethylene glycol vs. placebo). Lactulose and polyethylene glycol-treated patients produced stools after a median of 36 and 44 hrs, respectively, compared with 75 hrs for the placebo group (p = .001 for lactulose and polyethylene glycol vs. placebo). Length of stay in the intensive care unit was a median of 156 hrs for the lactulose group, 190 hrs for the polyethylene glycol group, and 196 hrs for the placebo group (p = .001). Intestinal pseudoobstruction or Ogilvie's syndrome occurred in 4.1% of patients in the placebo group, 5.5% of patients in the lactulose group, and 1.0% of patients in the polyethylene glycol group. There was no difference in hospital mortality. Administration of morphine was associated with a longer time before first defecation, except in the polyethylene glycol group. For all groups, defecation within 6 days after admission was associated with a shorter length of stay. CONCLUSIONS Both lactulose and polyethylene glycol are more effective in promoting defecation than placebo. Patients receiving polyethylene glycol had a slightly lower incidence of acute intestinal pseudoobstruction, whereas length of stay was shorter in lactulose-treated patients. Morphine administration was associated with delayed defecation except in the polyethylene glycol-treated group. Irrespective of study medication, early defecation was associated with a shorter length of stay.
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Affiliation(s)
- Johan I van der Spoel
- Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
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27
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Laxation of critically ill patients with lactulose or polyethylene glycol: A two-center randomized, double-blind, placebo-controlled trial *. Crit Care Med 2007. [DOI: 10.1097/00003246-200712000-00009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Alterations in spontaneous contractions of rat ileum and jejunum after peritonitis. Eur J Pharmacol 2007; 580:250-5. [PMID: 18029280 DOI: 10.1016/j.ejphar.2007.10.064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2007] [Revised: 10/17/2007] [Accepted: 10/22/2007] [Indexed: 11/23/2022]
Abstract
The aim of this study was to investigate the effects of peritonitis on spontaneous contractions of ileum and jejunum smooth muscles isolated from rats. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another group of 8 rats underwent a sham operation and acted as controls. Twenty-four hours after the operation, the rats were killed, and their ileum and jejunum smooth muscles were excised and placed in circular muscle direction in a 10 ml organ bath. Changes in the amplitude and frequency of spontaneous contractions were analyzed before and after the addition of different antagonists. Peritonitis induced the decrease in the amplitude and frequency of spontaneous contractions in ileum and jejunum smooth muscles. In control groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly elevated in the presence of N(G)-nitro-L-arginine (L-NNA) and indomethacin. In peritonitis groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly enhanced in the presence of L-NNA, aminoguanidine, indomethacin and celecoxib compared to control values. In conclusion, peritonitis induces the decrease in the amplitude and frequency of spontaneous contractions of ileum and jejunum that can be attributed to the rise of nitric oxide synthase and cyclooxygenase isoforms levels.
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Talukder MJR, Harada E. Bovine lactoferrin protects lipopolysaccharide-induced diarrhea modulating nitric oxide and prostaglandin E2 in mice. Can J Physiol Pharmacol 2007; 85:200-8. [PMID: 17487261 DOI: 10.1139/y07-004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Lactoferrin (Lf), an iron-binding multifunctional glycoprotein, is abundantly present in colostrum and milk of different species such as humans, bovines, and mice. Our previous observation revealed that bovine colostral Lf is transported into the systemic circulation and cerebrospinal fluid from gut-lumen through receptor-mediated transcytosis in calves. Diarrhea caused by Escherichia coli is one of the important causes of infant morbidity and mortality in developing countries. We investigated the effects of bovine lactoferrin (BLf) on lipopolysaccharide (LPS)-induced diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content in mice. LPS accumulated abundant fluid in the small intestine in a dose-dependent manner, induced diarrhea, but decreased the GIT. Pretreatment with BLf significantly attenuated the effects of LPS on the diarrheogenic activity and intestinal content, but reversed the GIT when compared with NG-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis). Both plasma NO and PGE2 in enterocytes were found to increase in LPS-treated mice and were reversed by BLf. These findings demonstrate that the action of BLf against LPS was specific and it exerts antidiarrheal activity through modulating the cyclooxygenase [NO and PGE2] pathway in the gut.
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Affiliation(s)
- M Jamilur R Talukder
- Department of Physiology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh.
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Chen CF, Leu FJ, Chen HI, Wang D, Chou SJ. Ischemia/Reperfusion-Induced Low Reactivity of the Rat Superior Mesenteric Vascular Bed is Associated With Expression of Nitric Oxide Synthases. Transplant Proc 2006; 38:2216-20. [PMID: 16980047 DOI: 10.1016/j.transproceed.2006.07.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
UNLABELLED Our objective was to investigate the mRNA and protein expressions of eNOS and iNOS in the mesenteric vascular bed after ischemia and reperfusion of the rat superior mesenteric artery (SMA) and the role of nitric oxide (NO) in the response of the vascular bed to vasoconstrictors following reperfusion of the SMA. METHODS Real-time polymerase chain reaction and immunohistochemistry were used to monitor the mRNA and protein expression of eNOS and iNOS after I/R challenge to the rat SMA. Ischemia was induced by clamping the SMA for 40 minutes, after which the flow was restored and the vessels were reperfused for 300 minutes. Blood samples were collected for assays of lactic dehydrogenase, tumor necrosis factor (TNF), hydroxyl radical, and NO. After ischemia/reperfusion, the vascular beds were separated for analysis of the expression of eNOS and iNOS. The SMA with its associated intestinal tissue was isolated and perfused in vitro with Tyrode's solution (N = 8) then challenged with phenylephrine. RESULTS Reperfusion of the SMA induced an increase in blood concentrations of lactic dehydrogenase (P < .001; N = 8), hydroxyl radical (P < .05), TNF (P < .001), and NO (P < .05). ENOS and iNOS mRNA expression increased 1.3 +/- 0.1-fold and 19.6 +/- 3.5-fold, respectively when compared to the sham-operated group. Protein expression increased 1.9 +/- 0.4-fold and 12.6 +/- 3.1-fold, respectively, after reperfusion (N = 3) when compared with sham-treated rats. In vitro challenge showed that administration of phenylephrine (10(-8) approximately 10(-4) nmol) produced vasoconstriction in a dose-related manner. Maximum contractile responses to phenylephrine were attenuated in reperfused SMA. Addition of the NOS inhibitor N(G)-nitro-L-arginine (L-NNA, 10(-4) M) resulted in full recovery of the response to phenylephrine. CONCLUSIONS Ischemia/reperfusion of the SMA results in a decrease in vascular reactivity of the mesenteric vessels that is dependent on NOS expression by the intestinal vascular bed.
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Affiliation(s)
- C F Chen
- Division of Gastroenterology, Department of Internal Medicine, Cheng Hsin General Hospital, and School of Health, Ming Chuan University, Taipei, Taiwan
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31
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Martinez V, Wang L, Taché Y. Peripheral adrenomedullin inhibits gastric emptying through CGRP8-37 -sensitive receptors and prostaglandins pathways in rats. Peptides 2006; 27:1376-82. [PMID: 16337713 DOI: 10.1016/j.peptides.2005.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2005] [Revised: 11/04/2005] [Accepted: 11/04/2005] [Indexed: 11/24/2022]
Abstract
The effects of intravenous (iv) adrenomedullin (AM) on gastric emptying were investigated in conscious rats. AM induced a maximal 50% inhibition of gastric emptying at a dose of 1.2 nmol/kg. AM was about two-fold less potent than alpha-calcitonin gene-related peptide (alpha-CGRP), which induced a similar 50% maximal inhibition of gastric emptying at 0.6 nmol/kg. Delayed gastric emptying induced by i.v. AM and alpha-CGRP was prevented by peripheral injection of the selective CGRP1 antagonist, CGRP8-37, and by pretreatment with indomethacin, while not altered by blockade of the sympathetic nervous system with propranolol. These data indicate that peripheral AM inhibits gastric emptying through the interaction with CGRP8-37 -sensitive receptors, likely CGRP1 receptors, and the recruitment of prostaglandin-dependent mechanisms.
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Affiliation(s)
- V Martinez
- CURE: Digestive Diseases Research Center, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
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Sun Y, Liu J, Qian F, Xu Q. Nitric oxide inhibits T cell adhesion and migration by down-regulation of β1-integrin expression in immunologically liver-injured mice. Int Immunopharmacol 2006; 6:616-26. [PMID: 16504925 DOI: 10.1016/j.intimp.2005.09.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Revised: 06/16/2005] [Accepted: 09/23/2005] [Indexed: 11/23/2022]
Abstract
Our previous study has reported that nitric oxide (NO) exerts a protective role in immunologically liver-injured mice induced by delayed-type hypersensitivity to picryl chloride. To explore the mechanism of the protection, we have now examined the effect of NO on T cell adhesion and migration. First, we isolated hepatocytes and nonparenchymal cells from the liver-injured mice and separated the nonparenchymal cells into Kupffer cell-enriched and lymphocyte-enriched populations. When these hepatocytes or the fractions of nonparenchymal cells were co-cultured with spleen T cells of the liver-injured mice in a Transwell system, the adhesive potential of the T cells was significantly inhibited in the presence of hepatocytes or the Kupffer cell-enriched population but not the lymphocyte-enriched population of nonparenchymal cells. This effect was dependent on NO production. The NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) could reverse this inhibition of cell adhesion and also decrease NO production. To confirm this effect of NO on T cells, we further examined the role of exogenous or endogenous NO on the adhesive activity of the Jurkat T cell line. As a result, the NO donor, S-nitroso-N-acetyl penicillamine (SNAP) caused a dose-dependent inhibition of the adhesion of Jurkat T cells. Furthermore, the binding ability of Jurkat T cells to collagen decreased gradually after co-incubation with macrophages stimulated by LPS+IFN-gamma, an effect which correlated well with the increasing NO level in the medium. Such opposite changes in cell adhesion and in NO production were also markedly reversed by L-NMMA. Moreover, treatment with SNAP reduced adhesion, transmigration, matrix metalloproteinase-9 production and beta1-integrin expression of spleen T cells of the liver-injured mice. Taken together, these findings suggest that NO can function as a down-regulator of T cell mobility, which might be one of the mechanisms by which NO exerts its protective effect in T cell-mediated liver injury.
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Affiliation(s)
- Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China
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33
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Barbara G, Stanghellini V, Brandi G, Cremon C, Di Nardo G, De Giorgio R, Corinaldesi R. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol 2005; 100:2560-2568. [PMID: 16279914 DOI: 10.1111/j.1572-0241.2005.00230.x] [Citation(s) in RCA: 206] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Commensal bacteria inhabiting the human intestine (i.e., intestinal microflora) participate in the development and maintenance of gut sensory and motor functions, including the promotion of intestinal propulsive activity. On the other hand, intestinal motility represents one of the major control systems of gut microflora, through the sweeping of excessive bacteria from the lumen. There is emerging evidence indicating that changes in this bidirectional interplay contribute to the pathogenesis of gut diseases, such as small intestinal bacterial overgrowth and intestinal pseudo-obstruction. Recent interest has also been directed to the potential role of intestinal microflora in the pathogenesis of the irritable bowel syndrome. Although the status of intestinal microflora in the irritable bowel syndrome remains unsettled, small intestinal bacterial overgrowth (as detected with breath testing) and increased fermentation of foods with gas production, provide indirect evidence that microflora may contribute to symptom generation in irritable bowel syndrome. The potential benefit of antibiotic and probiotic therapy is currently under investigation and opens new perspectives in irritable bowel syndrome treatment.
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Affiliation(s)
- Giovanni Barbara
- Department of Internal Medicine and Gastroenterology, Univeristy of Bologna, Bologna, Italy
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34
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Liang YC, Liu HJ, Chen SH, Chen CC, Chou LS, Tsai LH. Effect of lipopolysaccharide on diarrhea and gastrointestinal transit in mice: Roles of nitric oxide and prostaglandin E 2. World J Gastroenterol 2005; 11:357-61. [PMID: 15637744 PMCID: PMC4205337 DOI: 10.3748/wjg.v11.i3.357] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of lipopolysaccharide (LPS) on the diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content and the possible role of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastrointestinal functions of endotoxin-treated mice.
METHODS: Diarrheogic activity, GIT, and intestinal fluid content as well as nitric oxide and PGE2 products were measured after intraperitoneal administration of LPS in mice.
RESULTS: LPS dose-dependently accumulated abundant fluid into the small intestine, induced diarrhea, but decreased the GIT. Both nitric oxide and PGE2 were found to increase in LPS-treated mice. Western blot analysis indicated that LPS significantly induced the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 in mice intestines. Pretreatment with NG-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis) significantly attenuated the effects of LPS on the diarrheogenic activity and intestine content, but reversed the GIT.
CONCLUSION: The present study suggests that the pathogenesis of LPS treatment may mediate the stimulatory effect of LPS on nitric oxide and PGE2 production and NO/prostaglandin pathway may play an important role on gastrointestinal function.
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Affiliation(s)
- Yu-Chih Liang
- Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan, China
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Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharmacol 2004; 142:1247-54. [PMID: 15249429 PMCID: PMC1575196 DOI: 10.1038/sj.bjp.0705889] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The biological effects of cannabinoids (CB) are mediated by CB(1) and CB(2) receptors. The role of CB(2) receptors in the gastrointestinal tract is uncertain. In this study, we examined whether CB(2) receptor activation is involved in the regulation of gastrointestinal transit in rats. Basal and lipopolysaccharide (LPS)-stimulated gastrointestinal transit was measured after instillation of an Evans blue-gum Arabic suspension into the stomach, in the presence of specific CB(1) and CB(2) agonists and antagonists, or after treatment with inhibitors of mediators implicated in the transit process. In control rats a CB(1) (ACEA; 1 mg kg(-1)), but not a CB(2) (JWH-133; 1 mg kg(-1)), receptor agonist inhibited basal gastrointestinal transit. The effects of the CB(1) agonist were reversed by the CB(1) antagonist AM-251, which alone increased basal transit. LPS treatment increased gastrointestinal transit. This increased transit was reduced to control values by the CB(2), but not the CB(1), agonist. This inhibition by the CB(2) agonist was dose dependent and prevented by a selective CB(2) antagonist (AM-630; 1 mg kg(-1)). By evaluating the inhibition of LPS-enhanced gastrointestinal transit by different antagonists, the effects of the CB(2) agonist (JWH-133; 1 mg kg(-1)) were found to act via cyclooxygenase, and to act independently of inducible nitric oxide synthase (NOS) and platelet-activating factor. Interleukin-1 beta and constitutive NOS isoforms may be involved in the accelerated LPS transit. The activation of CB(2) receptors in response to LPS is a mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus.
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Affiliation(s)
- Ronald Mathison
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Winnie Ho
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Quentin J Pittman
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Joseph S Davison
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Author for correspondence:
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Tanabe Y, Calland JF, Schirmer BD. Effects of peritoneal injury and endotoxin on myoelectric activity and transit. J Surg Res 2004; 116:330-6. [PMID: 15013373 DOI: 10.1016/j.jss.2003.08.234] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2003] [Indexed: 11/17/2022]
Abstract
BACKGROUND The combined effects of peritoneal injury and intraabdominal infection on gastrointestinal motility in postoperative ileus are poorly understood MATERIALS AND METHODS Sprague Dawley rats underwent placement of three electrodes on the small intestine and a tube gastrostomy. Animals were divided into four groups: a control (n = 12), a peritoneal injury (PI, n = 12), a peritoneal injection of lipopolysaccharide (LPS, n = 12), and a LPS + PI group (n = 12). After myoelectric activity recording on postoperative day (POD) 1, half of the rats in each group underwent intestinal transit studies. The remainder of the rats underwent another myoelectric activity recording as well as intestinal transit study at 48 h after operation RESULTS Although six to eight of rats in the control, PI, and LPS groups recovered migrating myoelectric complex (MMC) on POD 1, no rats in the LPS + PI group recovered MMC by POD 1. The transit distance on POD 1 in the PI (36 +/- 2.5 cm) and LPS + PI group (38 +/- 2.8 cm) was shorter than that in the control group (53 +/- 2.0 cm, P < 0.05) CONCLUSIONS Full recovery of liquid intestinal transit precedes the return of MMC activity after abdominal surgery in the rats. Peritoneal injury causes decreased intestinal transit and when combined with intraabdominal injection of LPS may cause the delayed recovery of MMC activity.
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Affiliation(s)
- Yoshitaka Tanabe
- Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0709, USA
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CEREGRZYN M, KUWAHARA A. The effect of epigallocatechin gallate on intestinal motility in normal and endotoxemic mice. Biomed Res 2004. [DOI: 10.2220/biomedres.25.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Rebollar E, Guerrero-Lindner E, Arruebo MP, Plaza MA, Murillo MD. Role of prostaglandins in lipopolysaccharide effects on K+-induced contractions in rabbit small intestine. ACTA PHYSIOLOGICA SCANDINAVICA 2003; 179:299-307. [PMID: 14616246 DOI: 10.1046/j.0001-6772.2003.01189.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM The mediators of the pathophysiologcal symptoms of septic shock are not completely understood. The aim of this work was to investigate the effect of lipopolysaccharide (LPS) on the K+-induced response of longitudinal segments of rabbit small intestine in vitro and the possible role of prostaglandins. METHODS AND RESULTS Rabbits were treated with intravenously injected LPS. After 90 min animals were killed and intestinal segments were mounted in an organ bath. Lipopolysaccharide (0.2 microg kg-1) inhibited K+-induced contractions (60 mm) by 68% in duodenum, 58% in jejunum and 52% in ileum. Indomethacin antagonized LPS actions when injected 15 min before LPS. PGE2 reduced K+-induced contractions, imitating LPS effects. In contrast, contractions induced by K+ increased when intestinal segments were incubated in vitro with LPS for 90 min. The LPS (0.3 microg mL-1) increased K+-induced contractions (60 mm) by 46% in duodenum, 63% in jejunum and 85% in ileum. The LPS effect was antagonized by indomethacin at 10-6 m in duodenum and jejunum and at 10-8 m in ileum. PGE2 evoked dose-dependent contractions when added to the bath in duodenum, jejunum and ileum. CONCLUSION These results suggest that effect of LPS on K+-induced contractions in the rabbit small bowel may be mediated by prostaglandin E2.
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Affiliation(s)
- E Rebollar
- Departamento de Farmacología y Fisiología (Fisiología), Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
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Guerrero-Lindner E, Castro M, Muñoz JM, Arruebo MP, Murillo MD, Buéno L, Plaza MA. Central tumour necrosis factor-alpha mediates the early gastrointestinal motor disturbances induced by lipopolysaccharide in sheep. Neurogastroenterol Motil 2003; 15:307-16. [PMID: 12787340 DOI: 10.1046/j.1365-2982.2003.00402.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cytokines are involved in fever and other symptoms of the acute phase response induced by endotoxins. The aim of this work was to study the involvement of central tumour necrosis factor-alpha (TNF-alpha) in the changes induced by lipopolysaccharide (LPS) on gastrointestinal (GI) motility in sheep. Body temperature and myoelectric activity of the antrum, duodenum and jejunum was recorded continuously. Intravenous (i.v.) administration of LPS (0.1 micro g kg-1)-induced hyperthermia, decreased gastrointestinal myoelectric activity and increased the frequency of the migrating motor complex (MMC). These effects started 40-50 min after LPS and lasted for 6-7 h. TNF-alpha (50 and 100 ng kg-1) mimicked these effects when injected intracerebroventricularly (i.c.v.) but not i.v. Pretreatment with soluble recombinant TNF receptor (TNFR:Fc, 10 micro g kg-1, i.c.v.) abolished the TNF-induced actions and reduced those evoked by LPS. Furthermore, the effects induced by either LPS or TNF were suppressed by prior i.c.v. injection of indomethacin (100 micro g kg-1). In contrast, the i.v. injections of TNFR:Fc or indomethacin were ineffective. Our data suggest that LPS disturbs GI motility in sheep through a central pathway that involves TNF-alpha and prostaglandins sequentially.
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Affiliation(s)
- E Guerrero-Lindner
- Department of Pharmacology and Physiology, Veterinary Faculty, University of Zaragoza, Zaragoza, Spain
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Bruins MJ, Luiking YC, Soeters PB, Akkermans LMA, Deutz NEP. Effect of prolonged hyperdynamic endotoxemia on jejunal motility in fasted and enterally fed pigs. Ann Surg 2003; 237:44-51. [PMID: 12496529 PMCID: PMC1513961 DOI: 10.1097/00000658-200301000-00007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To determine the effects of hyperdynamic endotoxemia on the motility of the small intestine. SUMMARY BACKGROUND DATA Motility disorders of the gastrointestinal tract are a common complication of sepsis. It has been suggested that gram-negative endotoxin plays a role in the pathogenesis of the accompanying diarrhea frequently observed. METHODS Pigs were infused with lipopolysaccharide for a 24-hour period. During this fasting period jejunal motility was measured using ambulatory manometry. One and 4 days after cessation of endotoxin, pigs were enterally fed, and again motility was recorded. RESULTS Hyperdynamic endotoxemia was achieved in this model. Manometric pressure recordings revealed that endotoxin infusion accelerated the migrating motor complex (MMC) migration along the jejunum. Also, a simultaneous increase in MMC cycling frequency was observed in the endotoxin-treated group. Elevated MMC migration velocity and cycling frequency were maintained the following day after endotoxin during feeding and returned to basal values 4 days after endotoxin. CONCLUSIONS A small dose of continuously infused endotoxin significantly provokes jejunal motility disturbances that may contribute to diarrhea.
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Affiliation(s)
- Maaike J Bruins
- Department of Surgery, Maastricht University, Maastricht, The Netherlands.
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Calatayud S, García-Zaragozá E, Hernández C, Quintana E, Felipo V, Esplugues JV, Barrachina MD. Downregulation of nNOS and synthesis of PGs associated with endotoxin-induced delay in gastric emptying. Am J Physiol Gastrointest Liver Physiol 2002; 283:G1360-7. [PMID: 12433667 DOI: 10.1152/ajpgi.00168.2002] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A single intraperitoneal injection of endotoxin (40 microg/kg) significantly delayed gastric emptying of a solid nutrient meal. Blockade of nitric oxide synthase (NOS) with 30 mg/kg ip N(G)-nitro-L-arginine methyl ester or 20 mg/kg ip 7-nitroindazole [neuronal NOS (nNOS) inhibitor] significantly delayed gastric emptying in control animals but failed to modify gastric emptying in endotoxin-treated rats. Administration of 2.5, 5, and 10 mg/kg ip N(6)-iminoethyl-L-lysine [inducible NOS (iNOS) inhibitor] had no effect in either experimental group. Indomethacin (5 mg/kg sc), NS-398 (cyclooxygenase-2 inhibitor; 10 mg/kg ip), and dexamethasone (10 mg/kg sc) but not quinacrine (20 mg/kg ip) significantly prevented delay in gastric emptying induced by endotoxin but failed to modify gastric emptying in vehicle-treated animals. Ca(2+)-dependent NOS activity in the antrum pylorus of the stomach was diminished by endotoxin, whereas Ca(2+)-independent NOS activity was not changed. In addition, decreased nNOS mRNA and protein were observed in the antrum pylorus of endotoxin-treated rats. Our results suggest that downregulation of nNOS in the antrum pylorus of the stomach and synthesis of prostaglandins mediate the delay in gastric emptying of a solid nutrient meal induced by endotoxin.
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Affiliation(s)
- Sara Calatayud
- Unidad Mixta de Investigación, Hospital Clínico/Universidad de Valencia, Spain
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42
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Rebollar E, Arruebo MP, Plaza MA, Murillo MD. Effect of lipopolysaccharide on rabbit small intestine muscle contractility in vitro: role of prostaglandins. Neurogastroenterol Motil 2002; 14:633-42. [PMID: 12464085 DOI: 10.1046/j.1365-2982.2002.00364.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) on spontaneous contractions and acetylcholine (ACh) induced contractions of rabbit intestinal segments in vitro, with two different protocols: intestinal segments isolated from LPS-treated rabbits and intestinal segments incubated with LPS. The frequency of spontaneous movements decreased significantly in LPS-treated rabbits at 2 microg kg-1 in the duodenum and 20 microg kg-1 in the duodenum, jejunum and ileum. LPS (0.2 microg kg-1) reduced significantly the ACh contractions (10-6 mol L-1) in the duodenum (61%), jejunum (48%) and ileum (21%). Indomethacin (1, 5 and 10 mg kg-1) administered 15 min before LPS (0.2 microg kg-1) antagonized the LPS effects on the ACh-induced contractions. Prostaglandin (PG)E2 (8 microg kg-1) inhibited significantly the frequency of spontaneous contractions in the ileum and reduced the ACh-induced contractions in the three segments, mimicking the LPS effects. The amplitude and frequency of contractions in rabbit intestinal segments previously incubated with LPS (0.03, 0.3, 3 and 30 microg mL-1) were not modified with respect to the control. The ACh-induced contractions (10-4 mol L-1) were significantly reduced after 90 min of incubation with LPS. The inhibition of LPS (0.3 microg mL-1) was 43% in the duodenum, 35% in the jejunum and 17% in the ileum. Indomethacin added before LPS blocked the effect of LPS on the ACh-induced contractions in the duodenum, jejunum and ileum. These results show that LPS decreases intestinal contractility in rabbits and suggest that PGs are implicated in these actions.
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Affiliation(s)
- E Rebollar
- Pharmacology and Physiology Department (Physiology), Veterinary Faculty, Zaragoza University, Spain
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Bruins MJ, Lamers WH, Meijer AJ, Soeters PB, Deutz NEP. In vivo measurement of nitric oxide production in porcine gut, liver and muscle during hyperdynamic endotoxaemia. Br J Pharmacol 2002; 137:1225-36. [PMID: 12466232 PMCID: PMC1573617 DOI: 10.1038/sj.bjp.0704993] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2002] [Accepted: 09/17/2002] [Indexed: 10/27/2022] Open
Abstract
1. During prolonged endotoxaemia, an increase in arginine catabolism may result in limiting substrate availability for nitric oxide (NO) production. These effects were quantitated in a chronically instrumented porcine endotoxaemia model. 2. Ten days prior to the beginning of the experiments, pigs were catheterized. On day 0, pigs received a continuous infusion of endotoxin (3 microg kg(-1) h(-1)) over 24 h and were saline resuscitated. Blood was drawn from the catheters at 0 and 24 h during primed-infusion of (15)N(2)-arginine and P-aminohippurate to assess (15)N(2)-arginine to (15)N-citrulline conversion and plasma flow rates, respectively, across the portal-drained viscera, liver and hindquarter. 3. During endotoxin infusion a hyperdynamic circulation with elevated heart rate, cardiac index and decreased mean arterial pressure was achieved, characteristic of the human septic condition. 4. Endotoxin induced NO production by the portal-drained viscera and the liver. The increased NO production was quantitatively matched by an increase in arginine disposal. Nitrite/nitrate levels remained unchanged during endotoxaemia. 5. Despite an increased arginine production from the hindquarter and an increased whole-body arginine appearance rate during endotoxin infusion, the plasma arginine concentration was lower in endotoxin-treated animals than in controls. 6 On a whole-body level, the muscle was found to serve as a major arginine supplier and, considering the lowered arginine plasma levels, seems critical in providing arginine as precursor for NO synthesis in the splanchnic region.
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Affiliation(s)
- Maaike J Bruins
- Department of Surgery, Maastricht University, Maastricht, The Netherlands.
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Schwarz NT, Engel B, Eskandari MK, Kalff JC, Grandis JR, Bauer AJ. Lipopolysaccharide preconditioning and cross-tolerance: the induction of protective mechanisms for rat intestinal ileus. Gastroenterology 2002; 123:586-98. [PMID: 12145811 DOI: 10.1053/gast.2002.34777] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND & AIMS Endotoxin elicits an inflammatory response within the intestinal muscularis and causes intestinal muscle dysfunction. Our aims were to investigate intestinal muscle recovery after a single or repeated lipopolysaccharide (LPS) injections. We also investigated the ability of LPS to induce cross-tolerance to postoperative ileus. METHODS Motility was measured in vivo and in vitro by transit and organ-bath techniques. Nuclear factor kappa-B, nuclear factor interleukin 6, and signal transducer and activator of transcription were quantified by using electrophoretic mobility shift assay, and tumor necrosis factor alpha, interleukin 6, inducible nitric oxide synthase, and cyclooxygenase 2 were measured with reverse-transcription polymerase chain reaction. Myeloperoxidase histochemistry for neutrophils was performed in jejunal muscularis whole mounts. RESULTS Endotoxin-induced suppression of in vitro muscle contractility temporally recovered over 7 days with a similar profile whether after a single dose or during the continuous daily injection of LPS. Functional adaptation to continuous LPS was reflected in a significant blunting of transcription factor activation and cytokine messenger RNA up-regulation compared with the naive LPS-stimulated muscularis. Preconditioning of the muscularis showed significant cross-tolerance to the functional, molecular, and leukocytic sequelae of intestinal manipulation. CONCLUSIONS The muscularis externa recovered and developed tolerance to endotoxin over 7 days, which conferred cross-tolerance to intestinal manipulation. Thus, preconditioning induces protective mechanisms to a subsequent insult within the muscularis externa.
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Affiliation(s)
- Nicolas T Schwarz
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA
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Dial EJ, Romero JJ, Villa X, Mercer DW, Lichtenberger LM. Lipopolysaccharide-induced gastrointestinal injury in rats: role of surface hydrophobicity and bile salts. Shock 2002; 17:77-80. [PMID: 11795673 DOI: 10.1097/00024382-200201000-00013] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Sepsis of gastrointestinal origin can lead to life-threatening complications in vital organs due to bacterial overgrowth and/or translocation from the lumen into the blood. In a rat model of endotoxemia, changes in surface hydrophobicity (associated with barrier integrity) of the gastrointestinal mucosa were examined. Rats were treated with Escherichia coli lipopolysaccharide (LPS), and gastric and ileal tissue were collected for determination of surface hydrophobicity by contact angle analysis. A role for bile salts in hydrophobicity changes was tested by quantifying bile salts in the lumen of both the stomach and ileum after LPS and by the administration of LPS to bile duct-ligated rats. A single intraperitoneal dose of LPS induced a dose- and time-dependent reduction in hydrophobicity of both the stomach and ileum, with the stomach showing greater sensitivity at an earlier time than the ileum. LPS also induced gastric bleeding, reflux of bile acid into the gastric lumen, and decreased levels of bile salt in the ileum. The LPS-induced reductions in surface hydrophobicity of the stomach were prevented by prior bile duct ligation. We conclude that LPS disrupts gastrointestinal barrier integrity, in part by mechanisms involving bile constituents and an attenuation in the mucosa's hydrophobic characteristics.
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Affiliation(s)
- Elizabeth J Dial
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston Medical School, 77225, USA
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Malone ED, Kannan MS. Effects of intestinal ischemia on in vitro activity of adjacent jejunum in samples obtained from ponies. Am J Vet Res 2001; 62:1973-8. [PMID: 11763191 DOI: 10.2460/ajvr.2001.62.1973] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To determine whether intestinal ischemia would alter activity of the jejunum in vitro or alter staining characteristics for certain types of enteric neurotransmitters. SAMPLE POPULATION Jejunal samples obtained from 10 ponies. PROCEDURE Jejunal samples were obtained from locations proximal and distal to an area of small intestine made ischemic for 60 minutes. A portion of each sample was stained to detect substance P-like immunoreactivity, cholinergic and adrenergic neurons, and nitric oxide synthase. Portions of the remaining samples were suspended in muscle baths. General activity patterns (frequency and amplitude of contraction), responses to neuronal depolarization induced by electrical field stimulation (EFS), and responses to 1 microM norepinephrine (NE) were compared with responses of a normal section of small intestine obtained prior to ischemic insult. RESULTS Staining patterns were not altered. Proximal and distal sections had evidence of decreased contractility, compared with the normal section. Contraction frequency also was decreased, and distal sections had lower contraction frequency than proximal sections. Relaxation responses were decreased in distal sections. Responses to NE differed significantly for distal and proximal sections, compared with normal sections. CONCLUSIONS AND CLINICAL RELEVANCE Short-term ischemia can significantly affect adjacent bowel. Contractile and relaxation responses are impaired. Discrepancies in intestinal motility patterns and alterations in response to NE for sections proximal and distal to ischemic intestine could lead to clinical ileus or slowed transit of ingesta.
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Affiliation(s)
- E D Malone
- Department of Clinical and Population Sciences, College of Veterinary Medicine, University of Minnesota, St Paul 55108, USA
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Ceregrzyn M, Kamata T, Yajima T, Kuwahara A. Biphasic alterations in gastrointestinal transit following endotoxaemia in mice. Neurogastroenterol Motil 2001; 13:605-13. [PMID: 11903922 DOI: 10.1046/j.1365-2982.2001.00291.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Lipopolysaccharide (LPS)-induced alterations of gastrointestinal transit were studied in mice using activated charcoal. LPS (10 mg kg-1) induced biphasic alterations of intestinal transit. Increase (acceleration phase) and delay (lag phase) in gastrointestinal transit were observed at 90 and 480 min after LPS injection, respectively. LPS administration induced significant increases in tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and nitrate levels in blood serum with maximal levels observed at 1.5, 4, and 8 h after LPS administration, respectively. The effects of recombinant human lzactoferrin (rhLF) on LPS- induced alteration of gastrointestinal transit, and production of TNF-alpha, IL-1beta and nitrate were also studied. Animals were pretreated with rhLF 24 hours before intraperitoneal administration of LPS. RhLF significantly increased gastrointestinal transit during the lag phase. In addition, rhLF decreased the level of TNF-alpha in endotoxaemic animals. The levels of IL-1beta and nitrate were not significantly changed by rhLF. In conclusion, the effect of LPS on gastrointestinal transit is biphasic and the mechanism controlling the second phase most likely depends on TNF-alpha production, while the first phase most likely does not depend on TNF-alpha. On the other hand, it may be regulated by IL-1beta and nitric oxide production.
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Affiliation(s)
- M Ceregrzyn
- Laboratory of Environmental Physiology, Institute for Environmental Sciences, University of Shizuoka, Japan.
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Fan YP, Chakder S, Gao F, Rattan S. Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction. Am J Physiol Gastrointest Liver Physiol 2001; 280:G32-42. [PMID: 11123195 DOI: 10.1152/ajpgi.2001.280.1.g32] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We examined the effect of endotoxin lipopolysaccharide (LPS) on the basal tone and on the effects of different stimuli and agonists and transcriptional and translational expression of nitric oxide (NO) synthase (NOS) isozymes in the lower esophageal sphincter (LES), pyloric sphincter (PS), and internal anal sphincter (IAS). NO release was also examined before and after LPS. LPS caused a dose-dependent fall in the basal tone and augmentation of the relaxation caused by nonadrenergic, noncholinergic (NANC) nerve stimulation in the LES and IAS. In the PS, LPS had no significant effect on the basal tone and caused an attenuation of the NANC relaxation and an augmentation of the contractile response of muscarinic agonist. Interestingly, the smooth muscle relaxation by atrial natriuretic factor was suppressed in the LES and IAS but not in the PS. These changes in the sphincteric function following LPS may be associated with increase in the inducible NOS (iNOS) expression since they were blocked by iNOS inhibitor L-canavanine. Augmentation of NANC relaxation in the LES and IAS smooth muscle by LPS may be due to the increased activity of neuronal NOS and NO production.
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Affiliation(s)
- Y P Fan
- Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Abstract
BACKGROUND & AIMS Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut. This study aimed to identify the effect of chronic deprivation of NO derived from neuronal (nNOS) or endothelial (eNOS) nitric oxide synthase on gastric emptying. METHODS nNOS-deficient (knockout) mice were compared with wild-type mice for gastric size, fluoroscopic appearance after gavage of contrast, and histology of the pyloric sphincter. Wild-type mice treated with the NOS inhibitor N(omega)-nitro L-arginine (L-NA) and eNOS-deficient mice were also compared with wild-type and nNOS-deficient mice for liquid and solid gastric emptying. RESULTS nNOS-deficient mice showed gastric dilation. Fluoroscopy showed delayed gastric emptying of radiologic contrast. There was no marked localized hypertrophy or luminal narrowing at the pyloric sphincter by histology of relaxed wild-type, nNOS-deficient, and eNOS-deficient tissues. Gastric emptying of both solids (28% +/- 27%) and liquids (22% +/- 18%) was significantly delayed in nNOS-deficient mice compared with control wild-type mice (82% +/- 22% for solids; 48% +/- 17% for liquids). eNOS-deficient mice showed no significant difference from wild-type mice (74% +/- 28% for solids; 47% +/- 23% for liquids). Wild-type mice treated acutely with L-NA showed delay in emptying of solids (43% +/- 31%) but not liquids (39% +/- 15%). CONCLUSIONS Chronic depletion of NO from nNOS, but not eNOS, results in delayed gastric emptying of solids and liquids.
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Affiliation(s)
- H Mashimo
- West Roxbury Veterans Affairs Medical Center, West Roxbury, Massachusetts 02132, USA.
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Cullen JJ, Maes EB, Aggrawal S, Conklin JL, Ephgrave KS, Mitros FA. Effect of endotoxin on opossum gallbladder motility: a model of acalculous cholecystitis. Ann Surg 2000; 232:202-7. [PMID: 10903598 PMCID: PMC1421131 DOI: 10.1097/00000658-200008000-00009] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To determine whether endotoxin causes histologic changes in the gallbladder consistent with acalculous cholecystitis, and to determine the effects of endotoxin on gallbladder motility. SUMMARY BACKGROUND DATA Acute acalculous cholecystitis is frequently seen in critically ill, septic patients, after prolonged fasting and gallbladder stasis. The pathogenesis of acalculous cholecystitis is unknown; however, previous studies have suggested that ischemia may play a role. METHODS Adult opossums received Escherichia coli lipopolysaccharide. The gallbladder was removed for histologic examination or for physiologic studies 4 hours to 2 weeks later. For histologic examination, gallbladder strips underwent standard hematoxylin-and-eosin processing. For physiologic studies, they were mounted in a tissue bath to determine responses to cholecystokinin octapeptide or electrical field stimulation. RESULTS Intravenous endotoxin at a dose of 0.005 mg/kg resulted in disrupted mucosal surfaces and areas of hemorrhage; higher doses of endotoxin resulted in coagulation necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult. Endotoxin abolished the contractile response to cholecystokinin octapeptide in gallbladder strips 4 hours after endotoxin administration. The 0.005-mg/kg dose of endotoxin decreased the contractile response to cholecystokinin octapeptide for up to 96 hours after endotoxin administration and decreased the contractile response to electrical field stimulation for 48 hours after administration. Inhibition of nitric oxide synthase reversed the decreased contractile response to cholecystokinin octapeptide. CONCLUSIONS Endotoxin causes an ischemic insult to the gallbladder similar to that seen in acalculous cholecystitis. Also, endotoxin may lead to gallbladder stasis by decreasing gallbladder contractile responses to hormonal and neural stimuli.
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Affiliation(s)
- J J Cullen
- Departments of Surgery and Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa, USA
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