Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents

Kalff, Jörg C.; Schraut, Wolfgang H.; Billiar, Timothy R.; Simmons, Richard L.; Bauer, Anthony J.

doi:10.1016/s0016-5085(00)70214-9

Cited by 271 publications

(260 citation statements)

References 26 publications

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“…A representative mediator in POI is NO, which is as major inhibitory neurotransmitter in the gastrointestinal tract. 5 NO could not be detected in ME organ culture supernatants of unoperated control animals (5±6 μM/ 24 hr /mg tissue). In sham operated (laparotomy) mice basal NO levels of 53±36 μM/ 24 hr /mg tissue were observed.…”

Section: Morphological Studiesmentioning

confidence: 85%

“…5 By measuring the concentration of NO in the supernatant of cultured ME a statement about the inflammatory extent or the efficacy of therapeutics is possible. Several other molecules (Il-6, TNF-alpha etc) can be easily examined in the supernatants of cultured tissue by classical ELISA or multiplex approaches like Luminex Multiplex Immunoassay 13 (Invitrogen, Carlsbad, CA, USA).…”

mentioning

confidence: 99%

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Functional Assessment of Intestinal Motility and Gut Wall Inflammation in Rodents: Analyses in a Standardized Model of Intestinal Manipulation

Vilz

Overhaus

Stoffels

et al. 2012

JoVE

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Inflammation of the gastrointestinal tract is a common reason for a variety of human diseases. Animal research models are critical in investigating the complex cellular and molecular of intestinal pathology. Although the tunica mucosa is often the organ of interest in many inflammatory diseases, recent works demonstrated that the muscularis externa (ME) is also a highly immunocompetent organ that harbours a dense network of resident immunocytes.1,2 These works were performed within the standardized model of intestinal manipulation (IM) that leads to inflammation of the bowel wall, mainly limited to the ME. Clinically this inflammation leads to prolonged intestinal dysmotility, known as postoperative ileus (POI) which is a frequent and unavoidable complication after abdominal surgery. 3 The inflammation is characterized by liberation of proinflammatory mediators such as IL-6 4 or IL-1β or inhibitory neurotransmitters like nitric oxide (NO). 5 Subsequently, tremendous numbers of immunocytes extravasate into the ME, dominated by polymorphonuclear neutrophils (PMN) and monocytes and finally maintain POI.2 Lasting for days, this intestinal paralysis leads to an increased risk of aspiration, bacterial translocation and infectious complications up to sepsis and multi organ failure and causes a high economic burden. 6In this manuscript we demonstrate the standardized model of IM and in vivo assessment of gastrointestinal transit (GIT) and colonic transit. Furthermore we demonstrate a method for separation of the ME from the tunica mucosa followed by immunological analysis, which is crucial to distinguish between the inflammatory responses in these both highly immunoactive bowel wall compartments. All analyses are easily transferable to any other research models, affecting gastrointestinal function. Video LinkThe video component of this article can be found at http://www.jove.com/video/4086/ Protocol AnimalsMale C57Bl6/J mice with a mean weight of 25 g were obtained from Harlan Winkelmann (Borchen, Germany). All experiments were performed in accordance with the federal law regarding the protection of animals. The principles of laboratory animal care were followed. Animals were maintained on a 12-hr light/dark cycle and provided with commercially available rodent chow and tap water ad libitum. Animals should be housed at least 7 days after arrival in your animal facility before experiments. Note that all experiments can be easily adapted to rats or other species and with slight modifications into large animal models.

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Section: Morphological Studiesmentioning

confidence: 85%

mentioning

confidence: 99%

Functional Assessment of Intestinal Motility and Gut Wall Inflammation in Rodents: Analyses in a Standardized Model of Intestinal Manipulation

Vilz

Overhaus

Stoffels

et al. 2012

JoVE

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“…The functional, molecular, and cellular mechanisms determining POI are to be found within the intestinal muscularis. The changes within intestinal mucosa do not influence the cellular and molecular mechanisms of POI (35,37,39,41,42,67,80,82). Previously, we could show a recruitment of CD11bϩCD103ϩ dendritic cells into the intestinal muscularis, but not into the colonic muscularis after IM, which induced a T H 1 response by producing IL-12 at the manipulated site.…”

Section: Discussionmentioning

confidence: 75%

“…Most of them focused on singular proinflammatory mediators, such as IL-6 (88), and adhesion molecules and chemokines, such as ICAM-1 (36) and MCP-1 (84). Some authors described inhibitory kinetic factors such as nitric oxide or prostaglandins (39,42,71). Most of these strategies showed subsequent improvement of POI, but their clinical implementation has so far failed to display benefits for the patients (57).…”

Section: Discussionmentioning

confidence: 99%

Impact of CCR7 on the gastrointestinal field effect

Koscielny

Engel

Maurer

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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.2010.-Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune mediated. This study aimed to investigate the role of CCR7 in IM-induced FE. Since CCR7 is expressed on activated dendritic cells and T cells and is well known to control their migration, we hypothesized that lack of CCR7 reduces or abolishes FE. Small bowel muscularis and colonic muscularis from CCR7Ϫ/Ϫ and wild-type (WT) mice were obtained after IM of the jejunum or sham operation. FE was analyzed by measuring gastrointestinal transit time of orally given fluorescent dextran (geometric center), colonic transit time, infiltration of MPO-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of the inflammatory cytokine IL-6 were determined by RT-PCR. The number of dendritic cells and CD3ϩCD25ϩ T cells separately isolated from jejunum and colon was determined in mice after IM and sham operation. There was no significant difference in IL-6 mRNA upregulation in colonic muscularis between sham-operated WT and CCR7 Ϫ/Ϫ mice after IM. Contractility of circular muscularis strips of the colon was significantly improved in CCR7 Ϫ/Ϫ animals following IM and did not vary significantly from sham-operated animals. Additionally, inflammation of the colon determined by the number of MPO-positive cells and colonic transit time was significantly reduced in CCR7 Ϫ/Ϫ mice. In contrast, jejunal contractility and jejunal inflammation of transgenic mice did not differ significantly from WT mice after IM. These data are supported by a significant increase of CD3ϩCD25ϩ T cells in the colonic muscularis of WT mice after IM, which could not be observed in CCR7Ϫ/Ϫ mice. These data demonstrate that CCR7 is required for FE and postoperative ileus. CCR7 indirectly affects FE by inhibiting migration of activated dendritic cells and of T cells from the jejunum to the colon. These findings support the critical role of the adaptive immune system in FE. postoperative ileus; chemokine receptor 7 POSTOPERATIVE ILEUS (POI) is an inevitable sequela of abdominal surgery or trauma with a variably gradual manifestation. It leads to postoperative discomfort, prolonged hospitalization, and increased patient morbidity and has a high impact on socioeconomic costs (27,43,49,63). The pathophysiology of POI and postoperative gastrointestinal dysmotility, respectively, has been elucidated in recent years. POI is marked by a neurogenic phase and a clinically relevant prolonged inflammatory phase. Both the neuronal activation by intestinal manipulation (IM) and inflammatory cell infiltrates in the intestinal muscularis compromise gastrointestinal motility. These detrimental alterations are emphasized as major factors in the development of POI (4,8,9,15,16,[35][36][37][38][40][41][42]. We reported a time-and trauma-degree-dependent inflammatory cascade (35, 36); infiltration of leukocytes (40 -42...

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“…Smooth muscle contractility of the intestine during sepsis or after surgical manipulation is regulated, in part, by iNOS activity (25,26). To test the hypothesis that induced NO contributes to the impairment of smooth muscle function of the colon following MODS we performed immunohistochemical techniques to confirm the finding of iNOS production in the colon in MODS at the protein level.…”

Section: Inducible Nitric Oxide Synthase Production In Multiple Organmentioning

confidence: 99%

Roles of calcium and IP3 in impaired colon contractility of rats following multiple organ dysfunction syndrome

Zheyu

Yan

2007

Braz J Med Biol Res

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The purpose of the present study was to explore changes in rat colon motility, and determine the roles of calcium and inositol (1,4,5)-triphosphate (IP 3 ) in colon dysmotility induced by multiple organ dysfunction syndrome (MODS) caused by bacteria peritonitis. The number of stools, the contractility of the muscle strips and the length of smooth muscle cells (SMC) in the colon, the concentration of calcium and IP 3 in SMC, and serum nitric oxide were measured. Number of stools, fecal weight, IP 3 concentration in SMC and serum nitric oxide concentration were 0.77 ± 0.52 pellets, 2.51 ± 0.39 g, 4.14 ± 2.07 pmol/tube, and 113.95 ± 37.89 µmol/L, respectively, for the MODS group (N = 11) vs 1.54 ± 0.64 pellets, 4.32 ± 0.57 g, 8.19 ± 3.11 pmol/tube, and 37.42 ± 19.56 µmol/L for the control group (N = 20; P < 0.05). After treatment with 0.1 mM acetylcholine and 0.1 M potassium chloride, the maximum contraction stress of smooth muscle strips, the length of SMC and the changes of calcium concentration were 593 ± 81 and 458 ± 69 g/cm 3 , 48.1 ± 11.8 and 69.2 ± 15.7 µM, 250 ± 70 and 167 ± 48%, respectively, for the control group vs 321 ± 53 and 284 ± 56 g/cm 3 , 65.1 ± 18.5 and 87.2 ± 23.7 µM, 127 ± 35 and 112 ± 35% for the MODS group (P < 0.05). Thus, colon contractility was decreased in MODS, a result possibly related to reduced calcium concentration and IP 3 in SMC.

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Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents

Cited by 271 publications

References 26 publications

Functional Assessment of Intestinal Motility and Gut Wall Inflammation in Rodents: Analyses in a Standardized Model of Intestinal Manipulation

Functional Assessment of Intestinal Motility and Gut Wall Inflammation in Rodents: Analyses in a Standardized Model of Intestinal Manipulation

Impact of CCR7 on the gastrointestinal field effect

Roles of calcium and IP3 in impaired colon contractility of rats following multiple organ dysfunction syndrome

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