Pathophysiological role of nitric oxide in rat experimental colitis

Southey, A.; Tanaka, Sumiko; Murakami, Takanori; Miyoshi, Hidetaka; Ishizuka, Tohru; Sugiura, Masaki; Kawashima, Keisuke; Sugita, Takahisa

doi:10.1016/s0192-0561(97)00107-0

Cited by 50 publications

(22 citation statements)

References 23 publications

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“…However, during chronic inflammatory disease, they can contribute to host tissue pathology (26,41,49). In the present study, an increased neutrophil presence in the infected colons of FTY720-treated mice at day 14 p.i.…”

Section: Discussionsupporting

confidence: 47%

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

et al. 2012

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The sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, mesenteric lymph nodes (MLNs), and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogen Citrobacter rodentium. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenic Escherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the clearance of bacteria when mice were infected with luciferase-tagged C. rodentium. FTY720-treated C. rodentium-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colon histopathology, and neutrophil infiltration than vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages, and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance of C. rodentium.

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Section: Discussionsupporting

confidence: 47%

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

et al. 2012

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“…NOS2 expression and serum nitrite levels were also elevated in mice fed the doubly deficient diet. Nitric oxide has antimicrobial functions (reviewed in reference 17), but overexpression has been implicated in the pathology associated with colitis (52). Thus, elevated levels of nitric oxide at the site of infection also may enhance pathology in infected mice fed the doubly deficient diet.…”

Section: Discussionmentioning

confidence: 99%

The Pathogenicity of an EntericCitrobacter rodentiumInfection Is Enhanced by Deficiencies in the Antioxidants Selenium and Vitamin E

et al. 2011

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The pathogenesis of a Citrobacter rodentium infection was evaluated in mice fed diets with a single deficiency in either selenium or vitamin E or with a double deficiency in both selenium and vitamin E compared to mice on nutritionally adequate diets. Mice fed the selenium-and vitamin E-deficient diet for 6 weeks had increased loads of C. rodentium in the colon and spleen, which were not observed in mice fed either of the singly deficient diets or the adequate diet. Infected mice fed the doubly deficient diet had increased colon crypt hyperplasia and an influx of infiltrating cells along with gross changes to crypt architecture, including ulceration and denuding of the epithelial layer. Cytokine and chemokine mRNA levels in the colon were measured by real-time PCR. Expression of proinflammatory cytokines and chemokines was upregulated on day 12 after infection with C. rodentium in mice fed the doubly deficient diet compared to mice fed the control diet. Heme oxygenase 1, an enzyme upregulated by oxidative stress, also was more highly induced in infected mice fed the doubly deficient diet. Production of C. rodentium antigen-specific IgM and IgG antibodies was not affected by feeding the doubly deficient diet. The results indicated that selenium and vitamin E play an important role in host resistance and in the pathology induced by C. rodentium, an infection that mimics disease caused by common food-borne bacterial pathogens in humans.

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“…Activation of AMPK in macrophages, an important site of iNOS expression, also caused inhibition of interferon-␥-induced NO production. The latter finding is of important clinical relevance because macrophage/monocyte iNOS induction has been implicated in the pathogenesis or promotion of several inflammatory/immune disorders such as septic and hemorrhagic shock (42,43), multiple sclerosis (44), myocardial infarction (45,46), inflammatory bowel disease (47,48), and pancreatic ␤-cell dysfunction (49).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Inducible Nitric-oxide Synthase by Activators of AMP-activated Protein Kinase

Pilon¹,

Dallaire²,

Marette

2004

Journal of Biological Chemistry

150

121

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AMP-activated protein kinase (AMPK), an energysensing enzyme that is activated in response to cellular stress, is a critical signaling molecule for the regulation of multiple metabolic processes. AMPK has recently emerged as an attractive novel target for the treatment of obesity and type 2 diabetes because its activation increases fatty acid oxidation and improves glucose homeostasis. Here we show that pharmacological activation of AMPK by insulin-sensitizing drugs markedly inhibits inducible nitric-oxide synthase (iNOS), a proinflammatory mediator in endotoxic shock and in chronic inflammatory states including obesity-linked diabetes. AMPK-mediated iNOS inhibition was observed in several cell types (myocytes, adipocytes, macrophages) and primarily resulted from post-transcriptional regulation of the iNOS protein. AMPK activation in vivo also blunted iNOS induction in muscle and adipose tissues of endotoxin-challenged rats. Reduction of AMPK expression by small interfering RNA reversed the inhibitory effects of AMPK activators on iNOS expression and nitric oxide production in myocytes. These results indicate that AMPK is a novel anti-inflammatory signaling pathway and thus represents a promising therapeutic target for immune-inflammatory disorders. AMP-activated protein kinase (AMPK)1 is emerging as an important energy-sensing/signaling system in mammalian tissues. It is a member of a metabolite-sensing protein kinase family that acts as a fuel gauge by monitoring cellular energy levels (1). When AMPK "senses" decreased energy storage, it acts to switch off ATP-consuming pathways and switch on alternative pathways for ATP regeneration. AMPK is a heterotrimer consisting of a catalytic ␣-subunit and two regulatory subunits, ␤ and ␥. In response to cellular energy depletion, as reflected by an increase in the AMP/ATP ratio, AMPK is phosphorylated and activated by a still uncharacterized upstream AMPK kinase (2). It also can be activated allosterically by increases in the AMP/ATP and creatine/creatine-P ratios. The metabolic function of AMPK perhaps has been documented best in exercising skeletal muscle, where its activation seems to contribute to increased glucose transport and fatty acid oxidation (3, 4). AMPK can be activated chemically with 5-aminoimidazole-4-carboxamide riboside (AICAR), which is taken up by cells and phosphorylated by adenosine kinase to form 5-aminoimidazole-4-carboxamide ribonucleoside, a nucleotide that mimics the effect of AMP (5). More recent studies also have identified AMPK as the mediator of the metabolic effects of the adipose-derived peptidic hormones leptin and adiponectin in skeletal muscle and liver (6 -8).Chronic treatment of animal models of type 2 diabetes with the AMPK activator AICAR improves glucose homeostasis and insulin sensitivity (9 -11). These beneficial effects are thought to be explained mainly by the well known actions of AMPK on glucose metabolism and lipid oxidation in muscle and liver. Accordingly, the anti-diabetic drugs metformin and rosiglitazone also activat...

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Pathophysiological role of nitric oxide in rat experimental colitis

Cited by 50 publications

References 23 publications

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

The Pathogenicity of an EntericCitrobacter rodentiumInfection Is Enhanced by Deficiencies in the Antioxidants Selenium and Vitamin E

Inhibition of Inducible Nitric-oxide Synthase by Activators of AMP-activated Protein Kinase

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