Role of nitric oxide in inflammation-induced suppression  of secretion in a mouse model of acute colitis

MacNaughton, Wallace K.; Lowe, Sonya S.; Cushing, Kelly C.

doi:10.1152/ajpgi.1998.275.6.g1353

Cited by 47 publications

(62 citation statements)

References 38 publications

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“…We previously showed that cholinergic control of ion transport is perturbed in tissue from mice with DSS-induced colitis (38), complementing observations from other studies (21,34). However, the DSS model is intriguing, because CCh produced a sustained reduction in I sc , rather than a diminished transient increase in I sc observed in other models, such as those evoked by 2,4,6-trinitrobenzenesulfonic acid, 2,4-dinitrobenzenesulfonic acid (21,34), or oxazolone (unpublished observation). Underlying differences in the models may contribute to this discrepancy; for example, 2,4,6-trinitrobenzenesulfonic acid and 2,4-dinitrobenzenesulfonic acid elicit a polarized Th1-type inflammatory response and oxazolone produces a Th2-type response, whereas DSSinduced colitis involves a Th1-and a Th2-type inflammatory profile (reviewed in Ref.…”

Section: Discussionsupporting

confidence: 77%

“…In normal mammalian colon, the ion transport response to ACh or to synthetic derivatives (e.g., CCh) is dominated by activation of epithelial M 3 cholinergic receptors, the ligation of which causes a Cl Ϫ efflux from the cell (8,38). We previously showed that cholinergic control of ion transport is perturbed in tissue from mice with DSS-induced colitis (38), complementing observations from other studies (21,34). However, the DSS model is intriguing, because CCh produced a sustained reduction in I sc , rather than a diminished transient increase in I sc observed in other models, such as those evoked by 2,4,6-trinitrobenzenesulfonic acid, 2,4-dinitrobenzenesulfonic acid (21,34), or oxazolone (unpublished observation).…”

Section: Discussionsupporting

confidence: 52%

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Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Green¹,

Ho²,

Sharkey³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO. Am J Physiol Gastrointest Liver Physiol 287: G706 -G714, 2004. First published April 15, 2004 10.1152/ajpgi.00076.2004.-In normal colon, ACh elicits a luminally directed Cl Ϫ efflux from enterocytes via activation of muscarinic receptors. In contrast, in the murine model of dextran sodium sulfate (DSS)-induced colitis, an inhibitory cholinergic ion transport event due to nicotinic receptor activation has been identified. The absence of nicotinic receptors on enteric epithelia and the ability of nitric oxide (NO) to modulate ion transport led us to hypothesize that NO mediated the cholinergic nicotinic receptor-induced changes in ion transport. Midportions of colon from control and DSS-treated mice were examined for inducible NO synthase (iNOS) expression by RT-PCR and immunofluorescence or mounted in Ussing chambers for assessment of cholinergic-evoked changes in ion transport (i.e., shortcircuit current) with or without pretreatment with pharmacological inhibitors of NO production. iNOS mRNA and protein levels were increased throughout the tissue from DSS-treated mice and, notably, in the myenteric plexus, where the majority of iNOS immunoreactivity colocalized with the enteric glial cell marker glial fibrillary acidic protein. The drop in short-circuit current evoked by the cholinomimetic carbachol in tissue from DSS-treated mice was prevented by selective inhibitors of iNOS activity {N 6 -(1-iminoethyl)-lysine HCl and N- [3-(aminomethyl)benzyl]acetamidine} or an NO scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide] or by removal of the myenteric plexus. Thus, in this model of colitis, a "switch" occurs from muscarinic to nicotinic receptor-dominated control of cholinergic ion transport. The data indicate a novel pathway involving activation of nicotinic receptors on myenteric neurons, resulting in release of NO from neurons or enteric glia and, ultimately, a dampening of stimulated epithelial Cl Ϫ secretion that would reduce secretory diarrhea.short-circuit current; chloride; inflammatory bowel disease WATER MOVEMENT between the gut lumen and the interstitium is critically important for hydrating the surface of the enteric epithelium, providing the medium for contact digestion and nutrient absorption, and reducing the contact of pathogens and potentially noxious bacterial or environmental toxins with the enterocytes. This key function of the epithelium is accomplished by the coordinated activity of ion channels, cotransporters, and energy-dependent ion pumps that are asymmetrically arranged in the cell membrane of the polarized epithelium: this allows for vectorial ion transport, creating the driving forces for directed water movements (2). Many intrinsic and extrinsic agents influence epithelial ion transport, including neurotransmitters (e.g., ACh), biogenic amines, nu-

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 52%

Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Green¹,

Ho²,

Sharkey³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…RT-PCR was conducted as previously described (27) to determine the expression of PAR-1 mRNA in mouse colon. Expression of the housekeeping gene GAPDH was assessed as an internal control.…”

Section: Rt-pcrmentioning

confidence: 99%

“…The reaction mixture contained 5 l of 10ϫ PCR buffer, 1 l of 10 mM dNTP, 2 l of each of the 5Ј and 3Ј primers, 0.5 l of HotStartTaq DNA polymerase (Qiagen), 2 l of the cDNA template, and 38 l of DEP-treated H 2O (Invitrogen). The primer sequences used for PAR-1 amplification were 5Ј-ATGGGGCCGCGGCGGCT-GCT-3Ј and 5Ј-GGGCTGGTCAGATATCCGGA-3, whereas those used for GAPDH amplification were 5Ј-CGGAGTCAACGGATTT-GGTCGTAT-3Ј and 5Ј-AGCCTTCTCCATGGTGGTGAAGAC-3Ј (27). PCR for PAR-1 was stopped after 42 cycles (denaturation at 94°C for 1 min, annealing at 54°C for 1 min and elongation at 72°C for 1 min).…”

Section: Rt-pcrmentioning

confidence: 99%

“…Secretion of fluid into the lumen of the intestine serves, among other functions, to flush away potentially harmful luminal contents and thus slows or prevents the translocation of bacteria and antigens into the lamina propria of the intestine (2,47). The disruption of secretory function is characteristic of models of intestinal inflammation (2,17,27) and is observed in human IBD (1,22,33). The altered regulation of secretory function may in turn contribute to inflammatory conditions of the gut (2, 3).…”

mentioning

confidence: 99%

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Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro

Buresi

Vergnolle

Sharkey

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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The proteinase-activated thrombin receptor-1 (PAR-1) belongs to a unique family of G protein-coupled receptors activated by proteolytic cleavage. We studied the effect of PAR-1 activation in the regulation of ion transport in mouse colon in vitro. Expression of PAR-1 in mouse colon was assessed by RT-PCR and immunohistochemistry. To study the role of PAR-1 activation in chloride secretion, mouse colon was mounted in Ussing chambers. Changes in short-circuit current ( Isc) were measured in tissues exposed to either thrombin, saline, the PAR-1-activating peptide TFLLR-NH2, or the inactive reverse peptide RLLFT-NH2, before electrical field stimulation (EFS). Experiments were repeated in the presence of either a PAR-1 antagonist or in PAR-1-deficient mice to assess receptor specificity. In addition, studies were conducted in the presence of chloride-free buffer or the muscarinic antagonist atropine to assess chloride dependency and the role of cholinergic neurons in the PAR-1-induced effect. PAR-1 mRNA was expressed in full-thickness specimens and mucosal scrapings of mouse colon. PAR-1 immunoreactivity was found on epithelial cells and on neurons in submucosal ganglia where it was colocalized with both VIP and neuropeptide Y. After PAR-1 activation by thrombin or TFLLR-NH2, secretory responses to EFS but not those to forskolin or carbachol were significantly reduced. The reduction in the response to EFS was not observed in the presence of the PAR-1 antagonist, in PAR-1-deficient mice, when chloride was excluded from the bathing medium, or when atropine was present. PAR-1 is expressed in submucosal ganglia in the mouse colon and its activation leads to a decrease in neurally evoked epithelial chloride secretion.

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Intestinal epithelial secretory function: Role of proteinase‐activated receptors

Buresi

MacNaughton

2003

Drug Development Research

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The ability of enterocytes to secrete electrolytes and water into the intestinal lumen represents a critical feature of mucosal defense. During disease, this function may be altered and may initiate or exacerbate pathological conditions. Although many of the intracellular mechanisms linking stimulation to secretion have been elucidated, novel pathways continue to be revealed. These pathways provide potential for therapeutic manipulation of cellular function. In addition, the importance of the microenvironment surrounding enterocytes is increasingly being acknowledged, and the interactions between epithelial cells and their milieu are proving to be essential to the regulation of secretory function, both in health and disease. In this way, epithelial ion transport functions can be modulated by mediators released from neighboring nerves, inflammatory cells, and pathogens, or by endocrine factors. Much interest has recently been elicited by the discovery that proteinases can regulate cellular functions through the activation of proteinase-activated receptors (PARs). Because of the abundance of proteases within the gastrointestinal tract, particularly in the setting of development, inflammation, and healing, it is likely that PARs have an important role to play in these processes. PARs have been localized to a variety of cell types in the gastrointestinal tract, and have been shown to influence epithelial secretory function on several levels. In this review, we discuss the mechanisms by which proteases and PARs regulate intestinal secretory function, and the manner in which these modulations might contribute to inflammatory processes. Drug Dev. Res. 59:386-394, 2003.

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Role of nitric oxide in inflammation-induced suppression of secretion in a mouse model of acute colitis

Cited by 47 publications

References 38 publications

Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro

Intestinal epithelial secretory function: Role of proteinase‐activated receptors

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