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Am J Physiol Gastrointest Liver Physiol 293: G711-G718, 2007. First published August 2, 2007; doi:10.1152/ajpgi.00240.2007
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NEUROREGULATION AND MOTILITY

The protective effect of the vagus nerve in a murine model of chronic relapsing colitis

Jean-Eric Ghia, Patricia Blennerhassett, Rami T. El-Sharkawy, and Stephen M. Collins

Intestinal Diseases Research Programme, Health Science Center, McMaster University, Hamilton, Ontario, Canada

Submitted 29 May 2007 ; accepted in final form 31 July 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The vagus nerve inhibits the response to systemic administration of endotoxin, and we have recently extended this observation to show that the vagus attenuates acute experimental colitis in mice. The purpose of the present study was to determine whether there is a tonic counterinflammatory influence of the vagus on colitis maintained over several weeks. We assessed disease activity index, macroscopic and histological damage, myeloperoxidase (MPO) activity, and Th1 and Th2 cytokine profiles in chronic colitis induced by administration of dextran sodium sulfate (DSS) in drinking water for three cycles during 5 days with 11 days of rest between each cycle (DSS 3, 2, 2%) in healthy and vagotomized C57BL/6 mice and in mice deficient in macrophage-colony stimulating factor (M-CSF). A pyloroplasty was performed in vagotomized mice. Vagotomy accelerated the onset and the severity of inflammation during the first and second but not the third cycle. Although macroscopic scores were not significantly changed, histological scores as well as MPO activity and colonic tissue levels of IL-1{alpha}, TNF-{alpha}, IFN-{gamma}, and IL-18 but not IL-4 were significantly increased in vagotomized mice compared with sham-operated mice that received DSS. In control mice (without colitis), vagotomy per se did not affect any inflammatory marker. Vagotomy had no effect on the colitis in M-CSF-derived macrophage-deficient mice. These results indicate that the vagus protects against acute relapses on a background of chronic inflammation. Identification of the molecular mechanisms underlying the protective role of parasympathetic nerves opens a new therapeutic avenue for the treatment of acute relapses of chronic inflammatory bowel disease.

vagotomy; chronic experimental colitis; inflammatory bowel disease; cytokine; macrophages

INFLAMMATORY BOWEL DISEASES (IBD), including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract that result in significant morbidity. The pathogenesis of IBD is unknown but is thought to reflect an interaction of genetic and environmental factors; chronic inflammation results from immune dysregulation and an intolerance of commensal bacteria in the gut (25, 34, 35). Clinical observations also suggest that the nervous system influences the clinical course of IBD. This is supported by the beneficial effects of lidocaine (40) or nicotine (28) in at least a subset of IBD patients. More direct evidence of a neural modulation is from a case study in which spinal cord stimulation, a therapeutic strategy for treating neuropathic pain, induced relapses of ulcerative colitis (23).

The autonomic nervous system is altered both structurally and functionally in IBD; structural changes in autonomic nerves in the gut include changes in ganglia size and number as well as axonal necrosis (12). Up to 35% of patients with ulcerative colitis exhibit autonomic imbalance, with impaired parasympathetic function resulting in sympathetic dominance (24). Studies in animal models demonstrate that autonomic imbalance contributes to the inflammatory drive of experimental colitis. For example, sympathectomy improves experimental colitis (27) and administration of the parasympathomimetic nicotine improves colitis in animal models (13). Vagal modulation of endotoxic shock (1) and attenuation of inflammation in a model of acute experimental colitis (20) is mediated via nicotinic ACh receptors on macrophages. This has raised the possibility of using selective agonists of this receptor to suppress inflammation in patients with IBD and other chronic inflammatory conditions (43). However, to date evidence of vagal protection against gut inflammation is restricted to acute inflammatory responses induced in mice without preexisting inflammation and is not therefore strictly applicable to human IBD.

The dextran sodium sulfate (DSS) model, originally reported by Okayasu et al. (32), has been used extensively to investigate the role of the different cell types in colitis and macrophages, neutrophils, and monocytes (7, 11, 14, 42). This model is based on the oral administration of DSS in drinking water and can be used to study acute or chronic colitis by adjusting the concentration and duration of DSS administration (32).

In the present study, we have exploited the DSS model to determine whether the vagus nerve modulates a chronic inflammatory response in the murine colon. Our results show that the vagus nerve attenuates chronic colitis by a mechanism that involves macrophage-colony stimulating factor (M-CSF)derived macrophages but that this protection is transient.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals. Male C57BL/6 mice (7–9 wk old) were purchased from Taconic Animal Suppliers (Indianapolis, IN) and were maintained in the animal care facility at McMaster University under specific pathogen-free conditions. +/? breeding pairs were purchased from Jackson (Bar Harbor, ME). We used mice with a mutation in the gene encoding M-CSF; homozygotes (op/op) have a defect in osteoclast activity, are osteopetrotic, and lack a subset of macrophages (45, 49). Nonhomozygote mice (+/+ or +/op) were phenotypically indistinguishable and were used as controls (+/?), as previously described (18). Because osteopetrotic op/op mice lack teeth; they were fed a powdered diet, whereas +/? mice received conventional food. No differences in food intake or body weight were observed between these groups. Mice were housed under standard conditions for a minimum of 1 wk before experimentation. All experiments were approved by the McMaster University animal ethics committee and were conducted under the Canadian guidelines for animal research.

Vagotomy. Mice were anaesthetized with ketamine (150 mg/kg ip) and xylazine (10 mg/kg ip), and ventral and dorsal truncal branches of the subdiaphragmatic vagus were cut (1 cm above the gastroesophageal junction). Preliminary studies showed marked gastric dilatation in vagotomized mice, and a surgical pyloroplasty was therefore incorporated into the protocol. Vagotomy (VX) with pyloroplasty (P) was subsequently performed under the same anesthesia. No gastric dilatation was observed in mice undergoing this procedure. In sham-operated mice, vagal trunks were similarly exposed but not cut, but a pyloroplasty was performed. All mice were maintained on normal diet.

Validation of VX. The ability of cholecystokinin to reduce food intake is completely dependent on the integrity of the vagus nerve (22, 36). To determine the functional integrity of VX in our study, mice received 40 µg/kg of cholecystokinin octapeptide (CCK-8; Sigma) by intravenous tail injection (4) 10 days after VXP or sham surgery, and food intake was measured over 24 h. The integrity of VX lasts well beyond the time frame of the present studies, for as long as 62 days (19). Functional integrity of VXP was ascertained by the absence of a CCK-8-induced suppression of feeding. The completeness of VX was verified during postmortem inspection of vagal nerve endings by using a microscope.

Induction of DSS colitis. Two days after the end of the CCK-8 experiment, DSS (40 kDa; ICN Biomedicals, Aurora, OH) was added to the drinking water in a final concentration of 3% (wt/vol) for 5 days. Then mice were transferred to water for 11 days. This cycle was repeated twice more with 2% of DSS. Controls were all time matched and consisted of mice that received normal drinking water only. Mean DSS consumption was noted per cage each day.

Assessment of the severity of colitis: disease activity index. Disease activity index (DAI) scores have historically correlated well with the pathological findings in a DSS-induced model of IBD (8). DAI is the combined score of weight loss, stool consistency, and bleeding. Scores were defined as follows: weight: 0, no loss; 1, 5–10%; 2, 10–15%; 3, 15–20%; and 4, 20% weight loss; stool: 0, normal; 2, loose stool; and 4, diarrhea; and bleeding: 0, no blood; 2, presence (Hemoccult II "positive"; Beckman Coulter); and 4, gross blood. DAI was scored from day 0 to day 5 during DSS treatment.

Macroscopic scores. After the third cycle of treatment, the mice were killed and the abdominal cavity was opened, and observations on colonic distension, fluid content, hyperemia, and erythema were recorded. The colon was removed and opened longitudinally, and macroscopic damage was immediately assessed. Macroscopic scores were performed by using a previously described scoring system for DSS colitis (8).

Colonic histology and myeloperoxidase activity. Formalin-fixed colon segments were paraffin embedded, and 3-µm sections were stained with hematoxylin and eosin or Masson's trichrome. Colonic damage was scored based on a published scoring system (8) that considers architectural derangements, goblet cell depletion, edema/ulceration, and degree of inflammatory cell infiltrate. Myeloperoxidase (MPO) activity was determined by following an established protocol (2). Briefly, MPO activity, used as a marker of neutrophilic infiltration, was extracted and the activity was measured by using a modified version of the method described by Bradley (3). Tissue samples were homogenized (50 mg/ml) in ice-cold 50 mM potassium phosphate buffer (pH 6.0) containing 0.5% hexadecyltrimethylammonium bromide (Sigma). The homogenate was freeze thawed three times, briefly sonicated, and then centrifuged at 12,000 rpm for 12 min at 4°C. The supernatant was then added to a solution of o-dianisidine (Sigma) and hydrogen peroxide. The absorbance of the colorimetric reaction was measured by a spectrophotometer. MPO is expressed in units per milligram of wet tissue, 1 unit being the quantity of enzyme able to convert 1 µmol of hydrogen peroxide to water in 1 min at room temperature.

Cytokine levels. Colonic sample was homogenized in 700 µl of Tris·HCl buffer containing protease inhibitors (Sigma). Samples were centrifuged for 30 min, and the supernatant was frozen at –80°C until assay. Cytokine levels (IL-1beta, TNF-{alpha}, INF-{gamma}, IL-18, and IL-4) were determined by using an ELISA commercial kit (Quantikine M murine; R&D Systems, Minneapolis, MN).

Statistical analysis. Results are presented as means ± SE. Statistical analysis was performed by using one-way ANOVA followed by the Student-Newman-Keuls multiple-comparisons post hoc analysis, and a P value of <0.05 was considered significant, with n ≥ 9.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Responses to CCK-8. Food intake was significantly decreased by 78.7 ± 2.4% to 1.9 ± 2.3% following CCK-8 injection in sham-operated mice compared with VXP mice (data not shown). Those VXP mice in which CCK induced a significant reduction in food intake were excluded from subsequent studies, on the assumption that the VX was incomplete. Water intake was not different between VXP and sham-operated mice (5.7 ± 0.7 and 6.1 ± 0.6 ml/24 h, respectively).

Effect of VXP without colitis. VXP caused no changes in weight gain, colonic appearance or histology, MPO, or cytokine levels in C57BL/6 and M-CSF mice without colitis.

The effect of VXP on DSS-induced chronic colitis. DSS induced a colitis characterized by weight loss and frequent stools; this was evident by day 4 in sham-operated mice. In VXP mice, the onset of colitis and injury were accelerated, reflected in the DAI, as seen within 2 days of DSS. As shown in Fig. 1A, the DAI was significantly higher in VXP mice compared with the sham-operated mice on each of the 4 last days of colitis during the first cycle; the differences between groups reached statistical significance from day 2 up to day 9. During the second cycle of DSS + water, significant differences between the two groups were seen only during the DSS treatment phase. No significant differences were seen during the third cycle. VXP did not significantly increase the macroscopic scores after three cycles of DSS (1.6 ± 0.52 for sham-operated and 2 ± 0.29 for VXP group; Fig. 1B). There was a trend toward an increase in MPO activity in DSS-treated sham-operated mice after three cycles of DSS (Fig. 1C). In contrast, MPO activity was 1.17 ± 0.48 U/mg in sham-operated mice and 3.93 ± 0.75 U/mg in VXP mice (Fig. 2C). As shown in Fig. 2, A and B, VXP significantly increased the severity of colitis, with histological scores increasing from 2.58 ± 0.15 to 3.45 ± 0.18. This was associated with greater tissue damage and a large infiltrate of immune cells, including mononuclear cells, neutrophils, and eosinophils. As shown in Fig. 2B, collagen deposition, as reflected by Masson's trichrome staining, was significantly higher in the mucosa and submucosa in the VXP group compared with the sham-operated group. Subserosal focal bundles of collagen were found more frequently in the VXP mice compared with sham-operated controls.


Figure 1
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  		Fig. 1. A: effects of vagotomy associated with pyloroplasty (VXP) on disease activity index (DAI) during development of chronic dextran sulfate sodium (DSS)-induced colitis in mice. Mice were given DSS for 3 cycles (3, 2, and 2% DSS solution in drinking water) to induce colitis. VXP increases DAI during cycles 1 and 2 (n = 9). B: macroscopic scores in mice with chronic DSS colitis and in mice without colitis. Macroscopic scores are not significantly changed (n = 9). C: myeloperoxidase (MPO) activity is higher in VXP mice with chronic DSS colitis (n = 9). *P < 0.05; NS, not significant. Values are means ± SE.

 

Figure 2
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  		Fig. 2. A: histological scores in mice with chronic DSS colitis and in mice without colitis. Hematoxylin and eosin staining shows that VXP increases histological score (n = 9). B: Masson's trichrome staining shows that VXP significantly increases score; more collagen deposits are visible. Values are means ± SE. *P < 0.05, n = 9.

 
Significantly greater increases were found in the levels of IL-1beta (5.9-fold), TNF-{alpha} (2.5-fold), INF-{gamma} (1.63-fold), and IL-18 (1.3-fold) in the colon of DSS-treated mice with VXP compared with sham-operated mice (Fig. 3, A–C and E). In contrast, no significant changes in IL-4 were seen (Fig. 3D).


Figure 3
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  		Fig. 3. Effect of VXP on colonic cytokine level by ELISA measurements. VXP results in significant increases in chronic DSS-treated mice of IL-1beta (A), TNF-{alpha} (B), INF-{gamma} (C), and IL-18 (E) (n = 9). No significant changes are visible for IL-4 (D). Values are means ± SE. *P < 0.05, n = 9.

 
The effect of VXP on DSS-induced colitis on M-CSF-deficient mice. DSS induced a significant colitis in both op/op and +/? mice, although more inflammation was seen in the +/? mice, as described previously (20). The op/op mice exhibited a slower onset of DSS-induced colitis compared with +/? mice (data not shown). In contrast to the increased severity of colitis seen in C57BL/6 mice with VXP, VX did not alter the severity of colitis in op/op mice across all three cycles of DSS (Fig. 4A). Similarly, there was less macroscopic damage in op/op mice and in +/? mice with colitis compared with C57BL/6 mice, and this was not altered by VXP, as shown in Fig. 4B. Conversely, MPO activity was significantly increased after VXP in +/? mice (0.75 ± 0.27 and 1.4 ± 0.14 U/mg, respectively; Fig. 4C), but VXP had no effect in op/op mice (0.41 ± 0.48 and 0.8 ± 0.26 U/mg, respectively), as shown in Fig. 4C. Histological damage scores in DSS-treated op/op mice were significantly decreased compared with +/? mice, with scores decreasing from 2.31 ± 0.12 to 1.35 ± 0.31. As shown in Fig. 5, this pattern was not altered in op/op VXP mice with DSS colitis.


Figure 4
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  		Fig. 4. A: effects of VXP on DAI during development of a chronic DSS-induced colitis in mice. VXP does not increase disease severity score in op/op mice (n = 9). B: macroscopic scores in mice with chronic DSS-colitis and in mice without colitis. VXP does not increase macroscopic score in op/? and op/op mice (n = 9). C: VXP increases MPO in op/? mice (n = 9) but not in op/op mice (n = 9). Values are means ± SE. *P < 0.05.

 

Figure 5
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  		Fig. 5. Histological scores in op/op and op/? mice with chronic DSS colitis and in mice without colitis. Hematoxylin and eosin staining shows that VXP increases score in op/? mice (n = 9) but not in op/op mice (n = 9). Values are means ± SE.

 
We found significantly greater increases in the levels of IL-1beta (3.6-fold), TNF-{alpha} (2.3-fold), and INF-{gamma} (1.5-fold) in the colon of +/? DSS-treated mice with VXP, and this pattern was also evident in VXP op/op mice with colitis (Fig. 6, A–C). No significant changes were seen for either IL-4 or IL-18 across any group (Fig. 6, D and E).


Figure 6
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  		Fig. 6. Effect of VXP on colonic cytokine level by ELISA measurements. VXP increases levels of IL-1beta (A), TNF-{alpha} (B), and INF-{gamma} (C) in op/? mice (n = 9) but not in op/op mice (n = 9). No significant changes are visible for IL-4 (D) and IL-18 (E) (n = 9). Values are means ± SE. *P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was prompted by the recent demonstration of a macrophage-mediated vagal reflex that attenuated inflammation during acute colitis (20) and extends that work by showing that the vagus attenuates the inflammatory response during a chronic model of experimental colitis. Inflammation induced by three cycles of DSS was more severe in vagotomized mice compared with control. The absence of a protective role of the vagus in op/op mice with colitis implicates a role for M-CSF-derived macrophages in this vagal inhibition. Together, these findings extend the relevance of the previously described inflammatory reflex (41) to a chronic model of intestinal inflammation.

We used DSS (dissolved in the drinking water), and any difference in the inflammatory response following colitis could be attributed to changes in the intake or delivery of DSS to the gut secondary to surgery. It is therefore important to emphasize that no significant differences were seen in water intake between the sham-operated and VXP mice and that the pyloroplasty overcame the problem of gastric retention of DSS following VX. In addition, incompleteness of the VX, which could have confounded results, was excluded from consideration because mice that exhibited a reduction in feeding following CCK-8 were removed from the study.

Our results demonstrate a protective role of the vagus over a 48-day period of inflammation induced by repeated exposure to DSS. The paradigm is one of acute on chronic inflammation, and our results suggest that the protective role of the vagus is more evident during the acute exacerbations that temporally correlate with DSS exposure. The onset of inflammation occurred more rapidly in VXP mice during the first cycle, implying a role for the vagus in attenuating the early events of the inflammatory cascade. This most likely is mediated via suppression of proinflammatory cytokine release from macrophages as part of the initial innate immune response to DSS (10). A similar pattern was seen during the second cycle of DSS. In contrast, indices of inflammation were similar in VXP and sham-treated mice during the intervals between DSS exposure. In addition to the suppression of proinflammatory cytokine production by macrophages, it is possible that VXP altered mucosal barrier function and colonic contractions during the two first cycles, enhancing the exposure of the gut to DSS and other luminal factors such as bacterial antigen, because previous studies have shown that intestinal permeability is modulated by cholinergic nerves (39) and that VX increases permeability in rat intestine (21). An effect of altered colonic contractility, altering exposure time to DSS, is not excluded, because this is regulated in part by ACh (44). In addition, we acknowledge that parasympathetic impairment results in a dominant sympathetic drive, which is known to enhance colonic inflammation (27).

Recent studies have shown that the protective effect of the vagus does ultimately fade and that compensatory changes emerge to contain the acute inflammatory response (19). These include the increased secretion of corticosteroid as well as the production of counterinflammatory cytokines (19). Cytokines released systemically during colitis may act directly on the brain to activate pathways that modify the inflammatory response in the periphery. For example, at the level of the area postrema (AP), IL-1beta can act on endothelial cells to induce the synthesis of prostaglandins, which may act on neurons adjacent to the AP or directly on AP neurons connected to catecholamine neurons of the nucleus of the solitary tract (NTS). For example, IL-1beta can activate A1 noradrenergic cells of the ventrolateral medulla, A2 noradrenergic cells of the NTS, and also C1 and C2 adrenergic cells of the ventrolateral medulla and the NTS, respectively. Stimulation of corticotropin-releasing factor cells within the medial parvocellular division of the paraventricular nucleus leads to the release of ACTH and initiates a glucocorticoid response that can protect the against potentially toxic effects of cytokine (5, 37). However, those observations occurred in the context of a primary acute inflammation, and extrapolation to the present paradigm of acute inflammation on chronic inflammation may not be justified. Thus the basis for loss of vagal protection beyond two cycles of DSS remains unclear.

Chronic colitis induced by DSS involves both a Th1 and a Th2 cytokine response, in addition to the production of IL-1beta, TNF-{alpha}, INF-{gamma}, IL-4, and IL-18 (37). We found that the worsening of inflammation in VXP mice was accompanied by a further increase in the Th1 cytokine INF-{gamma} but not Th2 cytokine IL-4. Unlike IL-1beta and TNF-{alpha}, which are produced mainly by macrophages (9), IL-4 is restricted to Th2 cells CD4+ (30, 38) as well as basophils and mast cells activated by cross-linkage of the Fc fragment, and this likely explains the absence of an increase in this cytokine. In contrast, production of INF-{gamma} is a function of cytotoxic/suppressor T cells bearing the Ly-2 antigen and natural killer cells (6, 47) and is also produced by macrophages (16, 31). Whereas lymphocytic infiltration is a component of the chronic inflammatory response in this model, the effect of VX was more evident during the acute exacerbations of chronic inflammation, thus explaining the further increase in INF-{gamma} but not IL-4.

The present study identifies the macrophage as a critical cell in mediating the anti-inflammatory effect of the vagus during intestinal inflammation. We used mice deficient in M-CSF to elucidate the role of macrophages in the anti-inflammatory role of the vagus nerve. The M-CSF-deficient op/op mouse has reduced numbers of circulating and tissue-based macrophages, which are also limited in terms of their abilities to differentiate and proliferate (17, 45, 46, 48). Macrophages are considered to be important in the complete expression of colitis induced by DSS (15), and our findings support this, because we show a reduction in severity of colitis in op/op mice compared with +/? mice exposed to chronic DSS during the three cycles (data not shown). Previously (20), we found a significant degree of inflammation in DSS-treated op/op mice compared with control op/op mice, and this degree of inflammation would have been sufficient to identify a further worsening of colitis following VX. We therefore interpret the absence of any worsening of chronic colitis in M-CSF-deficient VXP-DSS-treated mice to reflect a critical role for macrophages in the protection against inflammation conferred by the vagus nerve.

This study extends our understanding of the counterinflammatory influence of the vagus nerve from a context of acute to chronic inflammation, reminiscent of the natural history of IBD. Previous studies were restricted to the induction of acute inflammation in healthy mice (9, 26, 33). Our results show that the modulatory effect of the vagus is also evident on a background of chronic inflammation but that it expires over time. Nevertheless, these results do not necessarily mitigate against a role for parasympathomimetic drugs and agonists of the {alpha}7-nicotinic receptor subtype in IBD. On the basis of the results of this study, we propose that such agents would be more beneficial in managing acute relapses rather than controlling chronic inflammation in IBD, and particularly in those with autonomic imbalance and parasympathetic impairment (29, 40).


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. M. Collins, Associate Dean Research, Faculty of Health, McMaster Univ. Medical Center, 1200 Main St. West, Hamilton, ON L8N 3Z5, Canada (e-mail: scollins{at}mcmaster.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405: 458–462, 2000.[CrossRef][Medline]
  2. Boughton-Smith NK, Wallace JL, Whittle BJ. Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease. Agents Actions 25: 115–123, 1988.[CrossRef][Web of Science][Medline]
  3. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78: 206–209, 1982.[CrossRef][Web of Science][Medline]
  4. Bucinskaite V, Kurosawa M, Lundeberg T. Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCK(A) receptors. Br J Pharmacol 129: 1649–1654, 2000.[CrossRef][Web of Science][Medline]
  5. Buller KM. Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic-pituitary-adrenal axis. Clin Exp Pharmacol Physiol 28: 581–589, 2001.[CrossRef][Web of Science][Medline]
  6. Celis E, Miller RW, Wiktor TJ, Dietzschold B, Koprowski H. Isolation and characterization of human T cell lines and clones reactive to rabies virus: antigen specificity and production of interferon-gamma. J Immunol 136: 692–697, 1986.[Abstract]
  7. Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 99: 14338–14343, 2002.[Abstract/Free Full Text]
  8. Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69: 238–249, 1993.[Web of Science][Medline]
  9. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immun 6: 844–851, 2005.[Medline]
  10. Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107: 1643–1652, 1994.[Web of Science][Medline]
  11. Domek MJ, Iwata F, Blackman EI, Kao J, Baker M, Vidrich A, Leung FW. Anti-neutrophil serum attenuates dextran sulfate sodium-induced colonic damage in the rat. Scand J Gastroenterol 30: 1089–1094, 1995.[Web of Science][Medline]
  12. Dvorak AM, Onderdonk AB, McLeod RS, Monahan-Earley RA, Cullen J, Antonioli DA, Blair JE, Morgan ES, Cisneros RL, Estrella P, Cohen Z, Silen W. Axonal necrosis of enteric autonomic nerves in continent ileal pouches. Possible implications for pathogenesis of Crohn's disease. Ann Surg 217: 260–271, 1993.[Web of Science][Medline]
  13. Eliakim R, Karmeli F, Rachmilewitz D, Cohen P, Fich A. Effect of chronic nicotine administration on trinitrobenzene sulphonic acid-induced colitis. Eur J Gastroenterol Hepatol 10: 1013–1019, 1998.[Web of Science][Medline]
  14. Elson CO, Cong Y, Brandwein S, Weaver CT, McCabe RP, Mahler M, Sundberg JP, Leiter EH. Experimental models to study molecular mechanisms underlying intestinal inflammation. Ann NY Acad Sci 859: 85–95, 1998.[CrossRef][Web of Science][Medline]
  15. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 109: 1344–1367, 1995.[CrossRef][Web of Science][Medline]
  16. Fernandez-Lago L, Rodriguez-Tarazona E, Vizcaino N. Differential secretion of interleukin-12 (IL-12) subunits and heterodimeric IL-12p70 protein by CD-1 mice and murine macrophages in response to intracellular infection by Brucella abortus. J Med Microbiol 48: 1065–1073, 1999.[Abstract/Free Full Text]
  17. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115: 182–205, 1998.[CrossRef][Web of Science][Medline]
  18. Galeazzi F, Haapala EM, van Rooijen N, Vallance BA, Collins SM. Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. Am J Physiol Gastrointest Liver Physiol 278: G259–G265, 2000.[Abstract/Free Full Text]
  19. Ghia JE, Blennerhassett P, Collins SM. Vagus nerve integrity and experimental colitis. Am J Physiol Gastrointest Liver Physiol (June 21, 2007). doi:10.1152/ajpgi.00098.2007.
  20. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131: 1122–1130, 2006.[CrossRef][Web of Science][Medline]
  21. Greenwood B, Mantle M. Mucin and protein release in the rabbit jejunum: effects of bethanechol and vagal nerve stimulation. Gastroenterology 103: 496–505, 1992.[Web of Science][Medline]
  22. Joyner K, Smith GP, Gibbs J. Abdominal vagotomy decreases the satiating potency of CCK-8 in sham and real feeding. Am J Physiol Regul Integr Comp Physiol 264: R912–R916, 1993.[Abstract/Free Full Text]
  23. Kemler MA, Barendse GA, Van Kleef M. Relapsing ulcerative colitis associated with spinal cord stimulation. Gastroenterology 117: 215–217, 1999.[CrossRef][Web of Science][Medline]
  24. Lindgren S, Lilja B, Rosen I, Sundkvist G. Disturbed autonomic nerve function in patients with Crohn's disease. Scand J Gastroenterol 26: 361–366, 1991.[Web of Science][Medline]
  25. Mahida YR, Rolfe VE. Host-bacterial interactions in inflammatory bowel disease. Clin Sci (Lond) 107: 331–341, 2004.[Medline]
  26. Mazelin L, Theodorou V, More J, Fioramonti J, Bueno L. Protective role of vagal afferents in experimentally-induced colitis in rats. J Auton Nerv Syst 73: 38–45, 1998.[CrossRef][Web of Science][Medline]
  27. McCafferty DM, Wallace JL, Sharkey KA. Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol Gastrointest Liver Physiol 272: G272–G280, 1997.[Abstract/Free Full Text]
  28. McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004: CD004722, 2004.
  29. Metz CN, Tracey KJ. It takes nerve to dampen inflammation. Nat Immun 6: 756–757, 2005.[Medline]
  30. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7: 145–173, 1989.[CrossRef][Web of Science][Medline]
  31. Munder M, Mallo M, Eichmann K, Modolell M. Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med 187: 2103–2108, 1998.[Abstract/Free Full Text]
  32. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98: 694–702, 1990.[Web of Science][Medline]
  33. Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D. Increased severity of experimental colitis in alpha 5 nicotinic acetylcholine receptor subunit-deficient mice. Neuroreport 16: 1123–1127, 2005.[CrossRef][Web of Science][Medline]
  34. Powrie F. Immune regulation in the intestine: a balancing act between effector and regulatory T cell responses. Ann NY Acad Sci 1029: 132–141, 2004.[CrossRef][Web of Science][Medline]
  35. Rioux JD. Progress towards identifying inflammatory bowel disease susceptibility genes. Novartis Found Symp 263: 3–11, 2004.[Medline]
  36. Ritter RC, Ladenheim EE. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin. Am J Physiol Regul Integr Comp Physiol 248: R501–R504, 1985.[Abstract/Free Full Text]
  37. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N. How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 223: 22–38, 2000.[Abstract/Free Full Text]
  38. Romagnani S. Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol 98: 279–285, 1992.[Web of Science][Medline]
  39. Saunders PR, Hanssen NP, Perdue MH. Cholinergic nerves mediate stress-induced intestinal transport abnormalities in Wistar-Kyoto rats. Am J Physiol Gastrointest Liver Physiol 273: G486–G490, 1997.[Abstract/Free Full Text]
  40. Taylor CT, Keely SJ. The autonomic nervous system and inflammatory bowel disease. Auton Neurosci 133: 104–114, 2007.[CrossRef][Web of Science][Medline]
  41. Tracey KJ. The inflammatory reflex. Nature 420: 853–859, 2002.[CrossRef][Medline]
  42. Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H, Tsujikawa K, Yamamoto H. Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol 171: 5507–5513, 2003.[Abstract/Free Full Text]
  43. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4: 673–684, 2005.[CrossRef][Web of Science][Medline]
  44. Unno T, Matsuyama H, Okamoto H, Sakamoto T, Yamamoto M, Tanahashi Y, Yan HD, Komori S. Muscarinic cationic current in gastrointestinal smooth muscles: signal transduction and role in contraction. Auton Autacoid Pharmacol 26: 203–217, 2006.[CrossRef][Medline]
  45. Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832, 1990.[Abstract/Free Full Text]
  46. Wiktor-Jedrzejczak W, Ratajczak MZ, Ptasznik A, Sell KW, Ahmed-Ansari A, Ostertag W. CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages. Exp Hematol 20: 1004–1010, 1992.[Web of Science][Medline]
  47. Yamada YK, Meager A, Yamada A, Ennis FA. Human interferon alpha and gamma production by lymphocytes during the generation of influenza virus-specific cytotoxic T lymphocytes. J Gen Virol 67: 2325–2334, 1986.[Abstract/Free Full Text]
  48. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444, 1990.[CrossRef][Medline]
  49. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444, 1990.[CrossRef][Medline]



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