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• W2168682720 abstract "Background & Aims: The recently proposed Inflammatory Reflex describes an interaction between the vagus nerve and peripheral macrophages, resulting in attenuation of proinflammatory cytokine release in response to systemic exposure to bacterial endotoxin. The purpose of this study was to determine whether a similar vagus/macrophage axis modulates the inflammatory responses in the colon in mice. Methods: We assessed the Disease Activity Index (DAI), macroscopic and histologic damage, serum amyloid-P level, and myeloperoxidase activity in colitis induced by administration of dextran sodium sulfate (DSS) in healthy and vagotomized C57BL/6 and in mice deficient in macrophage-colony stimulating factor (M-CSF)–induced and in hapten-induced colitis. A pyloroplasty was performed in vagotomized mice. Results: DAI, macroscopic and histologic scores, myeloperoxidase activity, levels of serum amyloid-P, and colonic tissue levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were increased significantly in vagotomized mice 5 days post-DSS and 3 days after hapten-induced colitis compared with sham-operated mice that received DSS or the hapten. Pretreatment with nicotine significantly decreased each of these markers in vagotomized mice with DSS colitis, and all markers except DAI and IL-6 in sham-operated DSS-treated mice. Conversely, hexamethonium treatment significantly increased each of these markers in the sham-operated DSS-treated mice. Vagotomy had no effect on the colitis in M-CSF–deficient mice. Conclusions: The vagus nerve plays a counterinflammatory role in acute colitis via a macrophage-dependent mechanism, involving hexamethonium-sensitive nicotinic receptors. The identification of a counterinflammatory neural pathway would open new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease. Background & Aims: The recently proposed Inflammatory Reflex describes an interaction between the vagus nerve and peripheral macrophages, resulting in attenuation of proinflammatory cytokine release in response to systemic exposure to bacterial endotoxin. The purpose of this study was to determine whether a similar vagus/macrophage axis modulates the inflammatory responses in the colon in mice. Methods: We assessed the Disease Activity Index (DAI), macroscopic and histologic damage, serum amyloid-P level, and myeloperoxidase activity in colitis induced by administration of dextran sodium sulfate (DSS) in healthy and vagotomized C57BL/6 and in mice deficient in macrophage-colony stimulating factor (M-CSF)–induced and in hapten-induced colitis. A pyloroplasty was performed in vagotomized mice. Results: DAI, macroscopic and histologic scores, myeloperoxidase activity, levels of serum amyloid-P, and colonic tissue levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were increased significantly in vagotomized mice 5 days post-DSS and 3 days after hapten-induced colitis compared with sham-operated mice that received DSS or the hapten. Pretreatment with nicotine significantly decreased each of these markers in vagotomized mice with DSS colitis, and all markers except DAI and IL-6 in sham-operated DSS-treated mice. Conversely, hexamethonium treatment significantly increased each of these markers in the sham-operated DSS-treated mice. Vagotomy had no effect on the colitis in M-CSF–deficient mice. Conclusions: The vagus nerve plays a counterinflammatory role in acute colitis via a macrophage-dependent mechanism, involving hexamethonium-sensitive nicotinic receptors. The identification of a counterinflammatory neural pathway would open new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease. Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder that affects up to 500 per 100,000 persons in Western countries,1Rutgeerts P. Protagonist: Crohn’s disease recurrence can be prevented after ileal resection.Gut. 2002; 51: 152-153Crossref PubMed Scopus (45) Google Scholar and is considered the consequence of an aberrant immune response to luminal antigens.2Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis.Gastroenterology. 1998; 115: 182-205Abstract Full Text Full Text PDF PubMed Scopus (1880) Google Scholar Tissue injury results from the release of inflammatory mediators, including acid metabolites and proinflammatory cytokines.3Papadakis K.A. Targan S.R. Role of cytokines in the pathogenesis of inflammatory bowel disease.Annu Rev Med. 2000; 51: 289-298Crossref PubMed Scopus (628) Google Scholar, 4Sartor R.B. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases.Am J Gastroenterol. 1997; 92: 5S-11SPubMed Google Scholar, 5Podolsky D.K. Inflammatory bowel disease (1).N Engl J Med. 1991; 325: 928-937Crossref PubMed Scopus (955) Google Scholar In particular, increased secretion of proinflammatory cytokines is considered to be important for exacerbation of IBD, and several assays of therapeutic approaches targeting inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), have been investigated extensively.6Atreya R. Mudter J. Finotto S. Mullberg J. Jostock T. Wirtz S. Schutz M. Bartsch B. Holtmann M. Becker C. Strand D. Czaja J. Schlaak J.F. Lehr H.A. Autschbach F. Schurmann G. Nishimoto N. Yoshizaki K. Ito H. Kishimoto T. Galle P.R. Rose-John S. Neurath M.F. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo.Nat Med. 2000; 6: 583-588Crossref PubMed Scopus (1080) Google Scholar, 7Ferretti M. Casini-Raggi V. Pizarro T.T. Eisenberg S.P. Nast C.C. Cominelli F. Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis.J Clin Invest. 1994; 94: 449-453Crossref PubMed Scopus (147) Google Scholar Cytokine production can be modulated by neurotransmitters, including those of the autonomic nervous system.8Matsunaga K. Klein T.W. Friedman H. Yamamoto Y. Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine.J Immunol. 2001; 167: 6518-6524Crossref PubMed Scopus (208) Google Scholar 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.9Dvorak A.M. Onderdonk A.B. McLeod R.S. Monahan-Earley R.A. Cullen J. Antonioli D.A. Blair J.E. Morgan E.S. Cisneros R.L. Estrella P. et al.Axonal necrosis of enteric autonomic nerves in continent ileal pouches Possible implications for pathogenesis of Crohn’s disease.Ann Surg. 1993; 217: 260-271Crossref PubMed Scopus (43) Google Scholar Up to 35% of patients with ulcerative colitis (UC) show autonomic with impaired parasympathetic function, resulting in sympathetic dominance.10Lindgren S. Lilja B. Rosen I. Sundkvist G. Disturbed autonomic nerve function in patients with Crohn’s disease.Scand J Gastroenterol. 1991; 26: 361-366Crossref PubMed Scopus (106) Google Scholar Studies in animal models have raised the possibility of autonomic imbalance, which contributes to the inflammatory drive in IBD. This is based on observations that the sympathectomy improves experimental colitis11McCafferty D.M. Wallace J.L. Sharkey K.A. Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat.Am J Physiol. 1997; 272: G272-G280PubMed Google Scholar and that administration of the parasympathomimetic nicotine improves colitis in the animal model.12Eliakim R. Karmeli F. Rachmilewitz D. Cohen P. Fich A. Effect of chronic nicotine administration on trinitrobenzene sulphonic acid-induced colitis.Eur J Gastroenterol Hepatol. 1998; 10: 1013-1019Crossref PubMed Scopus (41) Google Scholar Recently, attention has focused on the role of the vagus nerve in modulating inflammatory responses. Based on studies of cytokine release13Blalock J.E. Harnessing a neural-immune circuit to control inflammation and shock.J Exp Med. 2002; 195: F25-F28Crossref PubMed Scopus (57) Google Scholar after systemic exposure to bacterial lipopolysaccharide, Tracey14Tracey K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2654) Google Scholar postulated the existence of a vagally mediated anti-inflammatory reflex in which the presence of proinflammatory cytokines in the periphery is detected by vagal afferents, resulting in a vagal efferent response associated with an attenuation of cytokine release from macrophages via nicotinic acetylcholine receptors. It has been shown that vagotomy (VX) accelerated lipopolysaccharide-induced septic shock and increased systemic TNF-α production, and that selective inhibition of vagal afferent fibers worsened hapten-induced colitis.15Mazelin L. Theodorou V. More J. Fioramonti J. Bueno L. Protective role of vagal afferents in experimentally-induced colitis in rats.J Auton Nerv Syst. 1998; 73: 38-45Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Conversely, the stimulation of the vagus nerve selectively down-regulated production of proinflammatory cytokines.16van Westerloo D.J. Giebelen I.A. Florquin S. Daalhuisen J. Bruno M.J. de Vos A.F. Tracey K.J. van der Poll T. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis.J Infect Dis. 2005; 191: 2138-2148Crossref PubMed Scopus (273) Google Scholar, 17Wang H. Liao H. Ochani M. Justiniani M. Lin X. Yang L. Al-Abed Y. Metz C. Miller E.J. Tracey K.J. Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.Nat Med. 2004; 10: 1216-1221Crossref PubMed Scopus (993) Google Scholar This vagal reflex involves the release of acetylcholine, which interacts with the α 7 subunit nicotinic receptor on macrophages.18Wang H. Yu M. Ochani M. Amella C.A. Tanovic M. Susarla S. Li J.H. Yang H. Ulloa L. Al-Abed Y. Czura C.J. Tracey K.J. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.Nature. 2003; 421: 384-388Crossref PubMed Scopus (2498) Google Scholar This is supported further by demonstrations in vitro that nicotinic receptors are involved in the selective down-regulation of lipopolysaccharide-induced release of TNF-α, IL-6, and IL-1β in cultured macrophages.19Borovikova L.V. Ivanova S. Zhang M. Yang H. Botchkina G.I. Watkins L.R. Wang H. Abumrad N. Eaton J.W. Tracey K.J. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature. 2000; 405: 458-462Crossref PubMed Scopus (3046) Google Scholar Macrophages are an important component of the inflammatory response in IBD. Recruited macrophages are evident in the lamina propria in tissues from patients with IBD,20Mahida Y.R. Wu K. Jewell D.P. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn’s disease.Gut. 1989; 30: 835-838Crossref PubMed Scopus (378) Google Scholar and those cells are responsible for the production of proinflammatory cytokines.21Woywodt A. Ludwig D. Neustock P. Kruse A. Schwarting K. Jantschek G. Kirchner H. Stange E.F. Mucosal cytokine expression, cellular markers and adhesion molecules in inflammatory bowel disease.Eur J Gastroenterol Hepatol. 1999; 11: 267-276Crossref PubMed Scopus (81) Google Scholar The existence of the vagal inflammatory reflex has been promoted in the context of the acute paradigm of septic shock. The extent to which a similar vagus–macrophage axis exists in the context of intestinal inflammation remains to be determined. Thus, the present study examined the role of the vagus in 2 models of colitis induced by a lymphocyte-independent model by oral administration of dextran sodium sulfate (DSS)22Elson C.O. Sartor R.B. Tennyson G.S. Riddell R.H. Experimental models of inflammatory bowel disease.Gastroenterology. 1995; 109: 1344-1367Abstract Full Text PDF PubMed Scopus (1102) Google Scholar, 23Okayasu 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. 1990; 98: 694-702Abstract PubMed Google Scholar and by a lymphocyte-dependent model using intracolonic administration of dinitrobenzene sulfonic acid (DNBS),24Sturiale S. Barbara G. Qiu B. Figini M. Geppetti P. Gerard N. Gerard C. Grady E.F. Bunnett N.W. Collins S.M. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P.Proc Natl Acad Sci U S A. 1999; 96: 11653-11658Crossref PubMed Scopus (163) Google Scholar and determined whether a macrophage subset was involved. Male C57BL/6 mice (7–9 weeks old) were purchased from Harlan Animal Suppliers (Indianapolis, IN) and maintained in the animal care facility at McMaster University under specific pathogen-free conditions. Macrophage-Colony Stimulating Factor (M-CSF)-C57BL/6–deficient (op/op) and heterozygote op/? breeding pairs were purchased from Jackson (Bar Harbor, ME). Nonmutant mice (op/+ or +/+) are indistinguishable from each other and therefore are named op/?. Op/op mice have osteopetrosis and lack teeth; they were therefore fed a powdered diet, whereas op/? 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 week before experimentation. All experiments were approved by the McMaster University Animal Research Ethics Board and were conducted under the Canadian Council on Animal Care Guidelines. Mice were anesthetized using ketamine (150 mg/kg, intraperitoneally [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. VX and pyloroplasty (VXP) subsequently were 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. The ability of cholecystokinin octapeptide (CCK-8) to reduce food intake is completely dependent on the integrity of the vagus nerve.25Ritter R.C. Ladenheim E.E. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin.Am J Physiol. 1985; 248: R501-R504PubMed Google Scholar To determine the functional integrity of VX in our study, mice received 40 μg/kg IV of CCK-8 (Sigma, Oakville, Ontario, Canada) 10 days after VXP or sham surgery and food intake was measured over 24 hours. The integrity of VX lasts well beyond the time frame of the present studies, and for as long as 62 days (Ghia et al, unpublished observation). The 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 using microscopic inspection. Two days after the end of the CCK-8 experiment, DSS (molecular weight, 40 kilodaltons; ICN Biomedicals Inc, Aurora, OH) was added to the drinking water in a final concentration of 5% (wt/vol) for 5 days.26Verdu E.F. Deng Y. Bercik P. Collins S.M. Modulatory effects of estrogen in two murine models of experimental colitis.Am J Physiol. 2002; 283: G27-G36Google Scholar Controls were all time-matched and consisted of mice that received normal drinking water only. Mean DSS consumption was noted per cage each day. For the DNBS study, mice were anesthetized with enflurane (Abbott, Abott Park, IL). A 10-cm long PE-90 tubing (ClayAdam, Parsippany, NJ), attached to a tuberculin syringe, was inserted 3.5 cm into the colon. Colitis was induced by administration of 100 μL of 4 mg of DNBS solution (ICN, Biomedical Inc.) in 30% ethanol for 3 days.24Sturiale S. Barbara G. Qiu B. Figini M. Geppetti P. Gerard N. Gerard C. Grady E.F. Bunnett N.W. Collins S.M. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P.Proc Natl Acad Sci U S A. 1999; 96: 11653-11658Crossref PubMed Scopus (163) Google Scholar Control mice (without colitis) received saline. Mice with colitis were supplied with 8% sucrose in drinking water to prevent dehydration. Exposure to DSS (5%) commenced on the 14th day after surgery and continued for 5 days. In separate experiments, nicotine (20 μg/mL) was added to the drinking water 10 days before and for 5 days after the induction of colitis in VXP.12Eliakim R. Karmeli F. Rachmilewitz D. Cohen P. Fich A. Effect of chronic nicotine administration on trinitrobenzene sulphonic acid-induced colitis.Eur J Gastroenterol Hepatol. 1998; 10: 1013-1019Crossref PubMed Scopus (41) Google Scholar In separate experiments, hexamethonium (10 mg/kg) was administered by subcutaneous (SC) injection twice a day for 5 days27Galeazzi F. Blennerhassett P.A. Qiu B. O’Byrne P.M. Collins S.M. Cigarette smoke aggravates experimental colitis in rats.Gastroenterology. 1999; 117: 877-883Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar post-DSS in sham-operated mice. Disease Activity Index (DAI) scores historically have correlated well with the pathologic findings in a DSS-induced model of IBD.28Cooper H.S. Murthy S.N. Shah R.S. Sedergran D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis.Lab Invest. 1993; 69: 238-249PubMed Google Scholar DAI is the combined score of weight loss, stool consistency, and bleeding. Scores were defined as follows: for weight: 0, no loss; 1, 5%–10%; 2, 10%–15%; 3, 15%–20%; and 4, 20% weight loss; for stool: 0, normal; 2, loose stool; and 4, diarrhea; and for bleeding: 0, no blood; 2, presence (Hemoccult II positive; Beckman Coulter, Fullerton, CA); and 4, gross blood. DAI was scored from days 0–5 during DSS treatment. Blood was collected either 5 or 3 days after the beginning of the DSS or DNBS treatment, respectively, by intracardiac puncture in anesthetized (enflurane) mice. Serum amyloid-P (SAP), a major acute-phase protein in mice,29Szalai A.J. van Ginkel F.W. Dalrymple S.A. Murray R. McGhee J.R. Volanakis J.E. Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice.J Immunol. 1998; 160: 5294-5299PubMed Google Scholar was measured by an enzyme-linked immunosorbent assay as an acute inflammatory marker. A 96-well microplate (MaxiSorp; Nunc, Naperville, IL) was coated with a sheep anti-mouse SAP polyclonal antibody (Calbiochem, San Diego, CA) overnight. One-hundred microliters of either SAP standard or serum samples from mice were added and then incubated for 1.5 hours at room temperature. A rabbit anti-mouse SAP polyclonal antibody (Calbiochem) was added, and the plate was incubated for another 1.5 hours at room temperature. A horseradish-peroxidase–conjugated mouse anti-rabbit IgG (chain specific) monoclonal antibody (Sigma) was added, and the plate was incubated for another 1.5 hours at room temperature. Finally, substrate solution containing o-phenylenediamine (Sigma) was added to each well and incubated for 30 minutes at room temperature. The absorbance at 492 nm was measured with a microplate reader. Standard SAP samples were used to create a standard curve. The colon was removed and divided and used for the following measurements. Five days after the beginning of the DSS or 3 days after the beginning of the DNBS treatment, the mice were killed and the abdominal cavity was opened, the colon was located, and observations on distension, fluid content, hyperemia, and erythema were recorded. The colon was removed and opened longitudinally, and macroscopic damage was assessed immediately. Macroscopic scores were performed using a previously described scoring system for DSS colitis28Cooper H.S. Murthy S.N. Shah R.S. Sedergran D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis.Lab Invest. 1993; 69: 238-249PubMed Google Scholar and for DNBS.30Appleyard C.B. Wallace J.L. Reactivation of hapten-induced colitis and its prevention by anti-inflammatory drugs.Am J Physiol. 1995; 269: G119-G125PubMed Google Scholar Formalin-fixed colon segments were paraffin-embedded and 3-μm sections were stained with H&E. Colonic damage was scored based on a published scoring system that considers architectural derangements, goblet cell depletion, edema/ulceration, and degree of inflammatory cell infiltrate.28Cooper H.S. Murthy S.N. Shah R.S. Sedergran D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis.Lab Invest. 1993; 69: 238-249PubMed Google Scholar Myeloperoxidase (MPO) activity was determined following an established protocol.31Boughton-Smith N.K. Wallace J.L. Whittle B.J. Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease.Agents Actions. 1988; 25: 115-123Crossref PubMed Scopus (102) Google Scholar Briefly, MPO activity, used as a marker of neutrophilic infiltration, was extracted and the activity was measured using a modified version of the method described by Bradley et al.32Bradley P.P. Priebat D.A. Christensen R.D. Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker.J Invest Dermatol. 1982; 78: 206-209Crossref PubMed Scopus (3070) Google Scholar Tissue samples were homogenized (50 mg/mL) in ice-cold 50 mmol/L potassium phosphate buffer (pH 6.0) containing .5% hexadecyl trimethyl ammonium bromide (Sigma). The homogenate was freeze-thawed 3 times, briefly sonicated, and then centrifuged at 12,000 rpm for 12 minutes at 4°C. The supernatant then was 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 minute at room temperature. The colonic sample was homogenized in 700 μL of Tris-HCl buffer containing protease inhibitors (Sigma). Samples were centrifuged for 30 minutes, and the supernatant was frozen at 80°C until assay. Cytokine levels (IL-1β, IL-6, and TNF-α) were determined using an enzyme-linked immunosorbent assay commercial kit (Quantikine M murine; R&D Systems, Minneapolis, MN). Results are presented as means ± SD. Statistical analysis was performed using 1-way analysis of variance followed by the Student–Newman–Keuls multiple comparisons post hoc analysis and a P value of less than .05 was considered significant. Food intake was decreased significantly by 84.2% ± 1.8% after CCK-8 injection in sham-operated mice compared with VXP mice +2.7% ± 1.1% (data not shown). The VXP mice in which CCK induced a significant reduction in food intake were excluded from subsequent studies on the assumption that the vagotomy was incomplete. In contrast, water intake was not different between VXP and sham-operated mice (5.3 ± 0.6 and 6.5 ± 0.3 mL/24 h, respectively). VXP caused no changes in weight gain, colonic appearance, histology, SAP, MPO, or cytokine levels in C57BL/6 mice without colitis. TNF-α, IL-1β, and IL-6 colonic tissue levels were below the lowest standard of the assay in these mice (data not shown). DSS induced a colitis characterized by weight loss and frequent stools; this was evident by day 3 in sham-operated mice. In VXP mice, the onset of colitis was accelerated, as injury reflected in the DAI were seen within 2 days of DSS. As shown in Figure 1A, the DAI was significantly higher in VXP mice compared with the sham-operated mice on each of the 5 days of colitis, the differences between groups reached statistical significance on all 5 days of DSS regimen. As shown in Figure 1B, VXP increased the macroscopic scores significantly at day 5 after DSS. DSS increased MPO activity from 0.25 ± 0.15 U/mg in control mice to 2.57 ± 0.51 U/mg. As shown in Figure 1C, VXP resulted in significantly higher MPO activity of 7.22 ± 1.73 U/mg compared with sham-operated mice. SAP levels increased from 31.5 ± 8.9 in DSS sham-operated mice to 154.9 ± 19.4 μg/mL in DSS–VXP mice (Figure 1D). As shown in Figure 2, VXP significantly increased the severity of colitis with histologic scores increasing from 1.6 ± 0.6 to 2.7 ± 0.5 (Figure 2A). This was associated with a greater loss of tissue architecture, edema, and a massive, mixed immune cell infiltrate (mononuclear cells, neutrophils, and eosinophils) (Figure 2D). In addition, we found significantly greater fold increases in the levels of TNF-α (4.5-fold), IL-1β (3.2-fold), and IL-6 (11.4-fold) in the colon of DSS-treated mice with VXP compared with sham-operated mice (Figure 3).Figure 2(A) Histologic scores in mice 5 days post-DSS colitis and in mice without colitis. Five days after colitis, VXP increased the histologic score (n = 12) and nicotinic (Nico) treatment (20 μg/mL) decreased the score significantly (n = 10). Hexamethonium (Hex) (10 mg/kg, SC) increases the score in the sham-operated group significantly (n = 8) and nicotine tends to decrease it (n = 6). +P < .05 vs sham-DSS treated. ++P < .05. (B) VXP increases the score in op/? mice (n = 9), but not in op/op mice (n = 9). The values are shown as means ± SD. *P < .05 vs op/? sham-DSS treated. **P < .05. (A and B) □, Sham; ■, VXP. (C) Appearance of a control colon in a DSS-treated mouse, associated with one-third loss and shortening of crypts, a small mucosal erosion, mild inflammatory cell infiltration, and mild goblet cell depletion, (D) and in a vagotomized mouse higher areas of erosion are associated with more inflammatory cell infiltration. H&E staining: magnification, 10×.View Large Image Figure ViewerDownload (PPT)Figure 3Effect of VXP on colonic cytokine level by enzyme-linked immunosorbent assay measurements. VXP results in significant increases in DSS-treated mice of all 3 cytokines (n = 12). Nicotinic (Nico) treatment (20 μg/mL) decreases the cytokines significantly (n = 10). Hexamethonium (Hex) (10 mg/kg, SC) shows a significant increase of all 3 cytokines in sham-operated DSS-treated mice (n = 8). Nicotine induces a significant decrease of 2 cytokines in sham-operated DSS-treated mice (n = 6). Vagotomy increases levels in op/? mice (n = 9), but not in op/op mice (n = 9). +P < .05 vs sham-DSS treated. *P < .05 vs VXP-DSS treated. #P < .05 vs op/? sham-DSS treated.View Large Image Figure ViewerDownload (PPT) Nicotine treatment (20 μg/mL) significantly decreased the DAI during the first 3 days. Nicotine also significantly decreased the macroscopic damage scores in VXP–DSS–treated mice compared with VXP mice with DSS colitis; only macroscopic changes were reduced significantly in sham-operated DSS-treated mice (Figures 1A and B). MPO activity was decreased significantly in both VXP and sham-operated mice treated with nicotine during DSS treatment (3.77 ± 0.16 U/mg) (Figure 1C). Nicotine also reduced SAP levels significantly in VXP and sham-operated DSS-treated mice (Figure 1D). These mice also showed an improvement in histologic scores (Figure 2A). Nicotine treatment reduced the levels of all 3 proinflammatory cytokines in VXP mice significantly, but only TNF-α and IL-1β in sham-operated DSS-treated mice (Figure 3). Hexamethonium (10 mg/kg) was administered to sham-operated DSS mice and significantly increased the macroscopic score (Figure 1B), MPO activity (Figure 1C), and SAP levels (Figure 1D) compared with saline-treated mice. Hexamethonium also significantly increased histologic damage scores (Figure 2A) and the levels of IL-1b, TNF-α, and IL-6 as shown in Figure 3. To elucidate the role of the macrophage we used mice deficient in M-CSF. DSS induced significant colitis in both op/op and op/? mice, although more inflammation was seen in the op/? mice. As shown in Figures 4A and B, DSS 5% significantly increased macroscopic and histologic damage scores at day 5 in op/op and op/? mice. The histologic score increased from 0.45 ± 0.33 to 1.24 ± 0.15 for the op/op group and from 0.3 ± 0.3 to 2.12 ± 0.22 in op/? mice. Similarly, DSS 5% significantly increased MPO activity (Figure 4C) and SAP levels (Figure 4D). Op/op mice developed a slower onset of DSS-induced colitis compared with op/? mice, as shown in Figure 5A. In contrast to the increased severity of colitis seen in op/? mice with VXP compared with sham-operated op/? mice, VXP had no effect on the severity of colitis in op/op mice. Similarly, there was less macroscopic damage in op/op mice with colitis compared with op/? (Figure 5B). In keeping with this pattern, MPO activity in op/op mice was lower compared with op/? (1.23 ± 0.31 and 2.04 ± 0.54 U/mg, respectively). As shown in Figure 5C, VXP increased MPO in op/? mice with colitis but it had no effect in op/op mice. Measurements of SAP and cytokine levels followed a similar pattern, as shown in Figure 5D and Figure 3. Histologic damage scores in op/op DSS-treated mice were decreased significantly compared with op/? from 2.12 ± 0.22 to 1.24 ± 0.15 and VXP in op/op DSS-treated mice did not alter this difference, as shown in Figure 2B. As shown in Table 1, VXP significantly increased the macroscopic scores at day 3 after DNBS. DNBS increased MPO activity from 0.5 ± 0.13 U/mg in control mice to 1.74 ± 0.39 U/mg. As shown in Table 1, VXP resulted in significantly higher MPO activity of 4.72 ± 0.75 U/mg compared with sham-operated mice. SAP levels increased from 45 ± 5 μg/mL in DSS–sham-operated mice to 198 ± 12 μg" @default.
• W2168682720 created "2016-06-24" @default.
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• W2168682720 date "2006-10-01" @default.
• W2168682720 modified "2023-10-17" @default.
• W2168682720 title "The Vagus Nerve: A Tonic Inhibitory Influence Associated With Inflammatory Bowel Disease in a Murine Model" @default.
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