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1.
PLoS One ; 8(6): e66884, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23776699

RESUMO

BACKGROUND: The histamine-1 receptor (H1R) antagonist ketotifen increased the threshold of discomfort in hypersensitive IBS patients. The use of peripherally restricted and more selective H1R antagonists may further improve treatment possibilities. We examined the use of fexofenadine and ebastine to reverse post-stress visceral hypersensitivity in maternally separated rats. METHODS: The visceromotor response to colonic distension was assessed in adult maternally separated and nonhandled rats pre- and 24 hours post water avoidance. Subsequently rats were treated with vehicle alone or different dosages of fexofenadine (1.8 and 18 mg/kg) or ebastine (0.1 and 1.0 mg/kg) and re-evaluated. Colonic tissue was collected to assess relative RMCP-2 and occludin expression levels by Western blot and histamine-1 receptor by RT-qPCR. ß-hexosaminidase release by RBL-2H3 cells was used to establish possible mast cell stabilizing properties of the antagonists. KEY RESULTS: Water avoidance only induced enhanced response to distension in maternally separated rats. This response was reversed by 1.8 and 18 mg/kg fexofenadine. Reversal was also obtained by 1.0 but not 0.1 mg/kg ebastine. RMCP-2 expression levels were comparable in these two ebastine treatment groups but occludin was significantly higher in 1.0 mg/kg treated rats. There were no differences in histamine-1 receptor expression between nonhandled and maternally separated rats. Fexofenadine but not ebastine showed mast cell stabilizing quality. CONCLUSIONS: Our results indicate that the peripherally restricted 2(nd) generation H1-receptor antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rat. These data justify future IBS patient trials with these well tolerated compounds.


Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/etiologia , Privação Materna , Estresse Psicológico/complicações , Animais , Western Blotting , Butirofenonas/farmacologia , Relação Dose-Resposta a Droga , Mastócitos/efeitos dos fármacos , Ocludina/metabolismo , Piperidinas/farmacologia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Terfenadina/análogos & derivados , Terfenadina/farmacologia
2.
Am J Gastroenterol ; 107(5): 715-26, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22488080

RESUMO

OBJECTIVES: Repeated exposure to stress leads to mast cell degranulation, microscopic inflammation, and subsequent visceral hypersensitivity in animal models. To what extent this pathophysiological pathway has a role in patients with the irritable bowel syndrome (IBS) has not been properly investigated. The objective of this study was to assess the relationship between visceral hypersensitivity, microscopic inflammation, and the stress response in IBS. METHODS: Microscopic inflammation of the colonic mucosa was evaluated by immunohistochemistry in 66 IBS patients and 20 healthy volunteers (HV). Rectal sensitivity was assessed by a barostat study using an intermittent pressure-controlled distension protocol. Salivary cortisol to a psychological stress was measured to assess the stress response. RESULTS: Compared with HV, mast cells, T cells, and macrophages were decreased in IBS patients. Similarly, λ-free light chain (FLC)-positive mast cells were decreased but not immunoglobulin E (IgE)- and IgG-positive mast cells. There were no differences between hypersensitive and normosensitive IBS patients. No relation was found between any of the immune cells studied and the thresholds of discomfort, urge, first sensation, or IBS symptoms (e.g., abdominal pain, stool-related complaints, bloating). Finally, stress-related symptoms and the hypothalamic-pituitary-adrenal-axis response to stress were not correlated with the number of mast cells or the presence of visceral hypersensitivity. CONCLUSIONS: Although the number of mast cells, macrophages, T cells, and λFLC-positive mast cells is decreased in IBS compared with HV, this is not associated with the presence of visceral hypersensitivity or abnormal stress response. Our data question the role of microscopic inflammation as an underlying mechanism of visceral hypersensitivity, but rather suggest dysregulation of the mucosal immune system in IBS.


Assuntos
Mucosa Intestinal/imunologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/fisiopatologia , Reto/fisiopatologia , Adulto , Biópsia por Agulha , Contagem de Células , Colo/imunologia , Colo/patologia , Colo/fisiopatologia , Colonoscopia , Feminino , Humanos , Hidrocortisona/sangue , Imuno-Histoquímica , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/patologia , Síndrome do Intestino Irritável/psicologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Mastócitos/imunologia , Mastócitos/patologia , Pessoa de Meia-Idade , Pressão , Limiar Sensorial , Estresse Psicológico/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/patologia , Adulto Jovem
3.
Biochim Biophys Acta ; 1822(1): 74-84, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21496484

RESUMO

Cross-talk between the immune- and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)-cells they may function as important intermediate cells. This review summarizes the current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Our main focus is on mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation. Furthermore we discuss mechanisms involved in physical mast cell-nerve interactions. This article is part of a Special Issue entitled: Mast cells in inflammation.


Assuntos
Comunicação Celular , Intestinos/fisiopatologia , Mastócitos/metabolismo , Neuroimunomodulação , Nociceptividade , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/fisiopatologia , Intestinos/inervação , Intestinos/patologia , Neurônios Aferentes/metabolismo , Dor Nociceptiva/imunologia , Dor Nociceptiva/patologia , Dor Nociceptiva/fisiopatologia , Transdução de Sinais , Estresse Fisiológico
5.
Gastroenterology ; 137(3): 1029-39, 1039.e1-4, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19427310

RESUMO

BACKGROUND & AIMS: The vagus nerve negatively regulates macrophage cytokine production via the release of acetylcholine (ACh) and activation of nicotinic acetylcholine receptors (nAChR). In various models of intestinal inflammation, vagus nerve efferent stimulation ameliorates disease. Given the actively constrained cytokine responses of intestinal macrophages, we explored the effect of nAChR activation on endocytosis and phagocytosis by macrophages residing in the peritoneal and mucosal compartment. METHODS: The phagocytic uptake by intestinal and peritoneal macrophages was measured by fluorescence-activated cell sorter analysis, and the nAChR involved was determined by pharmacologic blockade, short hairpin RNA-assisted gene knockdown, and the use of specific nAChR knockout mice. The effect of electrical vagus nerve stimulation on epithelial translocation and macrophage uptake of luminal particles was studied in mice. RESULTS: In isolated intestinal and peritoneal macrophages, nAChR activation enhanced endocytosis and phagocytosis. This effect was mediated via stimulated recruitment of GTPase Dynamin-2 to the forming phagocytic cup. These effects involve nAChR alpha4/beta2, rather than nAChR alpha7. Despite enhanced bacterial uptake, acetylcholine reduced NF-kappaB activation and pro-inflammatory cytokine production, while stimulating anti-inflammatory interleukin-10 production. Vagus nerve stimulation in mice altered mucosal immune responses by augmenting epithelial transport and uptake of luminal bacteria by lamina propria macrophages. CONCLUSIONS: ACh enhances phagocytic potential while inhibiting immune reactivity via nAChR alpha4/beta2 in mouse macrophages. Hence, vagus nerve efferent activity may stimulate surveillance in the intestinal mucosa and peritoneal compartment.


Assuntos
Mucosa Intestinal/citologia , Macrófagos/fisiologia , Fagocitose , Receptores Nicotínicos/metabolismo , Nervo Vago/fisiologia , Acetilcolina/farmacologia , Animais , Células Cultivadas , Agonistas Colinérgicos/farmacologia , Dinamina II/metabolismo , Endocitose/fisiologia , Técnicas In Vitro , Macrófagos/imunologia , Macrófagos Peritoneais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicotina/farmacologia
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