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1.
J Leukoc Biol ; 102(6): 1299-1312, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28684600

RESUMO

Life stress is a major risk factor in the onset and exacerbation of mast cell-associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin-releasing factor receptor subtype 1 (CRF1) in mast cell degranulation and associated disease pathophysiology. In a mast cell-dependent model of IgE-mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF1-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell-deficient KitW-sh/W-sh mice engrafted with CRF1-/- bone marrow-derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted KitW-sh/W-sh mice. KitW-sh/W-sh mice engrafted with CRF1-/- BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL-2H3, and human LAD2 mast cells demonstrated that although CRF1 activation did not directly induce MC degranulation, CRF1 signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca2+ from intracellular stores. Taken together, our results revealed a prominent role for CRF1 signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.


Assuntos
Degranulação Celular , Mastócitos/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Fisiológico , Anafilaxia/fisiopatologia , Animais , Células da Medula Óssea/citologia , Cálcio/metabolismo , Linhagem Celular , AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Imunoglobulina E/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Permeabilidade , Ratos , Receptores de Hormônio Liberador da Corticotropina/agonistas , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Transdução de Sinais , Urocortinas/metabolismo
2.
PLoS One ; 8(4): e59838, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23637741

RESUMO

BACKGROUND AND AIMS: The clinical onset and severity of intestinal disorders in humans and animals can be profoundly impacted by early life stress. Here we investigated the impact of early weaning stress in pigs on intestinal physiology, clinical disease, and immune response to subsequent challenge with enterotoxigenic F18 E. coli (ETEC). METHODOLOGY: Pigs weaned from their dam at 16 d, 18 d, and 20 d of age were given a direct oral challenge of F18 ETEC at 26 d of age. Pigs were monitored from days 0 to 4 post-infection for clinical signs of disease. On Day 4 post-ETEC challenge, ileal barrier function, histopathologic and inflammatory cytokine analysis were performed on ileal mucosa. RESULTS: Early weaned pigs (16 d and 18 d weaning age) exhibited a more rapid onset and severity of diarrhea and reductions in weight gain in response to ETEC challenge compared with late weaned pigs (20 d weaning age). ETEC challenge induced intestinal barrier injury in early weaned pigs, indicated by reductions in ileal transepithelial electrical resistance (TER) and elevated FD4 flux rates, in early weaned pig ileum but not in late weaned pigs. ETEC-induced marked elevations in IL-6 and IL-8, neutrophil recruitment, and mast cell activation in late-weaned pigs; these responses were attenuated in early weaned pigs. TNF levels elevated in ETEC challenged ileal mucosa from early weaned pigs but not in other weaning age groups. CONCLUSIONS: These data demonstrate the early weaning stress can profoundly alter subsequent immune and physiology responses and clinical outcomes to subsequent infectious pathogen challenge. Given the link between early life stress and gastrointestinal diseases of animals and humans, a more fundamental understanding of the mechanisms by which early life stress impacts subsequent pathophysiologic intestinal responses has implications for the prevention and management of important GI disorders in humans and animals.


Assuntos
Escherichia coli Enterotoxigênica/imunologia , Infecções por Escherichia coli/veterinária , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Doenças dos Suínos/imunologia , Desmame , Animais , Animais Recém-Nascidos , Citocinas/imunologia , Citocinas/metabolismo , Dextranos/metabolismo , Escherichia coli Enterotoxigênica/patogenicidade , Íleo/imunologia , Íleo/metabolismo , Íleo/microbiologia , Íleo/patologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/patologia , Mastócitos/imunologia , Mastócitos/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Permeabilidade , Estresse Fisiológico/imunologia , Suínos
3.
Vet Immunol Immunopathol ; 153(1-2): 146-52, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23453768

RESUMO

HIV infection is associated with intestinal mucosal dysfunction and probiotics offer the therapeutic potential to enhance the mucosal barrier in HIV+ patients. To evaluate the response of immunocompromised hosts to probiotics, we orally administered Lactobacillus acidophilus to cats with chronic feline immunodeficiency virus (FIV) infection. FIV infection significantly affected transcellular, but not paracellular, transport of small molecules across the intestinal epithelium. Additionally, probiotic treatment of FIV+ cats resulted in changes in cytokine release and mucosal leukocyte percentages that were not paralleled in FIV- cats. These results suggest a novel role for FIV in upregulating transcellular transport across the gastrointestinal epithelial barrier and demonstrate the potential therapeutic use of probiotic bacteria to restore intestinal homeostasis.


Assuntos
Síndrome de Imunodeficiência Adquirida Felina/imunologia , Imunidade nas Mucosas/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Probióticos/farmacologia , Animais , Transporte Biológico , Gatos , Impedância Elétrica , Síndrome de Imunodeficiência Adquirida Felina/metabolismo
4.
PLoS One ; 7(6): e39935, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22768175

RESUMO

BACKGROUND AND AIMS: Psychological stress is a predisposing factor in the onset and exacerbation of important gastrointestinal diseases including irritable bowel syndrome (IBS) and the inflammatory bowel diseases (IBD). The pathophysiology of stress-induced intestinal disturbances is known to be mediated by corticotropin releasing factor (CRF) but the precise signaling pathways remain poorly understood. Utilizing a porcine ex vivo intestinal model, the aim of this study was to investigate the mechanisms by which CRF mediates intestinal epithelial barrier disturbances. METHODOLOGY: Ileum was harvested from 6-8 week-old pigs, mounted on Ussing Chambers, and exposed to CRF in the presence or absence of various pharmacologic inhibitors of CRF-mediated signaling pathways. Mucosal-to-serosal flux of 4 kDa-FITC dextran (FD4) and transepithelial electrical resistance (TER) were recorded as indices of intestinal epithelial barrier function. RESULTS: Exposure of porcine ileum to 0.05-0.5 µM CRF increased (p<0.05) paracellular flux compared with vehicle controls. CRF treatment had no deleterious effects on ileal TER. The effects of CRF on FD4 flux were inhibited with pre-treatment of tissue with the non-selective CRF(1/2) receptor antagonist Astressin B and the mast cell stabilizer sodium cromolyn (10(-4) M). Furthermore, anti-TNF-α neutralizing antibody (p<0.01), protease inhibitors (p<0.01) and the neural blocker tetrodotoxin (TTX) inhibited CRF-mediated intestinal barrier dysfunction. CONCLUSION: These data demonstrate that CRF triggers increases in intestinal paracellular permeability via mast cell dependent release of TNF-α and proteases. Furthermore, CRF-mast cell signaling pathways and increases in intestinal permeability require critical input from the enteric nervous system. Therefore, blocking the deleterious effects of CRF may address the enteric signaling of mast cell degranulation, TNFα release, and protease secretion, hallmarks of IBS and IBD.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/lesões , Mastócitos/enzimologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Degranulação Celular/efeitos dos fármacos , Dextranos , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/patologia , Fluoresceína-5-Isotiocianato/análogos & derivados , Íleo/efeitos dos fármacos , Íleo/patologia , Íleo/fisiopatologia , Técnicas In Vitro , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Peso Molecular , Testes de Neutralização , Ocludina/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeo Hidrolases/metabolismo , Permeabilidade/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos , Sus scrofa , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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