Mast cells
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PAPEL DEL EJE CEREBROINTESTINAL EN LA SALUD y LA ENFERMEDAD • “Come poco, cena más poco; que la salud de todo el cuerpo se fragua en laSantos, oficina del Javier MD,estómago.” Phd de Cervantes Grupo de Miguel Neuro-inmuno-gastroenterología de veces, investigación Enfermedades Digestivas •Unidad “Muchas una cenade ligera, un sueño tranquilo y Institut deenvalentonaron Recerca Vall d´Hebron una mañana serena hasta el heroísmo a Servicio de Gastroenterología Hospital d´Hebron un hombre que, con un estómago pesado,Vall pocas horas Universitad Autònoma Barcelona de sueño y una mañana lluviosa, de habría sido un cobarde.” Edmund Burke GALT BRAIN 25 MARCH 2005 VOL 307 SCIENCE www.sciencemag.org BRAIN-GUT INTERFACE medweb.bham.ac.uk/.../ Teaching/GIT/ENS1.gif ENS LA BARRERA INTESTINAL 1.5 T Food/Year Area 400 m2 Junctional complex Epithelium Permeable < 2Kda Epithelial cells Enteroendocrine cells M cells Goblet cells Stem cells Myofibroblasts Extracellular matrix EL SISTEMA INMUNE INTESTINAL 1.5 T Food/Year Epithelium Area 400 m2 Permeable < 2Kda Lamina Propria 80% Plasma cells Lymph = Spleen MCs, Eos, DC, M… EL CEREBRO INTESTINAL Epithelium Area 400 m2 Permeable < 2Kda Lamina Propria 80% Plasma cells Lymph = Spleen MCs, Eos, DC, M… ENS 100 M Neurons -Sensory -Motor -Interneurons LA FLORA INTESTINAL Gut lumen > 1000 Sp. bacteria 1200 Sp. phages Virus Epithelium Area 400 m2 Permeable < 2Kda Lamina propria 80% Plasma cells Lymph = Spleen MCs, Eos, DC, M… ENS 100 M Neurons -Sensory -Motor -Interneurons Extrinsic Innervation of the Gut Vagal & Spinal afferents & efferents -Energy and fluid homeostasis -Sensation of discomfort and pain -Taste buds -Release neuropeptides Holzer P, et al. J Physiol Pharmacol 2001, 52, 4, 505—521 Peptidergic innervation of GALT • Substance P • Somatostat in • Opioids • VIP • Neurokinin A • CGRP • NPY • CRH Bueno, L Gut 2000;47:63iv-65iv Mast cells: Integral players of cell-neural circuitry • 1) Direct and functional innervation by peptidergic and vagal afferents. Mast cells: Integral players of cell-neural circuitry • 2) Express receptors for endocrine and paracrine messengers contained in those associated nerve endings. DIRECT EVIDENCE NE α, β2 SP NK1 NGF TrkA, p75 His H2 CRH CRH1,2 SS ? NT ? VIP VIPR1 PGE2 EP2,3,4 INDIRECT EVIDENCE Ach muscarinic Opioids ?? NPY CGRP Mast cells: Integral players of cell-neural circuitry • 3) Activated by molecules relased upon nerve stimulation. Suzuki et al;J Immunol 1999, Biol Pharm Bull 2005;28: 155 Mast cells: Integral players of cell-neural circuitry Cytokines SCF, TNF-α, NGF, TGFβ1, GM-CSF, IFNγ, IFNα/β, MCP-1 RANTES,, I-309, MIP-1α, bFGF, lymphothactin, IL-1α • 4) endothelin, Synthethise, store, metabolize and PDGF-AB, VEGF, PD-ECGF, relaxin,IL-1β, release molecules thatIL-8, modulate neural IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, 1L-12, IL-13. Amines:responses. histamine, 5-HT Neutral Proteases: tryptases, chymases Proteoglycans: heparin, chondroitin sulfate Acid hydrolases: β-hexosaminidase, β-glucuronidase, β-D-galactosidase, Arylsulfatase A. Lipid mediators: eicosanoids, acetylated phospholipids (PAF..) Others: Cathepsin G, Carboxypeptidase, NO & Oxygen radicals, VIP, acetylcholinesterase Mast cells: effector & sensory cells Postganglionic sympathetic nerve terminal Mechanical Chemical Toxins Alergens Superallergens Blood vessels CRH SP NE Peptidergic/Vagal afferents Hist, 5-HT, tryptase NGF Cytokines Chemokines Adhesion molecules NO, Growth factors Other cells Amines Others THE MAST CELL-EOSINOPHIL AXIS Bischoff CS, Gebhardt T. Immune Mechanisms in Inflammatory Bowel Disease, 2006 MODELO BIO-PSICOSOCIAL IBS Functional Disorder Organic Disease IMMUNOHISTOCHEMISTRY: CD117 (c-Kit) HEALTHY D-IBS JEJUNAL MAST CELLS IN IBS Mast cell counts Tryptase mRNA * * Fold-change 4 3 2 1 0 Healthy Tryptase release Carboxypepetidase A3 mRNA 3 2 1 0 Guilarte et al Gut, 2007 * 4 Fold-change * D-IBS Healthy D-IBS IBS MAST CELLS Barbara et al; GE, 2004, 2007 MAST CELLS IBS COLON Barbara et al; GE, 2004, 2007 SII: ORIGEN DE LAS ALT MOTORAS Y SENSITIVAS HEALTHY Control-IBS Biosci Biotechnol Biochem 2010; 74:232 SII: ALT MOTORAS Y SENSITIVAS GASES, DISTENSIÓN ABDOMINAL Y FLATULENCIA “La soberbia no es grandeza sino hinchazón; y lo que está hinchado parece grande pero no está sano." San Agustín “I tell you, we are here on Earth to fart around, and don't let anybody tell you different.” Kurt Vonnegut, Jr. En condiciones normales expulsamos de 0.5 a 2 litros diarios de gas en forma, fundamentalmente, de ventosidades, y en menor cuantía como… “A nadie le huelen sus pedos, ni sus hijos le parecen feos". Y, si no lo expulsamos Do functional patients have more gas in the gut ? 400 mL healthy functional subjects patients 0 GAS HANDLING IN PATIENTS WITH BLOATING 600 patients * Gas retained (infused minus evacuated), ml healthy subjects 0 0 Gas infusion,min 120 Abdominal accommodation in healthy subjects 12 Diaphragm µV 8 12 Anterior wall µV 9 0 gas infusion, min 60 Abdominal accommodation in patients 20 with bloating Diaphragm µV 12 12 Anterior wall µV 7 0 gas infusion, min 60 ABDOMINAL BLOATING IN FUNCTIONAL GUT DISORDERS 200 * mL 0 150 * mm 75 60 * BASAL DISTENSION mm 0 Tórax *P < 0.05 vs basal Media ± Error St Tórax *P < 0.05 vs basal Media ± Error St ABDOMINAL BLOATING :TREATMENT OPTIONS improve gut tolerance enhance gut handling correct somatic response reduce gut contents Reduce gut content: EFFECT OF DIET 5 10 0 -5 0 Flatulence Bloating Distension basal diet Borborigmi Pain low-residue diet Comfort/discomfort Rectal evacuation NORMAL Vall d'Hebron IMPAIRED Correct somatic responses: BIOFEEDBACK EMG coordination ELEVADA COMORBILIDAD • • • • • • • • • • • • • • Ansiedad, Depresión, Somatización, Hipocondría, PTSD. Fibromialgia Síndrome de fatiga crónica Trastornos de la articulación témporo-mandibular Cefalea migrañosa o tensional Dolor pélvico crónico Síndrome de dolor miofascial Cistitis intersticial Sensibilidad química múltiple Síndrome de piernas inquietas Dispepsia no ulcerosa, disquinesia biliar, reflujo Alergia e intolerancia alimentaria Dermatitis, psoriasis Esclerosis múltiple,… Gastroenterology 2002;1140. Am J Gastroenterol 2009;104:Suppl 1 COMORBILIDAD • En estos pacientes: – Los síntomas de son más severos y difíciles de tratar. – Disminuye la calidad de vida – Aumenta el uso de recursos sanitarios y sociales. – Crece el absentismo laboral y disminuye la productividad. – Se multiplica la repercusión económica. Whitehead WE, Palsson O, Jones KR. Gastroenterol 2002;1140-1156. PREVALENCIA global del ESTREÑIMIENTO AGRADECIMIENTOS Maria Vicario, PhD Mar Guilarte, MD, PhD student Carmen Alonso, MD, PhD student Cristina Martinez, PhD student Beatriz Lobo, MD, PhD student Ana González, PhD Meritxell Guilá, PhD student Marc Pigrau, MD, PhD student María Antolín, PhD Montse Casellas, technician Milagros Gallart, technician Josefina Heredia, administrative Fernando Azpiroz, MD, PhD NEURONEURO-IMMUNOIMMUNO-GASTROENTEROLOGY: UNRAVELING INTESTINAL INFLAMMATION GENOMICS, PROTEOMICS METABONOMICS up 30 min. after down 30 min. after
