Mast cells

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