TRANSLOCAO

BACTERIANA
P r o f . J O O B AT I S TA TA J R A
C I R U R G I O G E R A L
M E S T R E E M C I R U R G I A

domingo, 16 de janeiro de 2011

HISTRICO

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TRAUMA X SEPSE X DMOS

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EVIDNCIAS

SIRS PERSISTENTE E DMOS

SIRS E DMOS
AUSNCIA DE FOCO
IDENTIFICVEL.

Paciente Grande Queimado

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Manuteno de um
estado inflamatrio
persistente e
desregulado?
R E S P O N S V E I S

? ? ? ? ?

QUAL O MOTOR DESTE ESTADO ???

domingo, 16 de janeiro de 2011

TRANSLOCAO
A BARREIRA INTESTINAL
LINFONODOS
ESTREIS
VEIA PORTA

Mecanismos de proteo

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estudos de
translocao
Modelo

Quebra
Crescimento
de
bacteriano
barreira

Defesa

Antibiticos

Queimadura

+/-

Choque

Ictercia

Isquemia
Heptica

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EVIDNCIAS

MODELOS EXPERIMENTAIS
Translocation of Certain Indigenous Bacteria from the
Gastrointestinal Tract to the Mesenteric Lymph Nodes and
Other Organs in a Gnotobiotic Mouse Model
RODNEY D. BERG* AND ALVA W. GARLINGTON
Department of Microbiology and Immunology, Louisiana State University Medical Center, School of
Medicine in Shreveport, Shreveport, Louisiana 71130

INFECTION AND IMMUNITY, Feb. 1979, p. 403411

Toll-like receptor-4 is required for intestinal response to epithelial injury and

limiting bacterial translocation in a murine model of acute colitis.
Masayuki Fukata, Kathrin S. Michelsen, Rajaraman Eri, Lisa S. Thomas, Bing Hu, Katie Lukasek, Cynthia C. Nast, Juan Lechago, Ruliang Xu,
Yoshikazu Naiki, Antoine Soliman, Moshe Arditi, and Maria T. Abreu
1

Am J Physiol Gastrointest Liver Physiol 288: G1055-G1065, 2005;

domingo, 16 de janeiro de 2011

1,5

TRANSLOCAO
BACTERIANA
CONCEITO
Deslocamento de bactrias ou seus produtos atravs
do TGI para stios estreis.
Wolochow et al 1966.
Berg e Garlington 1979.

domingo, 16 de janeiro de 2011

COMPONENTES DA
BARREIRA INTESTINAL
J ALLERGY CLIN IMMUNOL
JULY 2009

MECNICO
Peristalse
Muco
Epitlio
Renovao epitelial
Groschwitz e Hogan. J Allergy Clin Immunol 2009

1. Pathways of epithelial permeability. Transcellular permeability is

ociated with solute or water movement through intestinal epithelial
s. Paracellular permeability is associated with movement in the interular space between epithelial cells and is regulated by TJs localized at
Tipos de permeabilidade e funes de proteo.
junction of the apical-lateral membranes.
domingo, 16 de janeiro de 2011

COMPONENTES DA
BARREIRA INTESTINAL
MICROBIOLOGIA
Aquisio de flora materna.
desenvolvimento imune
Equilbrio como proteo.
Antagonismo bacteriano.
Resistncia a colonizao.
Inibio de contato.

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FUNO DA MICROBIOTA
Como o TGI consegue distinguir bactrias
comensais das patognicas?
Qual a importncia do sistema comensal no
desenvolvimento imunolgico em
mamferos?

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GALT
SISTEMA
IMUNE DE
DEFESA

Janine L. Coombes & Fiona Powrie

Nature Reviews Immunology 8, 435-446 (June 2008)

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Potenciais rotas de
translocao bacteriana
BLUK113-Langnas

November 26, 2007

17:58

Linfonodo
INVASO

CHAPTER 2

Linfa
Figure 2.1 Cross-section through jejunum
(left) and ileum (right) showing crypt-villus
structure. (Images kindly supplied by
P. Domizio.)

proximal large intestine, up to the distal third of the

transverse colon, is also from branches of the superior mesenteric artery. However, the distal large intestine receives its blood supply via branches of the inferior mesenteric artery. Corresponding veins drain blood
from both the small and large intestine into the portal
circulation. It can be seen that the superior mesenteric
artery and vein are of paramount importance to blood
supply to and from the intestine and is the reason why
infarction and thrombosis are so devastating.

Microscopic structure

Scattered throughout the lamina propria and submucosa of the small intestine, predominantly the
ileum, are visible aggregates of lymphoid tissue known
as Peyers patches. The mucosa overlying the Peyers
patches is flattened and contains numerous antigensampling M cells. In the colon, the lamina propria contains larger numbers of smaller lymphoid nodules. The
lamina propria is separated from the submucosa by a
thin inner circular layer and an outer longitudinal layer
of smooth muscle known as the muscularis mucosae.
The submucosa contains a network of blood vessels and
lymphatics as well as groups of neurons, which make
up Meissners plexus.
The muscularis externa, like the muscularis mucosae, consists of an inner circular layer and an outer
longitudinal layer of smooth muscle. In the large intestine, the outer smooth muscle layer forms three bands
known as teniae coli. Between the inner and outer
smooth muscle layers are blood vessels and lymphatics, and neurons which make up Auerbachs plexus.
The outer serosa is a thin layer of loose connective tissue containing vasculature and lymphatics, covered on
the outer surface by mesothelium.

Ducto torcico

Vascular

Both the small and large intestine are composed of four

distinct layers: the mucosa, the submucosa, the muscularis externa, and the serosa. The mucosa consists of a
layer of columnar epithelium below which lies the lamina propria, a loose connective tissue layer containing
blood vessels, lymphatics, and some lymphoid tissue.
In the small intestine, the mucosa forms fingerlike projections known as villi. These are most pronounced in
the ileum and serve to increase small intestinal surface
area about tenfold. Each villus contains a dense capillary network, which lies just below the epithelium, and
blind-ending lymphatic vessels, lacteals, which drain
into lymphatics forming a plexus in the lamina propria. In between and in continuity with the villi are the
intestinal crypts (Figure 2.1). These crypts contain intestinal epithelial stem cells which allow repopulation
and repair of the small intestinal mucosa. Although the
mucosa of the colon does not form villi, stem cells remain located in crypts.

domingo,
16 de janeiro de 2011
14

Fgado

Mucosal cell types

There are five main epithelial cell lineages, all of which
are derived from stem cells in the intestinal crypts.
The most plentiful cells in the mucosal epithelium are
columnar enterocytes, which make up the absorptive
surface of the intestine. The apical surface of these cells

Corao

EVOLUO DOS ESTUDOS

FOCO NA INFECO
FOCO NO HOSPEDEIRO

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COMPONENTES
ESTRUTURAIS
GROSCHWITZ AND HOGAN 5

Desmosomas laterais
Junes aderentes
(AJ) -Laterais
Tight junction (TJ)
- Apicais
Groschwitz e Hogan. J Allergy Clin Immunol 2009

G 2. Overview of intestinal epithelial junctional complexes. The intestinal

ithelium consists of a single layer of polarized epithelial cells. Adjacent
lls are connected by 3 main junctional complexes: desmosomes, AJs,
d TJs. Desmosomes are localized dense plaques that are connected to
ratin filaments. AJs and TJs both consist of transcellular proteins
nnected intracellularly through adaptor proteins to the actin cytoskele16 de janeiro of
de 2011
n.domingo,
The collection
proteins in the junctional complexes forms cytoplas-

Citoesqueleto

COMPONENTES ESTRUTURAIS DA
BARREIRA
J ALLERGY CLIN IMMUNOL
JULY 2009

Groschwitz
e Hogan.
J Allergy
Immunol
2009
the apical-lateral
membrane
junction.
They Clin
consist
of integral
transmembrane
s, and JAMs) that interact in the paracellular space with proteins on adjacent
omophilic (eg, claudin-1/claudin-1) or heterophilic (eg, claudin-1/claudin-3). The
nsmembrane proteins interact with PDZ domaincontaining adaptor proteins
TJ complex to the actin cytoskeleton. TJ proteins are regulated by means of
, phosphatases,
other signaling
molecules.
domingo, 16 and
de janeiro
de 2011

AJ -Caderinas/
cateninas.
TJ Ocludinas,claudinas,
molculas de adeso
funcional (JAMs)
Ocludinas - permeabilidade
paracelular.
Claudinas - canais seletivos inicos.
JAMs -Imunoglobulina de adeso
leucocitria.

MUTAES DETECTADAS EM
TRANSLOCAO

8 GROSCHWITZ AND HOGAN

TABLE I. Transgenic or knockout mice and effects on intestinal barrier function

Protein

Transgenic or knockout

Occludin
Claudin-1
Claudin-6

Gene deletion
Gene deletion
Epidermis transgenic

TJ protein
TJ protein
TJ protein

JAM-A

Gene deletion

TJ protein

IL-9

Intestinal transgenic

Cytokine

IL-10

Gene deletion

Cytokine

STAT-6

Gene deletion

Signaling molecule

Mcpt1

Gene deletion

Mast cell protease

Groschwitz e Hogan. J Allergy Clin Immunol 2009

domingo, 16 de janeiro de 2011

Function

Phenotype

No change in TJs or permeability

Die within 1 d of birth
Disrupted TJ formation
and increased epithelial
permeability
Increased intestinal permeability
Increased claudin-10 and
claudin-15 expression
Increased susceptibility to DSS
colitis
Increased intestinal mast cell
Increased intestinal permeability
Increased susceptibility to oral
antigen sensitization and
anaphylaxis
Increased permeability;
spontaneously have chronic
colitis similar to CD
Protected against IL-4 and IL13induced intestinal epithelial
barrier dysfunction
Protected against T spiralis
infestationinduced intestinal

JA

DISFUNO DA
BARREIRA INTESTINAL
Fatores exgenos.
Apoptose epitelial e capacidade de regenerao.
Citocinas sistmicas
Atividade imune intestinal
Sistema nervoso entrico

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ESTUDO MOLECULAR
FATORES PREDISPONENTES

12 GROSCHWITZ AND HOGAN

TABLE II. Diseases associated with altered TJ protein expression and intestinal epithelial barrier function
Disease state

TJ proteins

Inflammatory cell/cytokine

Food allergy

Not defined

Mast cells

IBD

Y Claudin-3, claudin-4,
claudin-5, and claudin-8
[ Claudin-2

CD41 T cells IL-10, IFN-g,

and TNF-a and MLCK

Celiac disease

Occludin and ZO-1

Zonulin

Diabetes
Stress

Not defined
Occludin and ZO-1

Zonulin
Mast cells and corticotrophinreleasing hormone

Groschwitz e Hogan. J Allergy Clin Immunol 2009

domingo, 16 de janeiro de 2011

Proposed mechanism

Mast cellmediated
degradation of TJ proteins
IFN-g and TNF-amediated
activation of MLCK
leading to TJ disruption
and dysregulation of
claudin and occludin
expression
Gliadin-induced zonulin
secretion by intestinal
epithelial cells
Zonulin-induced
downregulation of
occludin/ZO-1
Increased zonulin secretion
Destabilization and
redistribution of occludin/
ZO-1

ER 1

REGULAO
IMUNE
DAS
FUNES DE
BARREIRA
INTESTINAL

Relao de defesa:
Linfcito/Epitlio
e Hogan.
Allergy Clin
Immunol 2009
FIG 4. Immune regulation Groschwitz
of intestinal
barrier Jfunction.
T cellderived
IFN-g and TNF-a inhibit MLCKmediated phosphorylation of MLC, leading to TJ junction disruption and intestinal barrier dysfunction. IFNg can also promote the redistribution of TJ proteins, JAM-A, occludin, claudin-1, and claudin-4 from the
apical TJ border by means of a micropinocytosis process. TNF-a and IFN-g can alternatively disrupt TJ
stability and increase intestinal permeability through dysregulation of occludin expression. IL-4 and IL-13
induced increase in intestinal permeability is mediated through induction of epithelial apoptosis and
expression of the pore-forming TJ protein claudin-2. IL-4, but not IL-13, regulates ion conductance through
downregulation of epithelial cystic fibrosis transmembrane conductance regulator Cl2 channel expression.
Intraepithelial iIELgd1 lymphocytes (T-cell receptor Vg71) iIEL cells are important in serine phosphorylation
of occludin and TJ stabilization. Mast cell mediators, including the cytokine TNF-a, mast cell protease
1 (mcpt-1), and lipid mediators, including histamine, platelet-aggregating factor, and prostaglandins,
promote16
increased
Cl2 de
conductance
and increase intestinal permeability. Mcpt1 degrades the TJ protein
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de janeiro
2011

Intestino delgado: 1 para 10

Intestino Grosso: 2-5 por 100

Alterao de fluxo inico, permeabilidade e redistribuio de molculas de

adeso.

CONCEPTS IN THE CELLULAR CONTROL OF GI MOTILITY

501

Controle neural do tgi

Intestino -Fugal
Aferente

Motores

Cajal
Interneurnio

Cho
Cho

Vasomotor

Cel mucosa

Cajal

Aferente

Enterocromafin

Fig. 1. Types of neurons in the enteric nervous system. 1. interneuron; 2. excitatory longitudiMazzone,A.;Fraguai.; Neurogastroenterology. Gastroenterol Clin N Am, 2007
nal muscle
motor neuron; 3. myenteric intrinsic primary afferent neuron; 4. inhibitory longitudinal 16muscle
domingo,
de janeiromotor
de 2011 neuron; 5. intestinofugal neuron; 6. myenteric plexus interstitial cell of

Sistema nervoso entrico

Regulao de absoro e secreo.
Regulao de fluxo sangneo
Regulao de motilidade
Regulao da atividade imune
Regulao de atividade regenerativa

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Regenerao e tipos
celulares intestinais
BLUK113-Langnas

November 26, 2007

17:58

CHAPTER 2

Entercitos

TA cell

Paneth cell

Basement
membrane
Stem cell

Mesenchymal
cell

domingo, 16 de

earlier, division may be symmetrical, resulting in either two daughter cells or two stem cells. If the former
occurs, then that stem cell will be lost from the crypt.
This ultimately may lead to all cells in a crypt being descendants of a single stem cell. Conversely, if division
results in two stem cells then the total number of stem
cells in the crypt will increase. It has been proposed
that increases in stem cell number may be triggers for
janeiro de 2011
crypt fission, a process vital to intestinal growth and

Clulas produtoras de
muco.
Figure 2.2 Intestinal crypt. Stem cells
(red) are found at the crypt bases. Stem
cell progeny (yellow) known as transit
amplifying (TA) cells migrate up the crypt
undergoing further replication and
differentiation. Basement membrane and
mesenchymal cells (green) surround the
stem cell niche. (Reprinted from Spradling
et al. [5], with permission from Macmillan
Publishers Ltd.)

Clulas de Paneth
Enterocromafins
Stem cells

engraftment and differentiation into mesenchymal

cells have been demonstrated in humans and mice [7].
The possibility that bone marrow derived cells could
be used to populate and regenerate intestinal mucosa
is clearly exciting and of particular relevance to the field
of tissue engineering.

Regulao neural do
sistema imune do tgi
VIA ADRENRGICA

VIA COLINRGICA
Figure

ATIVIDADE
PR-INFLAMATRIA

domingo, 16 de janeiro de 2011

Estudos em trauma
Traumatic
brain injury and vagal activity
craniano.

ATIVIDADE
ANTI-INFLAMATRIA

Traumatic brain injury increases vagal tone directly or

result of elevated intracranial pressure. Subsequently,
activity attenuates inflammation via the cholinergic
inflammatory pathway. As a result, susceptibility towa
fections increases, resulting in worse outcome.

jects may, at least in part, result from incre

vagal activity and subsequent suppression of

CONCLUSES
As funes de Barreira so influenciadas por:
1. Equilbrio microbiolgico.
2.Atividades das clulas dendrticas.
3.Atividade neural
4.Estado de manuteno mecnico do epitlio.
5.Capacidade Regenerativa

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O INTESTINO BOMBA

A SEMENTE DA DESTRUIO NA SEPSE E TRAUMA

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OBRIGADO

jbtajra@uol.com.br
www.tajramed.com.br
domingo, 16 de janeiro de 2011