Clinical Aproach and The

Role of Defensive Factor in

Gastrointestinal Disease
Lukman Hakim Zain

Gastroenterology and Hepatology Division
Internal Medicine of Medical Faculty North
Sumatera University/ Adam Malik Hospital























Faktor AGRESIF Faktor DEFENSIF


- Pepsin - C empedu - Mukus mukosa
* Asam * Alkohol - Bikarbonat ion
* Obat [NSAID] - Stres [Vaskularisasi mukosa] - Prostaglandin
* HP - Radikal bebas - Vaskularisasi membran mukosa






Schwartz 1910 : NO ACID NO ULCER













Faktor lain : - CNS - Heredity
- Lingkungan
Gg keseimbangan :

Introduction of gastric ulcer :
Break of the mucosa extend to
muscularis mucosae creater
surrounded by acute & chronic
inflammatory cell infiltrate
Location GU mostly on fundal-antral
junction
Pathophysiology of GU :
Natural adaptive defenses of normal mucosa
against injury from the acid & peptic activity
gastric juice are overwhelmed by infection H
pylori, NSAIDs, psychological stress
The other factors acid secretory response,
increase vulnerability to erosive, inflammatory
or traumatic attack.
Patophysiology of GU :
Imbalanced of Aggressive factors & defensive
factors.
Aggressive factors acid + peptic
activity + overwhelming factors (H pylori,
NSAIDs, psychological stress)
Defensive factors change
condition of pre epithlial, epithelial & sub-
epithelial.
Defense mechanism of gastric
mucosa :
Two levels of defense mechanism : extra
mucosal & mucosal.
Extra mucosal : acid secreted into the
stomach is highly bactericidal.
Mucosal : correspond to anatomic
organization to gastric wall.
Mucosal Defense:

First Line Defense (mucus / bicarbonate barrier)
Second Line Defense (epithelial cell
mechanisms barrier function of apical plasma
membrane)
Third Line Defense (blood flow mediated
removal of back diffused hydrogen ions and
supply of energy)
EPITHELIAL CELL INJURY


DEFENSIVE Factors
Preepitelial
Mukus
Bikarbonat
Surface active
phospholipids
Epitelial
Cellular resistance
Restitution
Growth factors,
Prostaglandins
Cell proliferation
Subepitelial
Cellular resistance
Restitution
Growth factors,
Prostaglandins
Cell proliferation
Mikrosirkulasi
H
+
Pepsin

Lumen


pH 1-2
HCO
3
-

pH 7
HCO
3
-

Prostaglandin
1. EGF (epidermal growth factor)
2. TGF alfa (transforming growth factor alfa)
3. FGF (fibroblast growth factor)
Defensive factors of gastric
mucosa :
Mucus-bicarbonate barrier
Acid-resistant mucosal surface
Continual, rapid renewal of mucosal cells
Restitution of superficially damaged
epithelium
Mucosal circulation
Mucosal immune response
Neural and muscular defenses
Prostaglandins.

Mucus-bicarbonate barrier:
Columnar epithelial cells secreted
protective layer of mucus.
Protective effect depend on thickness &
quality of mucus
Bicarbonate secreted by epithelial cells
to neutralized very acidic condition in
the lumen H
+
back diffusion
Acid resistant mucosal
surface :
Gastric mucosal surface have specialized
apical surface membrane
maintaning pH about 2.0 resist to
H+ back diffusion.
Tight junction of apical cells acid
impermeable.
The basolateral cells to acid at pH 5.5, rapid
decay of resistance.
Restitution of superficially
damaged epithelium:
The mucoid cap will be promoting hemostasis
after superficial injury, limiting the back-
diffusion of acid, it facilitates platelet
aggregation.
When damage is deep, cell proliferation or
regeneration involving epithelial cells,
fibroblasts, and angiogenesis fill up the
mucosal defect.
The epithelial restitution and regeneration
depend extensively on vascular factors.

Restitution of superficially
damaged epithelium:(contd)
Cells damaged released mucus to form
mucoid cap of cellular debris, mucus & blood
components (fibrin)
Cells from the gastric pits begin to migrate
along the denuded basal lamina the
migrating cells form tight junctions, and
within 15 minutes to 1 hour, the epithelium is
again intact.

Mucosal circulation:

The mucosal blood flow that provides the
rapid removal of any substances that may
have breached the epithelial barrier, as well
as supplying oxygen and nutrients
The reactive hyperemia that follows epithelial
damage helps protect the mucosa from toxic
substances and provides additional buffering
capacity in the presence of acid back-
diffusion.
Mucosal circulation:(contd)
The mucosal vascular architecture deliver of
bicarbonate to the epithelium: to the
basolateral surfaces of parietal cells,
exchange of bicarbonate for chloride can be
made
The bicarbonate is then delivered to the
luminal surface, where it diffuses into the
epithelial cells, to be actively secreted in
exchange for chloride ions.


Mucosal immune response(1)
The inflammatory changes by the release of
cytokines & products of the arachidonic acid & recruit
and activate PMN cells, monocytes, and mast cells.
Secretion of immunoglobulin A (IgA) by mast cells in
the lamina propria.
Local IgG may reach the lumen by passive
intercellular diffusion & against infecting micro-
organisms immediately adjacent to the lumen, under
the protective umbrella of the mucus-bicarbonate
barrier.

Mucosal immune response(2)
Cell-mediated immune responses in the
gastrointestinal epithelium and lamina propria
are also quite specialized ( CD8+ & CD4+)
Significant numbers of intra-epithelial
lymphocytes rearrange their T-cell receptors
in the gut epithelium
To express potentially autoreactive
repertoires, in some circumstances they may
become active and contribute to epithelial
damage.
Neural and muscular defenses:

The ENS contain peptide neurotransmitters
reflex vasodilation in response to
certain barrier-breaching toxins as well as to
back-diffusion of acid
Nonvascular smooth muscle (muscularis
mucosae) maintain mucosal integrity
bymodulating the flow of blood through the
arterioles and collecting venules that pass
through it to and from the mucosa.

Prostaglandins biological actions :

Modulate blood flow
Effect gastrointestinal smooth-muscle
contractility
Modulate epithelial secretion by mediating ion
transport responses to luminal antigen and
stimulating the gastric epithelial secretion of
bicarbonate
Inhibit histamine-stimulated acid secretion
through direct, receptor-mediated effects on
the parietal cell.

Pathway of Arachidonic acid metabolism

Prostaglandins cytoprotections:

Increased mucus and bicarbonate secretion
Increased blood flow
Maintenance of endothelial integrity
Inhibition of granulocytic secretions
Stabilization of mast cells and lysosomal
membranes
Reduction of gastric contractility.

Epithelial function related to vascular, neural & immune factors
Gastric mucosal protection :
Cytoprotection, mucosal resistant
influenced by some factors internal or
external
Local or systemic pathway
The role of PG & non PG
Lesions depend on mucosal condition,
pre, intra & sub epithelial.
Quality of healing :
o Epithelial repair & renewal
o Epithel condition / apoptosis
o Mucus production to protect mucosa
o Pg concentration
o Epithelial growth factors :
> Epidermal growth factor
> TGF alfa (transforming growth factor alfa)
> FGF (fibroblast growth factor)

Basson MD, AJP 161/4,2002
Epidermal growth factor:
Inhibited gastric seceretion
Promoted ulcer healing
Hideyuki Shibata et al, Jpn Pharmacol Ther 26/8,1998
Hideyuki Shibata et al, Jpn Pharmacol Ther 26/8,1998
Conclusions of GU healing :
Balanced theory is the basic mechanism of
gastric mucosal lesion.
The role of defensive factors more influence on
gastric mucosal lesion & outcome of healing
Many factors in defensive mechanism related
to each other to prevent gastric mucosal lesion
To increase defensive factors have important
role on treatment of gastric mucosal lesion ,
especially for quality of healing

FUCOIDAN
Fucoidan is a complex sulfated polysaccharide,
derived from marine brown algae characterized
by the main constituents of fucose and sulfate
radical and galactose, xylose or uronic acid.
Fucoidans have many biological activities :
a. Anticoagulant
b. Activators AT III and heparin cofactor
c. Inhibit initial binding of sperm for penetration
of the human pellucide zone
d. Blocks the infection of human cells line in
several viral infection, HIV, herpes and CMV
The mechanism of the anti-ulcer effect was considered
to be acceleration of ulcer repair by the increased
production of cell growth such as a. epithelial growth
factor (EGF) b. Fibroblast growth
factor (FGF)
Hideyuki S, Masato N, Yumi T et.al Anti-ulcer effect of
fucoidan from brown seaweed, Cladosiphon okamuranus
TOKIDA, in rats the increase in the EGF content in
stomach was found as one of its physiological activities
Yoshihiro Y, Tsuyoshi S and Masanori H Effect
of mozuku-derived fucoidan and fucoidan-
containing tea on gastric ulcer and non-ulcer
dyspepsia :
1. Effect of the fucoidan sachet on subjective and
objective symptoms were improved in 4
(66%) out of 6 subjects who complained of the
symptoms before the administration
2. Severity of H pylori infection by the fucoidan
sachet by performing the 13C-urea breath
test the 13C-urea value decreased in 4 out
of 7 subject but the value increased slightly in
2 subject

3. Effect of the fucoidan-containing tea on subject
symptoms
a. Changes in the symptoms such as heavy stomach
and heartburn the success rate of 100mg fucoidan
was 60%(40% in the placabo group) and that of 300mg
fucoidan was 90%(60% in the placebo group)
b. The subjective symptoms revealed that stomach
condition was improved in 4 out of 10 subjects by
drinking 100mg fucoidan (1 out of 10 in the placebo
group) and 5 out of 10 subjects by drinking 300mg
fucoidan (3 out of 10 in the placebo group)
4.Comparison with respect to the drinking period of the
fucoidan containing tea The fucoidan-containing tea
drinking period was given as the period of best condition
most frequently in both groups with 100 and 300
fucoidan. The effect was not significant in the placebo
group.
5.Effect of the fucoidan-containing tea on the body mild
constipation was noted in 4 out of 20 subjects in the
drinking period of the fucoidan and 2 out of 20 subjects
in the placebo group.

Juffrie M, Rosalina I, Damayanti W et al. 17
patients fucoidan 100 mg and 16 patients
placebo (3 weeks)
significant improvement of grade of the ulcer
in the fucoidan groups 94%(16/17) compare to
the placebo group 37,5% (6/16) p:0,005
significant reduction of abdominal pain after
five days p:0,04
vomiting tends to decrease in days 6 p:0,9
Distended was significant decreased in days
3 p:0,02
Hyperacidity causes gastric injury, and in severe
situations, ulcer could develop.
The growth factors known as the basic fibroblast growth
factor (bFGF) and the epidermal growth factor (EGF)
have been recognized to promote ulcer healing.
Fucoidan is extracted from a brown seaweed of Okinawa
called Mozuku or Cladosiphon okamuranus.
Fucoidan is effective for the healing of gastric ulcers by
inducing epithelial cells to produce growth factors.
There was significant improvement of grade of the ulcer
in the fucoidan group 94% (16/17) compare to placebo
group 37.5% (6/16)

Figure3. Abdominal pain after 5 days observation

Abdominal pain
0
5
10
15
20
25
30
35
1 2 3 4 5
days
p
e
r
c
e
n
t
fucoidan
placebo
Figure 4. Vomiting after 6 days observation

Vomiting
0
5
10
15
20
25
1 2 3 4 5 6
days
p
e
r
c
e
n
t
fucoidan
placebo
Figure 5. Distended after 5 days observation

Distended
0
5
10
15
20
25
30
1 2 3 4 5
days
p
e
r
c
e
n
t
fucoidan
placebo
Ulcer cause by acute gastritis
The damage cause by : trauma, burns, sepsis,
liver and renal failures and shock, or certain
drug such as NSAID
This study showed fucoidan is strongly has anti
gastric ulcer effect
Fucoidan from Cladosiphon binds proteins,
inhibits peptides activity and prevent the bFGF
instability, as anti ulcer
Cladosiphon fucoidan does not stimulate
supreoxide generation and TNFalpha secretion
by inflammation cells
CF has an effect on the bFGF stabilizing activity
by sulfated polysaccharides stabilize bFGF by
binding to the peptide