Presentation Fucoidan

8/12/2019 Presentation Fucoidan

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Clinical Aproach and The

Role of Defensive Factor inGastrointestinal Disease

Lukman Hakim Zain

Gastroenterology and Hepatology Division

Internal Medicine of Medical Faculty North

Sumatera University/ Adam Malik Hospital


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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

Ggkeseimbangan :


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Introduction of gastric ulcer :

Break of the mucosa extend to

muscularis mucosae creater

surrounded by acute & chronicinflammatory cell infiltrate

Location GU mostly on fundal-antral

junction


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Pathophysiology of GU :

Natural adaptive defenses of normal mucosa

against injury from the acid & peptic activity

gastric juice are overwhelmed by infection Hpylori, NSAIDs, psychological stress

The other factors acid secretory response,

increase vulnerability to erosive, inflammatory

or traumatic attack.


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Patophysiology of GU :

Imbalanced of Aggressive factors & defensive

factors.

Aggressive factors acid + pepticactivity + overwhelming factors (H pylori,

NSAIDs, psychological stress)

Defensive factors change

condition of pre epithlial, epithelial & sub-

epithelial.


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Defense mechanism of gastric

mucosa : Two levels of defense mechanism : extra

mucosal & mucosal.

Extra mucosal : acid secreted into thestomach is highly bactericidal.

Mucosal : correspond to anatomic

organization to gastric wall.


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Mucosal Defense:

First Line Defense (mucus / bicarbonate barrier)

Second Line Defense (epithelial cell

mechanisms barrier function of apical plasmamembrane)

Third Line Defense (blood flow mediatedremoval of back diffused hydrogen ions and

supply of energy) EPITHELIAL CELL INJURY


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DEFENSIVE Factors

Preepitelial Mukus

Bikarbonat

Surface activephospholipids

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

HCO3-pH 7

HCO3-

Prostaglandin

1. EGF (epidermal growth factor)2. TGF alfa (transforming growth factor alfa)

3. FGF (fibroblast growth factor)


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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.


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Mucus-bicarbonate barrier:

Columnar epithelial cells secretedprotective layer of mucus.

Protective effect depend on thickness &quality of mucus

Bicarbonate secreted by epithelial cells

to neutralized very acidic condition inthe lumen H +back diffusion


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Acid resistant mucosal

surface : Gastric mucosal surface have specialized

apical surface membrane

maintaning pH about 2.0 resist toH+ back diffusion.

Tight junction of apical cells acid

impermeable.

The basolateral cells to acid at pH 5.5, rapid

decay of resistance.


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Restitution of superficially

damaged epithelium: The mucoid cap will be promoting hemostasis

after superficial injury, limiting the back-

diffusion of acid, it facilitates plateletaggregation.

When damage is deep, cell proliferation or

regeneration involving epithelial cells,

fibroblasts, and angiogenesis fill up themucosal defect.

The epithelial restitution and regeneration

depend extensively on vascular factors.


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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 isagain intact.


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Mucosal circulation:

The mucosal blood flow that provides therapid removal of any substances that mayhave breached the epithelial barrier, as wellas supplying oxygen and nutrients

The reactive hyperemia that follows epithelialdamage helps protect the mucosa from toxicsubstances and provides additional bufferingcapacity in the presence of acid back-diffusion.


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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 theepithelial cells, to be actively secreted in

exchange for chloride ions.


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Mucosal immune response(1)

The inflammatory changes by the release ofcytokines & products of the arachidonic acid & recruitand activate PMN cells, monocytes, and mast cells.

Secretion of immunoglobulin A (IgA) by mast cells inthe lamina propria.

Local IgG may reach the lumen by passiveintercellular diffusion & against infecting micro-organisms immediately adjacent to the lumen, underthe protective umbrella of the mucus-bicarbonatebarrier.


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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.


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Neural and muscular defenses:

The ENS contain peptide neurotransmitters

reflex vasodilation in response to

certain barrier-breaching toxins as well as toback-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.


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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.


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Pathway of Arachidonic acid metabolism


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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.


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Epithelial function related to vascular, neural & immune factors


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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.


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Quality of healing :

o Epithelial repair & renewal

o Epithel condition / apoptosis

o Mucus production to protect mucosao Pg concentration

o Epithelial growth factors :

> Epidermal growth factor

> TGF alfa (transforming growth factor alfa)

> FGF (fibroblast growth factor)


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Basson MD, AJP 161/4,2002

Epidermal growth factor:

Inhibited gastric seceretion

Promoted ulcer healing


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Hideyuki Shibata et al, Jpn Pharmacol Ther 26/8,1998


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Hideyuki Shibata et al, Jpn Pharmacol Ther 26/8,1998


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Conclusions of GU healing :

Balanced theory is the basic mechanism ofgastric 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


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FUCOIDAN

Fucoidan is a complex sulfated polysaccharide,derived from marine brown algae characterizedby the main constituents of fucose and sulfateradical and galactose, xylose or uronic acid.

Fucoidans have many biological activities :a. Anticoagulantb. Activators AT III and heparin cofactorc. Inhibit initial binding of sperm for penetration

of the human pellucide zoned. Blocks the infection of human cells line in

several viral infection, HIV, herpes and CMV


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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 ratsthe increase in the EGF content instomach was found as one of its physiological activities


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Yoshihiro Y, Tsuyoshi S and Masanori H Effectof mozuku-derived fucoidan and fucoidan-

containing tea on gastric ulcer and non-ulcerdyspepsia :

1. Effect of the fucoidan sachet on subjective andobjective symptoms were improved in 4

(66%) out of 6 subjects who complained of thesymptoms before the administration

2. Severity of H pylori infection by the fucoidansachetby performing the 13C-urea breath

testthe 13C-urea value decreased in 4 outof 7 subject but the value increased slightly in2 subject


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3. Effect of the fucoidan-containing tea on subject

symptoms

a. Changes in the symptoms such as heavy stomach

and heartburnthe success rate of 100mg fucoidan

was 60%(40% in the placabo group) and that of 300mgfucoidan was 90%(60% in the placebo group)

b. The subjective symptoms revealed that stomach

condition

was improved in 4 out of 10 subjects bydrinking 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)


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4.Comparison with respect to the drinking period of the

fucoidan containing teaThe 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 placebogroup.

5.Effect of the fucoidan-containing tea on the bodymild

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.


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Juffrie M, Rosalina I, Damayanti W et al. 17

patients fucoidan 100 mg and 16 patientsplacebo (3 weeks)significant improvement of grade of the ulcerin the fucoidan groups 94%(16/17) compare to

the placebo group 37,5% (6/16) p:0,005significant reduction of abdominal pain afterfive days p:0,04vomiting tends to decrease in days 6 p:0,9

Distended was significant decreased in days3 p:0,02


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Hyperacidity causes gastric injury, and in severesituations, ulcercould 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 cellsto 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)


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Figure3. Abdominal painafter 5 daysobservation

Abdominal pain

0

5

10

15

20

25

30

35

1 2 3 4 5

days

percent

fucoidan

placebo


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Figure 4. Vomitingafter 6 daysobservation

Vomiting

0

5

10

15

20

25

1 2 3 4 5 6

days

percent

fucoidan

placebo


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Figure 5. Distendedafter 5 daysobservation

Distended

05

10

15

20

25

30

1 2 3 4 5

days

percent

fucoidan

placebo


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Ulcercause 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 stronglyhas anti

gastric ulcereffect


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Fucoidan from Cladosiphon binds proteins,inhibits peptides activityandpreventthe bFGFinstability, as anti ulcer

Cladosiphon fucoidan does not stimulatesupreoxide generation and TNFalpha secretionby inflammation cells

CF has an effect on the bFGF stabilizing activityby sulfated polysaccharides stabilize bFGF bybinding to the peptide


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Presentation Fucoidan