Cellular And Molecular Mechanism Of Peritoneal Adhesion Formation.
Cellular and molecular mechanism
of peritoneal adhesion formation
Tri Hanggono Achmad
Department of Biochemistry & Health Research Unit
School of Medicine – Universitas Padjadjaran
Dipresentasikan pada Pertemuan Ilmiah Tahunan Feto-Maternal ke 5 - 2004
Hotel Gran Melia, Jakarta, 26-28 Februari 2005
Peritoneal adhesion :
Major health care problem
282,000 hospitalization – US $ 1.18 bil. (1988)
Source of morbidity :
bowel obstruction, infertility, pelvic pain etc
Adhesion-related research :
• Cellular and molecular mechanisms of adhesion formation
• Developing agents to prevent adhesion formation
T&t Multimedia
Peritoneal wound healing – adhesion formation:
The entire surface becomes epithelialized simultaneously
following peritoneal defect (not gradually from the borders
as of skin wounds)
Exhibits characteristics of “too much repair”
Formation of peritoneal adhesion displays many phenomena
which can also be observed in other tissues
T&t Multimedia
Regulation Of Angiogenesis and Wound Repair
Regeneration &
Compensatory
Hyperplasia
TISSUE INJURY
Wounds with
Uncontrolled
Proliferation
Normal Repair
Wounds that Heal to
Excess/Dysfunction
Cutaneous Lesions
Keloid
Hypertrophic Scar
Adhesion
Neoplasia
Invasion
Metastasis
Wounds that Heal Poorly
Cutaneous Ulcers
Decubitus
Diabetic
Venous Stasis
Arterial
T&t Multimedia
PLATELET
DEGRANULATION
ARACHIDONIC
ACID
METABOLISM
CYCLOOXYGENASE THROMBOXANE -VASOCONSTRICTION
PATHWAY
-PLATELET AGGREGATION
LTB4
PGI2
CYTOKINES- PDGF
TGF
TGF
VASOACTIVE PEPTIDES
MATRIX GLYCOPROTEINS
LIPOXYGENASE
PATHWAY
(-)
-VASODILATION
-ANTI- AGGREGATION
LEUKOTRIENES
VASOCONSTRICTION
INCREASED VASO-PERMEABILITY
CHEMOTAXIS
PMN AGGREGATION
PLATELET AGREGATION
VASCULAR
SPACE
PERITONEAL
SPACE
Cell
injury
INJURY
-trauma
-infection
-hypoxia
-metabolic disturbance
{
Oxygen free
radicals
O2 H2 O2
OH-
T&t Multimedia
Wound healing process :
Inflammation
Proliferation
Remodeling
Cytokines in inflammation
Recognition
Recruitment
Removal
Repair
: IL-1, TNF-
: IL-8, ENA-78, MCP-1
: INF-, IL-2, IL-6
: b-FGF, TGF- , IGF
T&t Multimedia
I N JU RY
CLOT FORMATI ON
AND RESOLUTI ON
FI BRI NOLYSI S
I NFLAMMATI ON
MACROPHAGES
PMN’S
EPI THELI ZATI ON
MATURATI ON
COVERAGE
AMOUNT
GRANULATI ON TI SSUE
FORMATI ON
ENDOTHELI UM
FI BROBLAST
ESNOPSER
COLL TYPE I
FI BROBLAST SECRETI ON
PRODUCT
COLL TYPE I I I
GAGS
TENSI LE
STRENGTH
COLLAGEN
SECRETI ON
70-80%
COLLAGEN CROSS-LI NKI NG
CLOT
WOUND COUNTRACTI ON
FORCE, RATE
DEVASCULARI ZATI ON
REMODELLI NG
COLLAGENASE
?
7
TI ME ( DAYS)
14
28
T&t Multimedia
T&t Multimedia
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
tPA
uPA
IL-4
IL-10
T&t Multimedia
Cellular events:
Mesothelial cell injury
PMN & macrophages migration
Mesothelial cells proliferation
Fibroblasts proliferation
Molecules involved :
Cytokines
- adhesiogenic (IL-6, TNF-, EGF, TGF-, IL-1 )
- anti adhesion (IL-10 – inhibits IL-1, IL-6 & TNF- expression,
IL-4 – inhibits monocytes & macrophages effect)
Fibrin
Collagens
Adhesive molecules
T&t Multimedia
Insult
Trauma
Infection
Ischaemia
FIBRIN RICH EXUDATE
FIBRINOUS ADHESIONS
INTACT PERITONEUM
LOWERED
PLAMINOGEN
ACTIVATOR
ACTIVITY
Trauma
Ischaemia
FIBRINOLYSIS
ADHESION FREE
HEALING
ORGANISATION
ADHESIONS
T&t Multimedia
Plasminogen activators
t-PA
u-PA
Plasminogen activator
Inhibitors
Plasminogen
PAI-1
PAI-2
PAI-3
Protease
Nexin
Plasmin
2-Antiplasmin
Fibrin
Fibrin degradation
Product
T&t Multimedia
Go to Normal
Go to Adhesive
T&t Multimedia
Rolling
Activation
Adhesion
Transmigration
Selectins
P, E, L
Integrins / immunoglobulins
(LFA 1, MAC 1 / ICAM 1)
(VLA-4 / VCAM-1)
PECAM-1
others
Chemoattractants
Activation
Stimulus
Chemotaxis
T&t Multimedia
INHIBITION
IL-10
IL-4
Steroids
STIMULATION
PDGF
EGF
IL-1/TNF
IL-6
TGF-
PROCOLLAGENASES
PROSTOMELYSINS
ACTIVATION
Plasminogen activators
Plasmin
Plasminogen
COLLAGENASES
STROMELYSINS
ECM
DEGRADED ECM
Inhibit
TIMPs
T&t Multimedia
Laminin
fibers
EXTRACELLULAR
MATRIX
Laminin
fibers
Collagen
Collagen
Fibronecting
Growth factor
Integrin
Integrin
Fibronecting
Growth
factor
Growth
factor
receptors
Growth
factor
receptors
Focal adhesion complexes
Actin cytoskeleton
SOLUBLE
SIGNALS
CYTOSKELETON-MEDIATED
SIGNALS
SOLUBLE
SIGNALS
Nucleus
PROLIFERATION, DIFFERENTIATION ,
PROTEIN SYNTHESIS, ATTACHMENT,
MIGRATION, SHAPE CHANGE
T&t Multimedia
T&t Multimedia
T&t Multimedia
Inflammatory response
Production of
Immune response
Phosphatidyl choline
Macrophage
Antigen
Phospholipase
PlateletNitric
Activating oxide
factor
Arachidonic acid
Cyclooxygenase
Interleukin-1
Fever
Lipooxygenase
T cells
Prostaglandins
Thromboxanes
Leukotrienes
Neutrophil function
Interleukin2 and 6
Tumor
necrosis
factor
T-cell proliferation
Vasodilation
Phagocytosis
Permeability
Leukocyte trapping
Bacterial killing
B-cell proliferation
Antibody production
T&t Multimedia
Conclusion
Formation of peritoneal adhesion displays many phenomena
which can also be observed in other tissues
The balance of cytokine production orchestered cellular and molecular
events in peritoneal response to injury
Minimizing cell injury may prevent adhesion formation
T&t Multimedia
T&t Multimedia
Powered
Powered by:
by:
MIR
MIR Center
Center FK
FK
UNPAD
UNPAD
T&t Multimedia
of peritoneal adhesion formation
Tri Hanggono Achmad
Department of Biochemistry & Health Research Unit
School of Medicine – Universitas Padjadjaran
Dipresentasikan pada Pertemuan Ilmiah Tahunan Feto-Maternal ke 5 - 2004
Hotel Gran Melia, Jakarta, 26-28 Februari 2005
Peritoneal adhesion :
Major health care problem
282,000 hospitalization – US $ 1.18 bil. (1988)
Source of morbidity :
bowel obstruction, infertility, pelvic pain etc
Adhesion-related research :
• Cellular and molecular mechanisms of adhesion formation
• Developing agents to prevent adhesion formation
T&t Multimedia
Peritoneal wound healing – adhesion formation:
The entire surface becomes epithelialized simultaneously
following peritoneal defect (not gradually from the borders
as of skin wounds)
Exhibits characteristics of “too much repair”
Formation of peritoneal adhesion displays many phenomena
which can also be observed in other tissues
T&t Multimedia
Regulation Of Angiogenesis and Wound Repair
Regeneration &
Compensatory
Hyperplasia
TISSUE INJURY
Wounds with
Uncontrolled
Proliferation
Normal Repair
Wounds that Heal to
Excess/Dysfunction
Cutaneous Lesions
Keloid
Hypertrophic Scar
Adhesion
Neoplasia
Invasion
Metastasis
Wounds that Heal Poorly
Cutaneous Ulcers
Decubitus
Diabetic
Venous Stasis
Arterial
T&t Multimedia
PLATELET
DEGRANULATION
ARACHIDONIC
ACID
METABOLISM
CYCLOOXYGENASE THROMBOXANE -VASOCONSTRICTION
PATHWAY
-PLATELET AGGREGATION
LTB4
PGI2
CYTOKINES- PDGF
TGF
TGF
VASOACTIVE PEPTIDES
MATRIX GLYCOPROTEINS
LIPOXYGENASE
PATHWAY
(-)
-VASODILATION
-ANTI- AGGREGATION
LEUKOTRIENES
VASOCONSTRICTION
INCREASED VASO-PERMEABILITY
CHEMOTAXIS
PMN AGGREGATION
PLATELET AGREGATION
VASCULAR
SPACE
PERITONEAL
SPACE
Cell
injury
INJURY
-trauma
-infection
-hypoxia
-metabolic disturbance
{
Oxygen free
radicals
O2 H2 O2
OH-
T&t Multimedia
Wound healing process :
Inflammation
Proliferation
Remodeling
Cytokines in inflammation
Recognition
Recruitment
Removal
Repair
: IL-1, TNF-
: IL-8, ENA-78, MCP-1
: INF-, IL-2, IL-6
: b-FGF, TGF- , IGF
T&t Multimedia
I N JU RY
CLOT FORMATI ON
AND RESOLUTI ON
FI BRI NOLYSI S
I NFLAMMATI ON
MACROPHAGES
PMN’S
EPI THELI ZATI ON
MATURATI ON
COVERAGE
AMOUNT
GRANULATI ON TI SSUE
FORMATI ON
ENDOTHELI UM
FI BROBLAST
ESNOPSER
COLL TYPE I
FI BROBLAST SECRETI ON
PRODUCT
COLL TYPE I I I
GAGS
TENSI LE
STRENGTH
COLLAGEN
SECRETI ON
70-80%
COLLAGEN CROSS-LI NKI NG
CLOT
WOUND COUNTRACTI ON
FORCE, RATE
DEVASCULARI ZATI ON
REMODELLI NG
COLLAGENASE
?
7
TI ME ( DAYS)
14
28
T&t Multimedia
T&t Multimedia
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
T&t Multimedia
IL-1
TNF-
IL-6
TGF-
tPA
uPA
IL-4
IL-10
T&t Multimedia
Cellular events:
Mesothelial cell injury
PMN & macrophages migration
Mesothelial cells proliferation
Fibroblasts proliferation
Molecules involved :
Cytokines
- adhesiogenic (IL-6, TNF-, EGF, TGF-, IL-1 )
- anti adhesion (IL-10 – inhibits IL-1, IL-6 & TNF- expression,
IL-4 – inhibits monocytes & macrophages effect)
Fibrin
Collagens
Adhesive molecules
T&t Multimedia
Insult
Trauma
Infection
Ischaemia
FIBRIN RICH EXUDATE
FIBRINOUS ADHESIONS
INTACT PERITONEUM
LOWERED
PLAMINOGEN
ACTIVATOR
ACTIVITY
Trauma
Ischaemia
FIBRINOLYSIS
ADHESION FREE
HEALING
ORGANISATION
ADHESIONS
T&t Multimedia
Plasminogen activators
t-PA
u-PA
Plasminogen activator
Inhibitors
Plasminogen
PAI-1
PAI-2
PAI-3
Protease
Nexin
Plasmin
2-Antiplasmin
Fibrin
Fibrin degradation
Product
T&t Multimedia
Go to Normal
Go to Adhesive
T&t Multimedia
Rolling
Activation
Adhesion
Transmigration
Selectins
P, E, L
Integrins / immunoglobulins
(LFA 1, MAC 1 / ICAM 1)
(VLA-4 / VCAM-1)
PECAM-1
others
Chemoattractants
Activation
Stimulus
Chemotaxis
T&t Multimedia
INHIBITION
IL-10
IL-4
Steroids
STIMULATION
PDGF
EGF
IL-1/TNF
IL-6
TGF-
PROCOLLAGENASES
PROSTOMELYSINS
ACTIVATION
Plasminogen activators
Plasmin
Plasminogen
COLLAGENASES
STROMELYSINS
ECM
DEGRADED ECM
Inhibit
TIMPs
T&t Multimedia
Laminin
fibers
EXTRACELLULAR
MATRIX
Laminin
fibers
Collagen
Collagen
Fibronecting
Growth factor
Integrin
Integrin
Fibronecting
Growth
factor
Growth
factor
receptors
Growth
factor
receptors
Focal adhesion complexes
Actin cytoskeleton
SOLUBLE
SIGNALS
CYTOSKELETON-MEDIATED
SIGNALS
SOLUBLE
SIGNALS
Nucleus
PROLIFERATION, DIFFERENTIATION ,
PROTEIN SYNTHESIS, ATTACHMENT,
MIGRATION, SHAPE CHANGE
T&t Multimedia
T&t Multimedia
T&t Multimedia
Inflammatory response
Production of
Immune response
Phosphatidyl choline
Macrophage
Antigen
Phospholipase
PlateletNitric
Activating oxide
factor
Arachidonic acid
Cyclooxygenase
Interleukin-1
Fever
Lipooxygenase
T cells
Prostaglandins
Thromboxanes
Leukotrienes
Neutrophil function
Interleukin2 and 6
Tumor
necrosis
factor
T-cell proliferation
Vasodilation
Phagocytosis
Permeability
Leukocyte trapping
Bacterial killing
B-cell proliferation
Antibody production
T&t Multimedia
Conclusion
Formation of peritoneal adhesion displays many phenomena
which can also be observed in other tissues
The balance of cytokine production orchestered cellular and molecular
events in peritoneal response to injury
Minimizing cell injury may prevent adhesion formation
T&t Multimedia
T&t Multimedia
Powered
Powered by:
by:
MIR
MIR Center
Center FK
FK
UNPAD
UNPAD
T&t Multimedia