Cellular and molecular mechanism
of peritoneal adhesion formation
Tri Hanggono Achmad
Department of Biochemistry & Health Research Unit School of Medicine – Universitas Padjadjaran
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 :
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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”
Regulation Of Angiogenesis and Wound Repair
TISSUE INJURY Regeneration &
Compensatory Hyperplasia
Wounds that Heal to Excess/Dysfunction
Cutaneous Lesions Keloid
Hypertrophic Scar Adhesion
Wounds that Heal Poorly Cutaneous Ulcers
Decubitus Diabetic
Venous Stasis Neoplasia
Invasion Metastasis
Normal Repair
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PLATELET
DEGRANULATION
CYTOKINES- PDGF TGF TGF VASOACTIVE PEPTIDES MATRIX GLYCOPROTEINS
VASCULAR SPACE
injury Oxygen free radicals
INCREASED VASO-PERMEABILITY CHEMOTAXIS
PMN AGGREGATION PLATELET AGREGATION
THROMBOXANE -VASOCONSTRICTION -PLATELET AGGREGATION
Wound healing process :
Inflammation Proliferation Remodeling
Cytokines in inflammation
Recognition : IL-1, TNF-
Recruitment : IL-8, ENA-78, MCP-1
Removal : INF-, IL-2, IL-6
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CLOT FORMATI ON AND RESOLUTI ON
I NFLAMMATI ON
EPI THELI ZATI ON
GRANULATI ON TI SSUE FORMATI ON
FI BROBLAST SECRETI ON PRODUCT
W OUND COUNTRACTI ON
DEVASCULARI ZATI ON FORCE, RATE
COLLAGEN CROSS- LI NKI NG GAGS
COLL TYPE I I I COLL TYPE I
FI BROBLAST
ENDOTHELI UM AMOUNT
COVERAGE
MATURATI ON PMN’S
MACROPHAGES FI BRI NOLYSI S
70-80% TENSI LE
STRENGTH COLLAGEN SECRETI ON CLOT
REMODELLI NG COLLAGENASE ?
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IL-1 TNF- IL-6 TGF-
tPA uPA
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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
Insult
Trauma Infection Ischaemia
FIBRIN RICH EXUDATE
FIBRINOUS ADHESIONS
INTACT PERITONEUM
FIBRINOLYSIS
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Plasminogen activators t-PA
u-PA
Plasminogen activator Inhibitors
PAI-1 PAI-2 PAI-3 Protease Nexin
Plasmin Plasminogen
Fibrin Fibrin degradation
Product
Go to Normal
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Chemoattractants
Stimulus Activation
Chemotaxis
Rolling Activation Adhesion Transmigration
Selectins
P, E, L
Integrins / immunoglobulins
PECAM-1 others
(LFA 1, MAC 1/ ICAM 1)
STIMULATION
Plasminogen activators
Plasmin Plasminogen
COLLAGENASES STROMELYSINS
ECM DEGRADED ECM
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Collagen
Fibronecting
Growth factor
Growth factor receptors
Growth factor
Growth factor receptors
EXTRACELLULAR MATRIX
Focal adhesion complexes
Actin cytoskeleton
PROLIFERATION, DIFFERENTIATION , PROTEIN SYNTHESIS, ATTACHMENT,
MIGRATION, SHAPE CHANGE
Inflammatory response Immune response
Production of
Platelet-Phosphatidyl choline
Arachidonic acid
Cyclooxygenase Lipooxygenase
Prostaglandins Thromboxanes
Leukotrienes
Neutrophil function Phagocytosis Bacterial killing Vasodilation
Permeability
Leukocyte trapping
Macrophage Antigen
Interleukin-1 Fever
T cells
Interleukin-2 and 6 Tumor necrosis factor T-cell proliferation
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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
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