utaustin | portugal workshop on modeling and simulation of physiological systems december 6-8, 2012,...
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UTAustin | Portugal Workshop on Modeling and Simulation of Physiological Systems
December 6-8, 2012, Lisbon, Portugal
“ Coagulation and Inflammation Physiological Process for Numerical Studies”
Carlota Saldanha and Ana Silva - Herdade
Instituto Superior Técnico
UTAustin | Portugal Workshop on Modeling and Simulation of Physiological Systems
December 6-8, 2012, Lisbon, Portugal
“ Coagulation and Inflammation Physiological Process for Numerical Studies”
Carlota Saldanha and Ana Silva - Herdade
Instituto Superior Técnico
InflammationHemostasis ( Platelets, Coagulation, Fibrinolysis, Anticoagulation) Interrelation between Hemostasis and Inflammation and Vice Versa
arteriole
venule
Vessels of Circulatory System
RouleauxPreStasis
Granular Blood Flow
Cell freePlasma
RigidRBC
Swelling ofEndothelial CellObstruct RBC flow
In: Exempla Haemorheologica Booklet 3. The Microcirculation in the terminal vascular bed
WBC
Type I Activation of Endothelial Cell
Nature Reviews Immunology 7, 803-815 (October 2007)
Stimulation- Rapid response independent of new genes expression Typically mediated by ligands
P-SelectinPAFResolves due receptor desensitization
Type II Activation of Endothelial Cell in Acute Inflammation
Nature Reviews Immunology 7, 803-815 (October 2007)
More sustained inflammatory responseSlow response dependent of new genes expression
TNFα; IL-1 are derivedfrom activated leukocytes
Open gapsLeakage of fibrinogenHard swelling
Leukocytes recruitmentmore effective
E –Selectin IL-8
VENULES(-) AP1 shut of E-Selectin>>VCAM1; ICAM-1 (+ byCytokines) Mononuclear –cell rich infiltrates
CAPILLARIES TNFα; IL-1. IFNγ EC deathFavours thrombosis; apoptotic cellslose their anticoagulant sheding heparan sulphate ; exocytosis microparticlesShuting off NOS3 and Trombomodulinby TNFα; TNFα; IL-1 induce Tf microparticles shed from cell surfaceThrombus: fibrin +plateles wall of infected tissue limit spread of microbes
Resolves by removal stimulus; by terminus NFk-β
juxtacrine
Creates a provisional matrix to support leukocytesentry to tissues
Microcirculation Normal / Inflamed
*
**
* Activation by Thrombin
Extrinsic and Intrinsic Coagulation CascadeInterwined Pathways
Fibrin Plolymer
FXIIIa
colagen
*
TFPI
Inflammation / Hemostasis
Hemostatic ClotCan trap invading microbe;> vascular permeabilityAntimicrobial lysis Gram+
Bleeding
Restore theIntegrity of damaged tissues
Proinflammatory Cytokines TNFα, IL-1, IL-6
Inflammation Affects Hemostasis
Brist J Haemat 2005; 131:417- 431 Circulation 2004;109:2698-2704J Leukoc Biol 2008; 83:536-545 Biochemia Medica 2012;22(1):49-62
Inflammation Affects Fibrinolytic System
•1st >> tPA•2nd >>PAI-1(ECs TN-Fα, IL-1β)<< fibrin removal•3rd endothelium dysfunction sustain <<tissue plasminogen activator (tPA)
+Platelets releasePAI-1
Biochemia Medica 2012;22(1):49-62
Inflammation Affects HemostasisPlatelet acting as proinflammatory cell
Fibrina
neutrophil
TNFα
CD40LIL-1β; PAF-4
GF
Tf – FVIIa-FXa
monocyte
MHC; ROS
Activated platelet
Mac-1
(PARs)
TNFα; IL-β
IL-6;IL-8; MCP-1
Contribute of Coagulation in Inflammation
IL-1β
ICAM; VCAM
P-Selectin
PSGPL
PSGPL
ECsECs
IL-8; MCP-1
Monocytes
IL-6TNFα; IL-1β
Blood 1996;87:5051-5060Circ Res 2005;96:1217Critical Concepts 2007
adhesion
adhesion
ROSleukocytes
TNFα, IL-1β on monocytes
IL-8; MCP-1 on ECs PAR-1, 3, 4
PAR-2
Contribute of Coagulation in Inflammationand Vice Versa
ECs
+
Fibg/Fibrin activate leukocyte recruitment(TLR ) Thol like receptor ; and expression
PAR-2 establish cross talk between inflammation-coagulation