Post on 19-Dec-2015
It’s ALIVE: It’s ALIVE: Atherogenesis, a Atherogenesis, a
Dynamic Inflammatory Dynamic Inflammatory ProcessProcess
Kathy Robinson, PhD, RN, CCNSKathy Robinson, PhD, RN, CCNSUniversity of North FloridaUniversity of North Florida
School of NursingSchool of NursingNTI, New Orleans, May, 2005NTI, New Orleans, May, 2005
www.culligan.com
RN Magazine
Concepts to RememberConcepts to Remember
Inflammatory/Immune responseInflammatory/Immune response EndotheliumEndothelium CytokinesCytokines Functions of “Good” CholesterolFunctions of “Good” Cholesterol Renin Angiotensin Aldosterone Renin Angiotensin Aldosterone
System (RAAS)System (RAAS)
INFLAMMATORY/IMMUNE INFLAMMATORY/IMMUNE RESPONSESRESPONSES
Inflammatory response:Inflammatory response:– GeneralizedGeneralized– Can be triggered by:Can be triggered by:
Microbial invadersMicrobial invaders Mechanical stressMechanical stress Chemical stressChemical stress Oxidative stressOxidative stress OtherOther
Inflammatory ResponseInflammatory Response
Four Basic PhenomenaFour Basic Phenomena– Changes in vascular tone of blood Changes in vascular tone of blood
vesselsvessels– Increased oxygen utilization by cells Increased oxygen utilization by cells
facilitating the responsefacilitating the response– Changes in blood vessel walls (short Changes in blood vessel walls (short
term: inc. capillary permeability; long term: inc. capillary permeability; long term: smooth muscle proliferation)term: smooth muscle proliferation)
– Changes in coagulation Changes in coagulation
Origination of Free Radicals/ Origination of Free Radicals/ ROSROS
absorption of extreme energy absorption of extreme energy sourcessources– ultraviolet lightultraviolet light– x-raysx-rays– Star Trek PhaserStar Trek Phaser
Endogenous (oxidative) reactionsEndogenous (oxidative) reactions Enzymatic metabolism of Enzymatic metabolism of
exogenous chemical or drugsexogenous chemical or drugs
Oxidative StressOxidative Stress
McCance & Heuther, Mosby Co.
Immune ResponseImmune Response
Much more specific than the Much more specific than the inflammatory responseinflammatory response
Involves memory and specificityInvolves memory and specificity Antigen/Antibody responseAntigen/Antibody response Can sustain inflammatory responseCan sustain inflammatory response
EndotheliumEndothelium
More than a plasma barrierMore than a plasma barrier Produces:Produces:
– Vasoconstrictors (endothelin [Et-1]) and Vasoconstrictors (endothelin [Et-1]) and vasodilators (nitric oxide [NO], vasodilators (nitric oxide [NO], prostacyclin [PGIprostacyclin [PGI22] )] )
– Pro-thrombotic, anti-thrombotic and Pro-thrombotic, anti-thrombotic and fibrinolytic substancesfibrinolytic substances
– Adhesion molecules (platelets, Adhesion molecules (platelets, monocytes, lymphocytes)monocytes, lymphocytes)
vv
Key PointKey Point
All atherogenesis is related to an All atherogenesis is related to an inflammatory response to endothelial inflammatory response to endothelial
damagedamage
CytokineCytokine
““Any of several regulatory proteins, Any of several regulatory proteins, such as the interleukins and such as the interleukins and lymphokines, that are released by lymphokines, that are released by cells of the immune system and act cells of the immune system and act as intercellular mediators in the as intercellular mediators in the generation of an immune response.”generation of an immune response.”
http://www.answers.com/topic/cytokine
BradykininBradykinin
bradykininbradykinin - - : : bradykinin \bradykinin \bra`dy*ki"nin\ n. a hypotensive bra`dy*ki"nin\ n. a hypotensive tissue hormone which acts on tissue hormone which acts on smooth muscle, dilates peripheral smooth muscle, dilates peripheral vessels and increases capillary vessels and increases capillary permeability. It is formed locally in permeability. It is formed locally in injured tissue and is believed to play injured tissue and is believed to play a role in the inflammatory process. a role in the inflammatory process.
Collaborative International Dictionary of English Collaborative International Dictionary of English v.0.48v.0.48
TNFTNF
Tumor Necrosis FactorTumor Necrosis Factor– One of a family of cytokines that has One of a family of cytokines that has
both anti-neoplastic and pro-both anti-neoplastic and pro-inflammatory effects.inflammatory effects.
The Renin Angiotensin Aldosterone The Renin Angiotensin Aldosterone System (RAAS)System (RAAS)
http://academic.pgcc.edu/
© The University of Florida
http://medinfo.ufl.edu/cme/grounds/cv/gibbons/slide21.html
Pro-Inflammatory Effects of Pro-Inflammatory Effects of Angiotensin IIAngiotensin II
Production of ROSProduction of ROS Production of CytokinesProduction of Cytokines Adhesion moleculesAdhesion molecules
Sources of Angiotensin IISources of Angiotensin II
Conversion of Angiotensin I to Conversion of Angiotensin I to Angiotensin II via ACEAngiotensin II via ACE
Up to 50% of all Angiotensin II is Up to 50% of all Angiotensin II is produced in the tissue, independent produced in the tissue, independent of the ACE pathway.of the ACE pathway.
Function of “Good” CholesterolFunction of “Good” Cholesterol
www.ha.org.hk/org/ antitb/images/hdl.gif
Other than Transport…..Other than Transport…..
Anti-inflammatoryAnti-inflammatory Anti-oxidativeAnti-oxidative Anti-aggregatoryAnti-aggregatory Anti-coagulantAnti-coagulant Pro-fibrinolyticPro-fibrinolytic
Jerzy-Roch Nofer, et al. (2001)Jerzy-Roch Nofer, et al. (2001)
Other than Transport…..Other than Transport…..
HDL Inhibits:HDL Inhibits:– Chemotaxis of monocytesChemotaxis of monocytes– Adhesion of leukocytesAdhesion of leukocytes– Endothelial dysfunctionEndothelial dysfunction– ApoptosisApoptosis– LDL OxidationLDL Oxidation– Complement activationComplement activation– Platelet activationPlatelet activation– Factor X activationFactor X activation
Other than Transport……Other than Transport……
HDL promotesHDL promotes– Endothelial cell repair/regenerationEndothelial cell repair/regeneration– Smooth muscle proliferationSmooth muscle proliferation– Synthesis of prostacyclinSynthesis of prostacyclin– Synthesis of naturietic peptideSynthesis of naturietic peptide– Activation of Protein C and Protein SActivation of Protein C and Protein S
The Basic Process of The Basic Process of Atheroma FormationAtheroma Formation
A Vicious Cycle is Born!!A Vicious Cycle is Born!!
ATHEROSCLEROSIS
ENDOTHELIALDISRUPTION
INFLAMMATION
KEY POINTKEY POINT
Atherogenesis is the result of AND Atherogenesis is the result of AND results in sustained chronic results in sustained chronic
inflammationinflammation
Treatment StrategiesTreatment Strategies AspirinAspirin
– Anti-inflammatory effects even at low dosesAnti-inflammatory effects even at low doses– Anti-platelet activityAnti-platelet activity
ACE Inhibitors/ARBsACE Inhibitors/ARBs– ACE Inhibitors block conversion of Angiotensin I to ACE Inhibitors block conversion of Angiotensin I to
Angiotensin II; also interferes with bradykinin productionAngiotensin II; also interferes with bradykinin production– ARBs block effects of Angiotensin II at receptor sites; ARBs block effects of Angiotensin II at receptor sites;
preserves bradykinin functionpreserves bradykinin function CarvedilolCarvedilol
– Suppresses inflammatory cytokinesSuppresses inflammatory cytokines– Anti-oxidantAnti-oxidant
Aldosterone blockadeAldosterone blockade
Treatment StrategiesTreatment Strategies
Drug eluting Drug eluting stents:stents:– Slowly releases Slowly releases
sirolimus sirolimus – Drug absorbed by Drug absorbed by
arterial wallarterial wall– Prevents endothelial Prevents endothelial
proliferationproliferation Next Generation:Next Generation:
– Drugs to enhance Drugs to enhance endothelial repairendothelial repair www.ptca.org
PULLING IT ALL PULLING IT ALL TOGETHERTOGETHER
Insults to EndotheliumInsults to Endothelium
AGEs: Advanced glycosylation AGEs: Advanced glycosylation endproductsendproducts
Reactive Oxygen SpeciesReactive Oxygen Species HyperinsulinemiaHyperinsulinemia HypertensionHypertension HomocysteineHomocysteine Activated T-Cells/LymphocytesActivated T-Cells/Lymphocytes Small dense LDLSmall dense LDL
Relationship to Risk Relationship to Risk FactorsFactors
Central AdiposityCentral Adiposity
SmokingSmoking
Causes intimal injuryCauses intimal injury Promotes oxidationPromotes oxidation Promotes inflammatory response in Promotes inflammatory response in
respiratory tractrespiratory tract Enhances platelet aggregationEnhances platelet aggregation Promotes vasoconstrictionPromotes vasoconstriction
Diabetes MellitusDiabetes Mellitus
Production of AGEsProduction of AGEs Hyperglycemia induces inflammatory Hyperglycemia induces inflammatory
responseresponse Frequently co-exists with small dense Frequently co-exists with small dense
LDLLDL Insulin growth factor promotes Insulin growth factor promotes
smooth muscle proliferationsmooth muscle proliferation
Hypertension Obesity Hyper-insulinemia
DiabetesHypertri-
glyceridemiaSmall,
dense LDLLow HDL Hypercoagu-
lability
Atherosclerosis
Insulin Resistance
Interrelation Between Atherosclerosis Interrelation Between Atherosclerosis
and Insulin Resistanceand Insulin Resistance
Chronic InfectionChronic Infection
How is chronic infection relation to How is chronic infection relation to atherogenesis?atherogenesis?
Possible Agents:Possible Agents:– Peridontal diseasePeridontal disease– Chlamydia pneumoniaeChlamydia pneumoniae– Helicobacter pyloriHelicobacter pylori– Herpes simplex virusHerpes simplex virus– CytomegalovirusCytomegalovirus
Inflammatory MarkersInflammatory Markers
Homocysteine levelsHomocysteine levels IL6IL6 Chlamydia titersChlamydia titers Serum amyloidsSerum amyloids CRPCRP
Future Treatment StrategiesFuture Treatment Strategies
Genomic therapyGenomic therapy Synthetic HDLSynthetic HDL Antibiotics?Antibiotics? Renin/Aldosterone BlockadeRenin/Aldosterone Blockade pFOX (partial fatty oxidation)pFOX (partial fatty oxidation)
This presentation will be available at This presentation will be available at http://www.unf.edu/~krobinso/nti.hthttp://www.unf.edu/~krobinso/nti.html from May 16ml from May 16, 2005 until June 1, 2005., 2005 until June 1, 2005.