Module 8 Flashcards
Definition
inflammation is a normal immunological response to tissue damage (injury or infection)
Inflammatory cells
Neutrophils Eosinophils Basophils Mast cells Platelets Monocytes/Macrophages
Inflammatory Mediators
cytokines that contribute to an inflammatory response
located in the plasma or produced by local cells
prostaglandins
leukotrienes
histamine
Histamine
released by basophils and mast cells
early acute inflammatory response
vasodilation
increase vascular permeability
pain production
Prostaglandins/Leukotrienes
derived from plasma membrane phospholipids
produced by various tissue cells
later acute inflammatory response
vasodilation
increase vascular permeability
anaphylactic hypersensitive reactions
Bradykinins
plasma protein
vasodilation
increase vascular permeability
pain production
Types of Inflammation
Acute
Chronic
Systemic
Stages of Acute Inflammation
Vascular
Cellular
5 Cardinal Signs of Inflammation
Redness Swelling Pain Warmth Partial loss of function
Vascular stage of AI
1) stimulation of local mast cells/tissue areas –> release of inflammatory mediators (prostaglandins, leukotrienes, histamine)
2) inflammatory mediators –> retraction of endothelial cells –> leaking of exudate –> edema (swelling, pain)
3) inflammatory mediators –> relax smooth muscle –> vasodilation –> increased blood flow (warmth, redness)
Cellular stage of AI
1) margination: inflammatory mediators cause endothelial cells to present cell adhesion molecules (proteins) on membrane. circulating WBC’s attach to CAMs and begin to “roll” down endothelium
2) adhesion: WBCs eventually fully adhere to endothelial lining due to cell adhesion molecules (selectin)
3) transmigration: white blood cells begin to squeeze through intercellular gaps caused by endothelial retraction
4) chemotaxis: release of chemokines attract white blood cells to injured area
5) activation + phagocytosis: neutrophils + macrophages
Function of Inflammation
1) clear cellular debris
2) dilute toxin/infectious agent
3) promote healing / prepare tissue for repair
Opsonization
molecules bind to antigens and flag them for phagocytosis. facilitate the adhesion of microbes and phagocytes
complement proteins, antibodies,
Plasma-derived inflammatory mediators
liver proteins
1) complement proteins –> involved in various functions of the immune system
2) clotting proteins –> hemostasis
3) acute phase proteins –> involved in systemic infection
Cell-derived inflammatory mediators
preformed granules found in local cells or synthesized by cells upon stimulation
produced by
mast cells
neutrophils
platelets
monocytes/macrophages
Serotonin
inflammatory mediator released by platelets
vasodilation
increased vascular permeability
Prostaglandin formation
formed from arachidonic acid + cyclooxygenase enzyme
Leukotriene formation
formed from arachidonic acid + lipooxygenase enzyme
Cytokines
proteins expressed by immune and other cells involved in chemical messaging
modulate function of nearby cells
paracrine (outside cells) + autocrine (same cell) function
produced by macrophages + lymphocytes endothelial cells epithelial cells fibroblasts
Cytokines released by macrophages
activated macrophages release tumor necrosis factor alpha (TNF-a) and interleukin-1 in response to inflammation
TNF-a & IL-1 Effects
cause endothelial cells to express cell adhesion molecules
stimulate release of cytokines, chemokines, reactive oxygen species
margination of neutrophils
activate systemic inflammation acute-phase response
Chemokines
type of cytokine involved in chemotaxis
chemoattracts that recruit + direct inflammatory + immune cells
Exudate
fluid that leaks from blood vessel –> interstitial fluid
fluid, plasma proteins, leukocytes
Types of exudate
fibrous (high levels of fibrinogen --> fibrin) serous (watery, blister) hemorrhagic (blood) purulent (pus) sanguinous (oozing)
Abscess
localized area of inflammation containing purulent exudate
central necrotic core + surrounding layer of neutrophils
Ulcer
localized inflammation of epithelium + subepithelium
epithelium becomes necrotic + eroded
Resolution of Acute inflammation
1) recovery –> normal function restored
2) progression to chronic inflammation –> occurs when offending agent not removed
3) scarring/fibrosis –> results from significant injury or nonregenerative tissue
Etiology of Chronic Inflammation
1) results from acute inflammation
2) continued exposure to a low-grade irritant
Chronic Inflammation Characteristics
infiltration of leukocytes
angiogenesis
fibrosis
Causes of chronic inflammation
foreign agents
viruses
bacteria
injured tissue
hypersensitive/inappropriate immune reactions
obesity (white adipose tissue = inflammatory)
Granuloma
occurs with chronic inflammation
lesion containing macrophages and lymphocytes
Systemic inflammation
occurs when inflammatory mediators enter the circulation
Clinical manifestations of systemic inflammation
acute phase response white blood cell count fever increased heart rate anorexia somnolence malaise
Acute phase response
changes in concentrations of plasma proteins
skeletal muscle catabolism
negative nitrogen balance
increased erythrocyte sedimentation rate (ESR)
leukocytosis
C-Reactive Protein
major acute phase protein
involved in opsonization.
CRP levels rise during acute inflammation
White Blood Cell Count
in response to infection, bone marrow is stimulated to increase production of WBCs to defend against infection
values increase from 4000-10000 cells/uL to 15000-20000 cells/uL
WBC involved in bacterial infection
neutrophils
WBC involved in allergic/parasitic infection
eosinophil
WBC involved in viral infection
decrease in neutrophils
increase in lymphocytes
Fever
increase in body temperature due to a resetting of the thermoregulatory center in the hypothalamus
Functions of fever
create an inhospitable environment for invading microbes (high temp –> denatures proteins)
increase cellular metabolism –> promote healing
Atherosclerosis
accumulatio of fatty plaques on the tunica intima of medium and large elastic arteries
causes vessel occlusion –> increased resistance –> increased blood pressure
Modifiable Risk Factors
Smoking Diet Obesity Hyperlipidemia (high LDL (bad), low HDL) Inflammation Chronic conditions (diabetes, hypertension, chronic renal disease)
Non-modifiable Risk Factors
Age Gender (men at higher risk) Family History of cardiovascular disease Genetic Poor lipid metabolism
Nontraditional Risk Factor
Inflammation caused by C-Reactive Protein
Effects of smoking
vasoconstriction increases blood pressure reduces myocardial oxygen supply increases inflammation oxidation of LDL cholesterol
3 Types of Atherosclerotic Plaques
1) fatty streaks (non-pathological)
2) fibrous atherosclerosis
3) complicated lesion
Fatty streaks
yellow lines found on major arteries do not cause atherosclerosis but can progress into fibrous plaques develop early (8 years old) but do not cause clinical complications
made up of smooth muscle cells filled with cholesterol + macrophages
Complications from atherosclerosis
angina coronary artery disease carotid artery disease stroke peripheral vascular disease thrombosis/thromboembolism hypertension aneurysms endothelial injury renal disease
Complicated atherosclerotic lesion
occurs when fibrous plaque breaks open –> release of lipids and cellular debris into bloodstream
can cause a blood clot
Endothelial Characteristics
single layer of endothelial cells
tight cell junctions
selectively permeable
normally anti-thrombotic (expression of cell adhesion molecules –> margination)
Where atherosclerotic plaques
bifurcated arteries
areas of turbulent blood flow
Foam cells
when macrophages ingest oxidized LDL they form foam cells that become compacted in atherosclerotic plaques
Clinical Manifestation
atherosclerosis is typically asymptomatic until it causes a significant medical event
myocardial infarction
stroke
Role of macrophages
increased cholesterol levels increase macrophage & endothelial cellular reactions
macrophages burrow into tunica media –> release inflammatory mediators that result in local inflammation
oxidation of LDL –> endothelial injury
when macrophages ingest oxidized LDL –> foam cells
Atherosclerosis of large elastic arteries
thrombus formation
aneurysm
Atherosclerosis of medium elastic arteries
ischemia
infarction
Commonly affected organs
brain –> stroke
heart –> coronary artery disease, myocardial infarction
kidneys –> renal disease
lower extremities
Pathophysiological process
1) damage to endothelium
2) migration of inflammatory cells
3) lipid accumulation + smooth muscle proliferation
4) formation of plaque structure
Causes of endothelial damage leading to atherosclerosis
hypertension hyperlipidemia high levels of blood insulin due to diabetes smoking inflammation
Hyperlipidemia
elevated levels of cholesterol and triglycerides in blood
Dyslipidemia
elevated levels of LDL cholesterol or low levels of HDL cholesterol
Lipoproteins
spherical particles made up of cholesterol, proteins and phospholipids that transport lipids in the bloodstream
Four types of lipoproteins
chylomicron
very low density lipoprotein
low density lipoprotein
high density lipoprotein
Chylomicron
made in the small intestine
transports dietary lipids from small intestine –> adipose tissue
Very low density lipoprotein
made in the liver
transports triglycerides made in the liver –> adipose cells around body
Low density lipoprotein
formed in the blood by the removal of triglycerides from VLDLs
transports 75% of cholesterol in the bloodstream
high LDL cholesterol contributes to atherosclerosis
High density lipoprotein
made in the liver
transports excess cholesterol from body tissues to liver for destruction
high HDL cholesterols contributes to heart health
What is atherosclerosis
is an inflammatory diseases leading to the build up of fatty plaques in large and medium arteries
What blood vessels does atherosclerosis affect
large and medium sized elastic arteries
Where do atherosclerotic plaques typically form
bifurcated arteries
curves in area
areas of disturbed blood flow
Shear stress
parallel frictional force that blood exerts on the endothelial surface
Laminar blood flow
normal blood flow. concentric layers moving in a parallel direction to the blood vessel
laminar blood flow = high shear stress
Turbulent blood flow
occurs when blood flow pathway becomes disorganized
caused by atherosclerosis, aneurysm, bifurcated arteries
turbulent blood flow = low shear stress
Stages of Atherosclerosis
1) endothelial injury
2) migration of LDL into subendothelial space
3) oxidation of LDL
4) migration of monocytes/macrophages
5) phagocytosis and development of foam cells
6) apoptosis of foam cells –> build up of fatty plaque –> release of cytokines that attract more WBCs
7) growth factors released by macrophages stimulate smooth muscle proliferation + development of fibrous cap
8) smooth muscle cells cause calcification of fatty plaque
Treatment
risk factor treatment (chronic conditions)
smoking cessation
dietary modification
lifestyle changes
physical activity
pharmacotherapy (antiplatelet, antiatherogenic)
Plaque Stability Factors
plaque composition (contents)
wall stress (fibrous cap strength)
size and location of core
configuration of plaque in relation to blood flow
Recommended blood cholesterol levels
5.18 mmol/L
Elevated blood cholesterol
5.19-6.18 mmol/L
High blood cholesterol
> 6.22 mmol/L
Recommended HDL levels
1.55 mmol/L
Low HDL levels
1.0-1.55 mmol/L
Very low HDL levels
<1.0 mmol/L
Recommended LDL levels
<2.59 mmol/L
Elevated LDL levels
2.59-4.12 mmol/L
High LDL levels
> 4.15 mmol/L
Recommended Triglyceride levels
<1.70 mmol/L
Elevated Triglyceride levels
> 1.70 mmol/L
Acute phase proteins
synthesized in the level
serum proteins whos levels decrease/increase by >25% in response to inflammation
Positive acute phase proteins
C-reactive protein Fibrinogen Alpha-1 antitrypsin Procalcitonin Interleukin-1 receptor antagonist Haptoglobin Hepodin
Negative acute phase proteins
Albumin
Transferrin
Transthyretin
