tunica intima
Innermost layer of blood vessel, made of epithelium
tunice media
middle layer of blood vessel, smooth muscle
Thicker in arteries than veins
tunice adventitia
outermost layer of blood vessel, fibrous tissue
longitudinally oriented collagen, elastic fibers
Thicker in veins than arteries
Merges with CT of body
Capillary
Blood vessel with ONLY tunica intima
Single layer of endothelial cells and their basal lamina
Allow gas, waste, nutrient exchange with tissues
Permit one RBC cell at a time to pass
Three layers of tunica intima
Endothelium (single layer of squamous epithelial cells) - direct contact with blood
Basal lamina - thin layer of ECM (collagen, proteoglycans, glycoproteins)
Subendothelial layer of LCT
What distinguishes small arteries and arterioles?
Number of smooth muscle cells in tunica media
arterioles
1-2 layers of smooth muscle cells
Contract smooth muscle to control blood flow
Direct effect on distribution of blood flow and systemic arterial blood pressure
arteries
Up to 8 layers of smooth muscle cells
precapillary sphincters
control the blood flow into capillary beds.
Slight thickening of smooth muscle at the origin of capillary bed.
Three types of capillaires
continuous, fenestrated, sinusoid
Continous capillary
Least permeable capillary - only allow the passage of
small molecules (less than 10,000 Daltons) between adjacent endothelial cells
each endothelial cell is linked to it neighbors by occluding cell-cell
junctions.
muscle, skin, brain, and spinal cord
Pino
Fenestrated capillary
Capillary with channels through which things can pass. Found in endocrine glands and sites where fluid and metabolite absorption occurs, such as the gallbladder, kidney, GI tract.
Complete basement membrane
Pinocytic vesicles
Discontinuous/Sinusoid capillaries
Large intracellular gaps and incomplete basement membranes in capillary. Intracellular clefts.
liver, spleen, bone marrow
Pericytes
promote capillary structural stability and they have contractile properties, which are controlled by nitrous oxide (NO) produced by endothelial cells
Vasodilation
(NO, low oxygen levels)
smooth muscle in wall of the arteriole to relax, resulting in increased blood flow into capillaries, which also leads to increased pressure within capillaries and some plasma fluid is then driven into surrounding tissue
Peripheral
Vasoconstriction
mediated by norepinephrine from the adrenal gland, or signals from the autonomic nervous system or certain endothelial-derived factors)
can result in decreased capillary blood flow and decreased capillary pressure, which can increase the absorption of tis
Postcapillary venules
main site of action for vasoactive agents such as histamine and serotonin - extravasion of fluid
mediate the emigration of white blood cells from vessels during inflammatory and allergic responses
Veins tend to...
have thinner walls and larger lumina
3 tunics - not really distinct
Lymphatic vessels
Convey lymph from tissue back into venous system
Passive
Start as blind-ended tubes within microcapillary beds
Lymphatic Capillaries
Tubes of endothelium that lack a continuous basal lamina - permeable (lymph slips through spaces between endothelial cells)
Anchoring filaments maintain patency
More permeable than blood capillaries - drain lymph
Convey proteins and lipids that are too la
Lymph
Excess protein-rich fluid from intercellular spaces
LARGE PROTEINS
Vascular endothelium
Direct contact with blood
Flattened, elongated cells - long axis in direction of blood flow
become activated by bacterial and viral antigens, cytotoxins, complement products, lipid products, and hypoxic conditions
When activated, express different adhesio
Functions of endothelial cells
1. Selective permeability
2. Modulate platelet function and coagulation - prevent thrombosis
3. Vasomotive - regulate blood flow
Paracellular pathways
Pinocytosis
Receptor mediated endocytosis
Vasoconstrictors released by endothelial cells
endothelins, angiotensin converting enzyme (ACE), prostaglandin H2 and thromboxane
Decrease vessel diameter
Vasodilators released by endothelial cells
nitrous oxide (NO), prostacyclin
reduction in blood vessel luminal diameter and high vascular resistance, thereby reducing blood flow
Pinocytotic Vesicles
Transport bulk material from blood into endothelial cell, Clathrin-independent
Plasma-derived mediators
Produced by liver
Inactive precursors circulate in plasma
Activated by proteolytic cleavage
End products of a cascade of serially activated serine proteases
Cell-derived mediators
Produced by leukocytes, endothelial cells
Sequestered in intracellular granules (Released by exocytosis) or synthesized de novo
plasma
consists mostly of water as well as various electrolytes, enzymes, clotting factors and a number of other proteins.
Contains FIRBRINOGEN
serum
plasma without clotting factors
Zymogens
activated in a step wise manner by a previously activated enzyme, so they form a cascade of sorts
circulating in the plasma, as I mentioned, but they are also sequestered in the extracellular matrix of our tissues, where they are ready to respond to tissu
Complement system
Cascade with roles in vascular permeability, chemotaxis, and opsonization
Biologic impact of complement cascade
1. Inflammation via anaphylatoxins
2. Phagocytosis via C3b opsonization
3. Cell lysis via formation of membrane attack complex
Anaphylatoxins
Stimulate histamine release from mast cells - increase vascular permeability and causes vasodilation
C5a
powerful chemotactic agent for neutrophils, monocytes, eosinophils and basophils
Can also activate the lipooxygenase pathway (more cell derived mediators) in arachidonic acid metabolism in neutrophils and monocytes leading to further release of inflammato
Kinins
vasoactive peptides derived from plasma proteins known as kininogens by the activity of specific proteases called kallikreins
Bradykinin
increases vascular permeability, vasodilation, smooth muscle contraction (bronchi and uterus
lung (cough)
mediates pain.
Binds GPCRs B1 and B2
B2
Constitutively expressed GPCR, binds bradykinin
B1
GPCR induced by IL-1, TNF-alpha, IFN-gamma, binds bradykinin
Kininase and Angiotensin Converting Enzyme
Rapidly inactivate bradykinin
Symptoms of ACE inhibitors
Cough and angioedema
Factor XIII (Hageman Factor)
cross-links insoluble fibrin; strengthens fibrin clots
Activated to Factor XIIa by contact with negatively charged molecules - collagen, basement membrane, activated platelets -- increased due to vascular permeability
Fibrin
an insoluble protein formed from fibrinogen during the clotting of blood. It forms a fibrous mesh that impedes the flow of blood.
Plasmin
Lyses fibrin blood clots.
During inflamm, cleaves C3
Fibrinolytic System
Curbs clot formation, via plasmin
Activated by Factor XIIa
Most important plasma derived inflammatory mediators
Bradykinin, C3a, C5a, and thrombin
Factor XIIa activates...
Kinin system
Clotting system
Fibrinolytic system
Complement system
Bradykinin, C3a, C5a
Mediators of increased vascular permeability
Major cell types that produce cell-derived mediators
platelets, neutrophils, monocytes/ macrophages, mast cells, some mesenchymal cell types (endothelium, smooth muscle, fibroblasts)
Cell-derived mediators
Arachidonic acid (AA) metabolites: Prostaglandins, leukotrienes and lipoxin
Platelet-activating factor (PAF)
Nitric oxide (NO)
Vasoactive amines: Histamine, serotonin
Eicosanoids
lipids derived from arachidonic acid
Prostaglandins, leukotrienes, lipoxins
Prostaglandin
synthesized by cyclooxygenase and are produced by mast cells, macrophages, endothelial cells and many other cell types.
involved in the vascular and systemic reactions of inflammation
PGE2, PGD2, PGF2?, PGI2 (prostacyclin), and TxA2 (thromboxane)
Prostacyclin (PGI2)
prostaglandin that causes vasodilation, inhibits platelet aggregation
Produced by endothelial cells via prostacyclin synthetase
Thromboxane A2 (TXA2)
Prostaglandin produced by platelets via thromboxane synthetase
Vasoconstrictor, platelet aggregator, bronchoconstriction
PGE2
Prostaglandin that mediate pain and fever
vasodilation and increased vascular permeability
PGD2
Major prostaglandin of mast cells, bronchoconstriction, vasodilation, increase vascular permeability, recruitment of eosinophils
PGF2a
Prostaglandin
uterine smooth muscle contraction and initiates parturition (giving birth), bronchoconstriction
leukotriones
chemoattractants for leukocytes
5-HETE
Leukotriene produced in neutrophils (PMN) and is a potent chemotactic factor for PMNs
LTB4
potent chemotactic agent for PMNs, activates PMNs leading to their aggregation and adhesion to the endothelium of venules at the site of tissue/ cell injury.
leads to the generation of reactive oxygen species needed for PMNs killing of microbes and releas
LTC4, LTD4, LTE4
induce bronchoconstriction (important in asthma) and vasoconstriction and increase vascular permeability.
increase vascular permeability in venules
Lipoxins
Synthesized in platelets via a transcellular pathway, 12-lipoxygenase in platelets
inhibit leukocyte recruitment and the cellular components of inflammation
inhibit neutrophil chemotaxis and neutrophil adhesion to endothelial cells.
Corticosteroids
Reduce the transcription of genes encoding COX-2, PLA2 and the pro-inflammatory cytokines (IL-1, TNF) and iNOS. iNOS produces nitric oxide (NO)
Inhibit entire AA pathway
Aspirin and NSAIDs
inhibit prostaglandin synthesis by inhibiting cyclooxygenase
Lipoxygenase inhibitors
diminish leukotriene production, while other drugs have been designed to inhibit leukotriene receptors.
Used to treat asthma
Fish-oil supplements
favors the production of certain anti-inflammatory lipid mediators (such as resolvins and protectins)
Platelet-activating factors
phospholipid-derived mediator
Derived from membranes of PMN, monocytes, activated ECs, platelets, basophils
Bind consitutively expressed GPCR (PAFR) on platelets, ECs, leukocytes
PLA2 stimulated by....
Bradykinin, cytokines
Lipid mediators are...
derived from organelle membranes and not stored
Edema due to increased hydrostatic pressure
Venous obstruction
Impaired venous return
pulmonary edema
can occur due to increased hydrostatic pressure in association with congestive heart failure and impaired venous return.
Congestive heart failure
the inability of the left side of the heart to pump out an appropriate volume of blood with each contraction. blood backs up into pulmanory venous system
Cutaneous (Pitting) Edema
accumulation of interstitial fluid in the skin, often in the extremities.
Decreased oncotic pressure
Increased protein (albumin) loss
Decreased protein (albumin) synthesis
Excess IV fluid resuscitation
Increased hydrostatic pressure
Impaired venous return
Venous obstruction
Systemic edema (anasarca)
Decrease in plasma oncotic pressure - protuberant abdomen and enlarged extremities
Lymphedema
Unilateral, exacerbated by gravity. Physical exam: increased diameter of limb, pitting edema or weep, sensory and range of motion problems, increased risk of infections.
Lymphedema
amount of edema in the interstitial tissue exceeds the ability of the lymphatic system to drain it so the value of Q decreases
Impaired lymphatic drainage
Secondary lymphedema
Infection and inflammation
Obstruction/fibrosis
Surgical dissection (lymphadenectomy)
Hyperemia
Increased blood flow in an organ or tissue due to arteriole dilation
ACTIVE process
exercise and inflammation
Congestion
Reduced blood outflow from an organ or tissue
PASSIVE process
Systemic (cardiac) or focal (isolated venous obstruction)
Increases organ weight and size, often accompanies or precedes edema
Appears blue - stalls venous blood flow
Right sided heart failure
venous blood starts to
pool proximal to the right side of the heart
Congestion of liver, spleen, lower limbs
Cyanosis (blue skin), hepatomegaly, distention of jugular vein, splenomegaly, ascites (effusion in abdominal cavity)
Venous blood pressure is elev
Left sided heart failure
Pulmonary congestion
Presence of hemosiderin
Dyspnea, orthopnea, more white splotches in x-ray
early activators of endothelial cells
histamine
bradykinin
PAF
Thrombin
Increased vasodilation and vascular permeability
quick release via enzymatic reaction
late activators of endothelial cells
IL-1-beta
TNF-alpha
IFN-gamma
Proteins - require gene expression
other mediators of endothelial cells
complement
bacterial products
hypoxia
viruses
Activated endothelial cells
Synthesize:
PGI2, NO, EDHF - vasodilation
Endothelins, angiotensin II - vasoconstriction
Pro and anti-thrombotic factors
ECM components
Cytokines
Contraction of myosin (histamine, bradykinin, leukotrienes) - vasopermeability
Retraction cytoskeletal elemen
Vasopermeability
Contraction of myosin (histamine, BK, leukotriones)
Retract cytoskeletal elements
Transudate
Low protein content, few cells
Edema
Opaque
No endothelial cell damage
Exudate
High protein content, cell poor
Seen in acute inflammation
Cloudy fluid - fibrin rich, purulent, sanguineous
Damaged endothelium
Pus
purulent exudate
filled with neutrophils
fibrinous exudate
thick exudate, usually on heart surface, SI (mesothelial lined)
protein rich, cell boor
little pus/PMN and blood
Steps in neutrophil arrival
1 Margination
2 Rolling - selectin
3. Adhesion - cellular adhesion molecules, integrins
4 Transmigration and chemotaxis
5 Phagocytosis
6 Destruction of phagocytosed material
7 Resolution
P-selectin
Weibel-Palade bodies mediated by histamine
Translocate to surface following activation
Binds mucin, PSGL-1
E-selection
Induced by TNF and IL-1 (helps rolling of leukocytes)
Binds mucin, ESL-1
Firm adhesion of leukocytes to ECs
CAMs-Integrin interaction
Chemoattractants for neutrophils
IL-8, C5a, Bacterial products, LTB4
Selectin
single chain transmembrane glycoproteins that mediate endothelial cell and leukocyte adhesion.
P-selectin is found in Weibel-Palade bodies of inactive endothelial cells. Activation by histamine, PAF, and thrombin results in these bodies translocating to t
Vesiculo-vacolar organelle
Used to transport leukocyte across endothelial cell
transcellular migration
Chemotaxis
unidirectional movement of activated leukocytes to the site of injury, along a concentration gradient of small molecular weight chemotactic factors.
Chemotactic factors
C5a
LTB4
Chemokines (e.g. IL-8)
Bacterial formylated proteins and lipids PAF (platelet activating factor) Extracellular matrix components
Acute Inflammation
Neutrophils and macrophages
Fast
Small vessel dilation, extravascular accumulation of leukocytes, edema
Fibrinous inflammation
Fibrin-rich exudate
acute inflammation
heart, SI, lungs
Suppurative (Purulent) Inflammation
Cloudy exudate
PMN, cell debris, fibrin
Cell rich, protein rich
Acute bronchopneumonia, appendicitis
Abscess
cavity filled with liquefactive necrosis - rich in cell and tissue debris, macrophages and PMN
Often "walled off" from the adjacent normal tissue by fibrin and later by fibrous tissue.
Pseudomembranous inflammation
acute inflammatory exudate (think volcanic eruption) forming a gray, adherent, yellowish-gray, plaque-like, adhesions that form a mushroom-shaped pseudomembrane on the epithelial surface of the colon and pharynx.
mucosal surface containing a membrane of n
Ulcer
Necrotic and eroded appearing area of an epithelial surface with underlying acute and chronic inflammation.
trauma, toxins, and ischemia.
epithelial lined surface that is excavated by shedding of inflamed necrotic tissue.
skin, GI tract and urinary bladde
Ulcer
surface defect is filled with acute and/or chronic inflammation, necrotic tissue and a healing base with granulation tissue.
Types of acute inflammation
Serous
Fibrinous
Suppurative (Purulent(
Pseudomembranous
Ulcers
Chronic inflamamtion
Persistent infections
Hypersensitivity immune reactions
Exogenous and endogenous toxic agents
NO neutrophils!!
Diseases related to chronic inflammation
Cancer
Diabetes
Cardiovascular
Alzheimer's disease
Pulmonary diseases
Arthiritis
Autoimmune diseases
Neurological diseases
Infiltrative chronic inflammation
Nonspecific chronic inflammation with lymphocytes and macrophages.
LOF due to atrophy
thickness due to edema
Granuloma
focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.
Epitheliod Histiocytes
specialized, activated macrophages that may coalesce to form multinucleated giant cells. These are the cells that define a granuloma.
Sarcaidosis
Non-caseating granulomas inflammation lack a known etiologic agent
Autoimmune disorder
Acute Phase Response Proteins
C-reactive protein (CRP)
Serum amyloid protein (SAA)
Mannose-binding lectin (MBL)
?-2 macroglobulin
Proteins that reduce iron availability: Haptoglobulin, ferritin, hepcidin, ceruloplasmin
?1 anti-trypsin and ?1 anti-chymotrypsin Coagulation proteins
Comp
Fever (pyrexia)
Increase in body temperature that exceeds the normal daily variation
with increase in hypothalamic set point
Hyperpyrexia
body temperature exceeds 40C
Severe infections and CNS hemorrhage
Diurnal variation
mean body temperature is 36.8o� 0.4oC (98.2o� 0.7oF) and we refer to this as the normal set point.
normal low at about 6 am everyday and its normal high around 4-6 pm every day
Leukocytosis
large increase in the number of leukocytes (absolute WBCs) in the blood.
Leukocyte numbers usually respond by increasing to between 15,000 and 20,000 cells per microliter
leukomoid reaction
resembles the increase in white blood cell numbers seen in the blood of many leukemia patients;
however, the cells are normal white blood cells and not malignant
Neutrophilia
Increase in neutrophils
Bacterial infections
Eosinophilia
Increase in eosinophils
Asthma, hay fever, parasite
Lymphocytosis
Increase in lymphocytes
Viral infections, chronic inflammatory states
Bands
precursor cells to the mature segmental neutrophil.
The bone marrow gets so revved up in bacterial infections it starts sending out neutrophil precursor cells into the blood stream (bandemia)
Leukopenia
Abnormally low white blood cell count
can be seen in bacteria, viral, protozoa, overwhelming infection, also encountered as a side effect or complication of certain drugs such as chemotherapy
Leukocyte Adhesive Deficiency
Delayed separation of the umbilical cord - omphalitis. Severe recurrent bacterial infections with NO pus formations - localed to skin and mucosal membranes - ginigivitis, periodontitis. [CBC - neutrophilia (leukocytosis), Flow cytometry - lack of CD18, mu
Chronic Granulomatous Disease (CGD)
Mutation or defect in phagocyte respiratory enzyme, NADPH oxidase. Dysfunctional oxidative burst limits microbial killing.
Primary immunodeficiency affecting the innate immune system. Genetically heterogeneous. 70% X-linked recessive. 30% autosomal recess
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Inhibit cyclooxygenase
Inhibition of COX-1 leads to GI toxicity ? PGE1 protects gastric mucosa
Effects: Analgesic, antipyretic, anti-inflammatory; some are ucisoric
Ames Test
A procedure using bacteria to identify potential carcinogens
Tests whether frameshift or substitution mutation occurs - only mutated organisms grow.
Sensitive Test
21 CFR 50
Protection of Human Subjets/Informed Consent
21 CFR 54
Financial Disclosure by Clinical Investigators
21 CFR 56
Institutional Review Boards
21 CFR 312
Responsibility of sponsors and investigators (Form 1572)
Randomization
Each subject must have an equal likelihood of being in any treatment group.