Physiology of Blood

I. Components, Characteristics, Functions of Blood

A. Major Components of Blood

1. formed elements - the actual cellular components of blood (special connective tissue)

a. erythrocytes - red blood cellsb. leukocytes - white blood cellsc. platelets - cell fragments for clotting

2. blood plasma - complex non-cellular fluid surrounding formed elements; protein & electrolytes

B. Separation of Components in a Centrifuge

VOLUME LAYER

1. clear/yellowish PLASMA 55% top

2. thin/whitish buffy coat <1% middle

with LEUKOCYTES & PLATELETS

3. reddish mass - ERYTHROCYTES 45%bottom

hematocrit - percentage by VOLUME of erythrocytes when blood is centrifuged (normal = 45%)

C. Characteristics of Blood

1. bright red (oxygenated)2. dark red/purplish (unoxygenated)3. much more dense than pure water4. pH range from 7.35 to 7.45 (slightly alkaline)5. slightly warmer than body temperature 100.4 F6. typical volume in adult male 5-6 liters7. typical volume in adult female 4-5 liters8. typically 8% of body weight

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D. Major Functions of Blood

1. Distribution & Transporta. oxygen from lungs to body cellsb. carbon dioxide from body cells to lungsc. nutrients from GI tract to body cellsd. nitrogenous wastes from body cells to kidneyse. hormones from glands to body cells

2. Regulation (maintenance of homeostasis)a. maintenance of normal body pH

i. blood proteins (albumin) & bicarbonateb. maintenance of circulatory/interstitial fluid

i. electrolytes aid blood proteins (albumin)

c. maintenance of temperature (blushed skin)

3. Protectiona. platelets and proteins "seal" vessel damageb. protection from foreign material & infections

i. leukocytes, antibodies, complement proteins

II. Erythrocytes (red blood ells; RBCs)

A. Structure

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1. 7.5 micron diameter; 2.0 micron thick2. biconcave disk shape; ideal for gas exchange

i. spectrin - elastic protein; allows shape change3. mature cells are anucleate (no nucleus)3. very few organelles; mainly a hemoglobin carrier

i. hemoglobin – 33% of cell mass; carries oxygen5. no mitochondria; only anaerobic respiration6. ratio erythrocytes:leukocytes = 800:17. red blood cell count: # cells per cubic millimeter

i. normal male count - 5.1 to 5.8 millionii. normal female count - 4.3 to 5.2 million

B. Functions (oxygen & carbon dioxide transport)

1. hemoglobin - large molecules with globin and hemesa. globin - complex protein with 4 polypeptides

(2 alpha and 2 beta polypeptides)b. heme group - IRON containing pigment part of

hemoglobin to which oxygen bindsi. each polypeptide has one heme group;each

heme carries one O2

c. normal hemoglobin levels (grams/l00 ml blood)i. infants 14-20 grams/l00 mlii adult female 12-16 grams/100 mliii adult male 13-18 grams/l00 ml

2. states of hemoglobina. oxyhemoglobin - when oxygen is bound to IRONb. deoxyhemoglobin - no oxygen bound to IRONc. carbaminohemoglobin - when carbon dioxide

bound (to polypeptide chain)

C. Hematopoiesis and Erythropoiesis1. hematopoiesis (hemopoiesis) - the maturation, development and formation of blood cells

a. red bone marrow (myeloid tissue) - location of hematopoiesis; in blood sinusoids which connect with capillaries; mainly in axial skeleton and heads of femur & humerus

b. hemocytoblast (stem cell) - the mitotic precursor to blood cells before differentiationi. differentiation - maturing cell becomes

"committed" to being certain type blood cell2. erythropoiesis - the maturation, development, and

formation of Red Blood Cells (erythrocytes)

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hemocytoblast ->proerythroblast -> early (basophilic) erythroblast -> late (polychromatophilic) erythroblast -> (hemoglobin) normoblast -> (nucleus ejected when enough hemoglobin)reticulocyte -> (retaining some endoplasmic reticulum) ERYTHROCYTE

hemocytoblast -> reticulocyte 3-5 DAYSreticulocyte -> ERYTHROCYTE 2 DAYS (in

blood)ERYTHROCYTE lifespan 100-120 DAYS(primarily destroyed by macrophages in the spleen)

3. Regulation of Erythropoiesis

a. hormonal controls - erythropoietin is the hormone that stimulates RBC production

DECREASED oxygen level in blood causes KIDNEYS to increase release of erythropoietin

1. Less RBCs from bleeding2. Less RBCs from excess RBC destruction3. Low oxygen levels (high altitude,

illness)4. Increased oxygen demand (exercise)

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Eythropoietin now genetically engineered and synthesized by AMGEN of Thousand Oaks.

Testosterone can also mildly stimulate production of RBCs in humans

b. Iron - essential for hemoglobin to carry oxygen

i. 65% of Fe in body is in hemoglobinii. liver and spleen store most excess Fe

bound to ferritin and hemosideriniii. Fe in blood bound to transferriniv. daily Fe loss: 0.9 mg men/l.7 mg womenv. women also lose Fe during menstrual flow

c. B-complex Vitamins - Vitamin B12 and Folic Acid essential for DNA synthesis in early mitotic divisions leading to erythrocytes

D. Erythrocyte Disorders (Anemias & Polycythemias)

1. Anemias - a symptom that results when blood has lower than normal ability to carry oxygena. Insufficient erythrocyte count

i. hemorrhagic anemia - loss of blood from bleeding (wound, ulcer, etc.)

ii. hemolytic anemia - erythrocytes rupture (hemoglobin/transfusion problems, infection)

iii. aplastic anemia - red marrow problems (cancer treatment, marrow disease, etc.)

b. Decrease in Hemoglobini. iron-deficiency anemia - low Iron levels

(diet; absorption, bleeding, etc.)ii. pernicious anemia - low Vitamin B12

(diet, intrinsic factor for Vit B absorption)

c. Abnormal Hemoglobin (usually genetic)i. thalassemia - easily ruptured RBCs (Greek & Italian genetic link)ii. sickle-cell anemia - sickle-shaped RBCs

(genetic Africa, Asia, southern Europe link)

2. Polycythemia - excess RBC count, causes thick blooda. polycythemia vera - bone marrow problem;

hematocrit may jump to 80%

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b. secondary polycythemia - high altitude (normal); or too much erythropoietin release

c. blood doping in athletes - RBCs previously withdrawn are transfused before an event; more RBCs, more oxygen delivery to the body

III. Leukocytes (white blood cells; WBCs)

A. General Structure and Function1. protection from microbes, parasites, toxins,

cancer2. 1% of blood volume; 4-11,000 per cubic mm blood3. diapedesis - can "slip between" capillary wall4. amoeboid motion - movement through the body5. chemotaxis - moving in direction of a chemical6. leukocytosis - increased "white blood cell count"

in response to bacterial/viral infection7. granulocytes - contain membrane-bound granules

(neutrophils, eosinophils, basophils)8. agranulocytes - NO membrane-bound granules

(lymphocytes, monocytes)

B. Granulocytes - granules in cytoplasm can be stained with Wright's Stain; bilobar nuclei; 10-14micron diameter; all are phagocytic cells (engulf material)

1. neutrophils - destroy and ingest bacteria & fungi (polymorphonuclear leuks.; "polys")a. most numerous WBC b. basophilic (blue) & acidophilic (red)c. defensins - antibiotic-like proteins

(granules)d. polymorphonuclear - many-lobed nucleie. causes lysis of infecting bacteria/fungif. HIGH poly count --> likely infection

2. eosinophils - lead attack against parasitic wormsa. only 1-4% of all leukocytesb. two-lobed, purplish nucleusc. acidophilic (red) granules with digest

enzymesd. phagocytose antigens & antigen/antibody

complexe. inactivate chemicals released during

allergies

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3. basophils - releases Histamine which causes inflammation, vasodilation, attraction of WBCs

a. RAREST of all leukocytes (0.5%)b. deep purple U or S shaped nucleusc. basophilic (blue) granules with HISTAMINEd. related to "mast cells" of connective tissuee. BOTH release Histamine with "IgE" signalf. antihistamine - blocks the action of

Histamine in response to infection or allergic antigen

C. Agranulocytes - WBCs without granules in cytoplasm

1. lymphocytes - two types of lymphocytes

a. T lymphocytes - (thymus) respond against virus infected cells and tumor cells

b. B lymphocytes - (bone) differentiate into different "plasma cells" which each produce antibodies against different antigens

c. lymphocytes primarily in lymphoid tissuesd. very large basophilic (purple) nucleuse. small lymphocytes in blood (5-8 microns)f. larger lymphocytes in lymph organs (10-17

mic)

2. monocytes - differentiate to become macrophages; serious appetites for infectious microbesa. largest of all leukocytes (18 microns)b. dark purple, kidney shaped nucleus

D. Leukopoiesis and Colony Stimulating Factors (CSFs)

1. leukopoiesis - the production, differentiation, and development of white blood cells

2. colony stimulating factors (CSF) - hematopoietic hormones that promote leukopoiesisa. produced by Macrophages and T lymphocytes

i. macrophage-monocyte CSF (M-CSF)ii. granulocyte CSF (G-CSF)iii. granulocyte-macrophage CSF (GM-CSF)iv. multi CSF (multiple lymphocyte action)v. interleukin 3 (IL-3) (general

lymphocytes)

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3. leukopoiesis - all cells derived from hemocytoblast

E. Disorders of Leukocytes

1. leukopenia - abnormally low WBC counta. HIV infection, glucocorticoids, chemotherapy

2. leukemia - cancerous condition of "line" of WBCsa. myelocytic leukemia (myelocytes)b. lymphocytic leukemia (lymphocytes)c. acute leukemia - cancer spreads rapidlyd. chronic leukemia - cancer progresses slowlye. anemia, fever, weight loss, bone painf. death from internal hemorrhage or infectiong. chemotherapy & radiation therapy used to

treat

3. infectious mononucleosis - caused by Epstein-Barr virus, excessive monocytes and lymphocytes; fatigue, sore throat, fever; 3 week course

IV. Platelets (thrombocytes - "clotting")

A. General Characteristics

1. very small, 2-4 microns in diameter2. approximately 250-500,000 per cubic millimeter3. essential for clotting of damaged vasculature4. thrombopoietin - regulates platelet production

B. Formation of Platelets

hemocytoblast-> myeloid stem cell->megakaryoblast->promegakaryocyte->megakaryocyte-> (large multilobed nucleus) platelets (anucleated parts of megakaryocyte cytoplasm)

V. Plasma (the liquid part of blood)

A. General Characteristics

1. plasma makes up 55% of normal blood by volume2. water is 90% of the plasma by volume3. many different SOLUTES in the plasma

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a. albumin - pH buffer & osmotic pressureb. globulins - binding proteins & antibodiesc. clotting proteins - prothrombin & fibrinogend. other proteins - enzymes, hormones, otherse. nutrients - glucose, fatty acids, amino

acids, cholesterol, vitaminsf. electrolytes - Na+, K+, Ca++, Mg++, Cl-,

phosphate, sulfate, bicarbonate, others

VI. Hemostasis (stoppage of blood flow after damage)

A. General Characteristics1. vascular spasms (vasoconstriction at injured site)2. platelet plug formation (plugging the hole)3. coagulation (blood clotting - complex mechanism)

B. Vascular Spasms1. first response to vascular injury -

VASOCONSTRICTION is stimulated by:

a. compression of vessel by escaping bloodb. injury "chemicals" released by injured cellsc. reflexes from adjacent pain receptors

C. Formation of a Platelet Plug1. damage to endothelium of vessel2. platelets become spiky and sticky in response3. platelets attach to damaged vessel wall to plug it4. platelets produce thromboxane A2 - granule release5. serotonin release enhances vascular spasm6. ADP - attracts and stimulates platelets at site7. prostacylin - inhibits aggregation at other sites

VII. Coagulation (blood clotting)A. General Events in Clotting

platelet cells activated by damage->PF3 and/or Tissue Factor produced by platelet cells->Factor X activated->prothrombin activator (enzyme) produced->prothrombin conversion -> thrombin (another enzyme)thrombin stimulates: fibrinogen----> fibrin mesh

1. anticoagulant - chemical that inhibits clotting2. procoagulant - chemical that promotes clotting

3. intrinsic pathway - within the damaged vessel

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a. more procoagulants needed (I-XIII) toward PF3 and Factor X

b. allows more "scrutiny" before clotting occurs

4. extrinsic pathway - in outer tissues around vessel

a. tissue thromboplastin (Tissue Factor) - skips intrinsic steps straight to PF3 and Fac Xb. allows rapid response to bleeding out of vessel (clot can form in 10 to 15 seconds)

5. After activation of Factor X, common pathway:

Factor X, PF3 (thromboplastin), Factor V, Ca++ -->prothrombin activator ->prothrombin converted -> thrombin (active enzyme)thrombin stimulates: fibrinogen -> fibrin

(meshwork)Ca++ & thrombin -> Factor XIII (fibrin stabilizer)

B. Clot Retraction (shrinking of clot)

1. actomyosin - causes contraction of platelets2. blood serum - plasma WITHOUT clotting Factors3. platelet-derived growth factor (PDGF) - stimulates

fibroblast migration and endothelial growthC. Clot Eradication (Fibrinolysis)

1. healing occurs over 2 - 10 days2. tissue plasminogen activator (TPA) - causes the

activation of plasminogen3. plasminogen--> plasmin4. plasmin degrades proteins within the clot

D. Factors Limiting Growth and Formation of Clots1. Limiting Normal Clot Growth

a. blood moves too fast to allow procoagulantsb. factors interfere with normal clotting

i. prothrombin III - deactivates thrombinii. protein C - inhibits clotting Factorsiii. heparin - inhibits thrombin; prevents

adherence of platelets to injured site

VII. Disorders of HemostasisA. Thromboembolytic Disorders (undesirable clotting)

1. thrombus - blood clot in normal blood vessel2. embolus -blood clot/gas bubble floating in blood

a. TPA, streptokinase - can dissolve a clot

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b. aspirin - inhibits Thromboxane formationc. heparin - inhibits thrombin & platelet

depositd. dicumarol - anticoagulant, blocks Vitamin K

B. Bleeding Disorders1. thrombocytopenia - reduced platelet count;

generally below 50,000 per cubic millimeter; can cause excessive bleeding from vascular injury

2. impaired liver function - lack of procoagulants (Clotting Factors) that are made in liver a. vitamin K - essential for liver to make Clotting Factors for coagulation

3. hemophilias - hereditary bleeding disorders that occur almost exclusively in malesa. hemophilia A - defective Factor VIII (83%)b. hemophilia B - defective Factor IX (10%)c. Genentech. Inc. - now produces genetically

engineered TPA and Factor VIII; patients do not need transfusions as often

VIII. Blood Transfusions and Blood Typing

A. Transfusion of Blood1. whole blood transfusion - all cells and plasma;

anticoagulants (citrate and oxalate salts) used2. packed red blood cells - most of the plasma has

been removed prior to transfusionB. Human Blood Groups

1. agglutinogens - glycoproteins on the surface of blood cells; causes "agglutination" (clumping)

2. ABO Blood Groups - determined by presence or absence of Type A and Type B agglutinogen proteins on cell membrane

3. agglutinins - antibodies against either A or B agglutinogen (whichever is not present) a. transfusion reaction - patient's antibodies attack the donor blood

i. A (anti-B) receives A,O (not B)ii. B (anti-A) receives B,O (not A)iii. AB (none) receives A, B, AB, O universal

recipientiv. O (anti-A,anti-B) receives O universal

donor

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b. agglutination - when incorrect blood transfused, antibodies will "clump" new blood

c. hemolysis - after clumping, RBCs may rupture, releasing hemoglobin, harming kidney i. dilute hemoglobin, administer diuretics

4. Rh factor - a different group of agglutinogensa. Rh positive (Rh+) - an Rh factor is presentb. Rh negative (Rh-) - NO Rh factorc. transfusion reaction - delayed and less

severe than in ABO confrontationd. erythroblastosis fetalis - Rh- mother

antibodies attack Rh+ of older newborn; results in anemia and low oxygen levels (hypoxia)i. RhoGAM - serum with anti-Rh agglutinins

which will clump the Rh factor, blocking the reaction of mothers antibodies

ii. exchange transfusion - directly from the mother (Rh-) to the newborn (Rh+)

5. Blood Typing - mixing Donors Blood with Recipient Antibodies (Anti-A, Anti-B, anti-Rh) in order to identify agglutination

6. Expanding Blood Volume to Avoid Shocka. pure plasma without antibodiesb. plasma expanders - purified human serum

albumin, plasminate, dextranc. isotonic saline - normal electrolyte solution

isotonic to blood plasma (Ringer's Solution)7. Diagnostic Blood Tests

a. anemia - low hematocrit (below 35%)b lipidemia - high in fat; yellowish plasmac. diabetes - blood glucose leveld. infection - generally higher WBC counte. leukemia - significantly higher WBC countf. differential WBC count - counts % of each of

the different leukocytes (helps diagnose)g. prothrombin time - time for clotting to occurh. platelet count - diagnose thrombocytopeniai. complete blood count - overall blood review

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Heart Physiology

I. Cardiac Muscle (compare to Skeletal Muscle)

Cardiac Muscle Cells

fairly shortsemi-spindle shapebranched, interconnectedconnected (intercalated discs)electrical link (gap junction)common contraction (syncytium)1 or 2 central nucleidense "endomysium"high vasculatureMANY mitochondria (25% space)almost all AEROBIC (oxygen)myofibers fuse at endsT tubules wider, fewer

Skeletal Muscle Cells

very longcylindrical shapeside-by-sideno tight bindingno gap junctionsindependent contractmultinucleated

light "endomysium"medium vasculatureless mitochondria (2%)aerobic & anaerobicmyofibers not fusedT tubules at A/I spot

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II. Mechanism of Contraction of Contractile Cardiac Muscle Fibers

1. Na+ influx from extracellular space, causes positive feedback opening of voltage-gated Na+ channels; membrane potential quickly depolarizes (-90 to +30 mV); Na+ channels close within 3 ms of opening.

2. Depolarization causes release of Ca++ from sarcoplasmic reticulum (as in skeletal muscle), allowing sliding actin and myosin to proceed.

3. Depolarization ALSO causes opening of slow Ca++ channels on the membrane (special to cardiac muscle), further increasing Ca++ influx and activation of filaments. This causes more prolonged depolarization than in skeletal muscle, resulting in a plateau action potential, rather than a "spiked" action potential (as in skeletal muscle cells).

Differences Between Skeletal & Cardiac MUSCLE Contraction

1. All-or-None Law - Gap junctions allow all cardiac muscle cells to be linked electrochemically, so that activation of a small group of cells spreads like a wave throughout the entire heart. This is essential for "synchronistic" contraction of the heart as opposed to skeletal muscle.

2. Automicity (Autorhythmicity) - some cardiac muscle cells are "self-excitable" allowing for rhythmic waves of contraction to adjacent cells throughout the heart. Skeletal muscle cells must be stimulated by independent motor neurons as part of a motor unit.

3. Length of Absolute Refractory Period - The absolute refractory period of cardiac muscle cells is much longer than skeletal muscle cells (250 ms vs. 2-3 ms), preventing wave summation and tetanic contractions which would cause the heart to stop pumping rhythmically.

III. Internal Conduction (Stimulation) System of the Heart

A. General Properties of Conduction

1. heart can beat rhythmically without nervous input

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2. nodal system (cardiac conduction system) - special autorhythmic cells of heart that initiate impulses for wave-like contraction of entire heart (no nervous stimulation needed for these)

3. gap junctions - electrically couple all cardiac muscle cells so that depolarization sweeps across heart in sequential fashion from atria to ventricles

B. "Pacemaker" Features of Autorhythmic Cells

1. pacemaker potentials - "autorhythmic cells" of heart muscle create action potentials in rhythmic fashion; this is due to unstable resting potentials which slowly drift back toward threshold voltage after repolarization from a previous cycle.

Theoretical Mechanism of Pacemaker Potential:

a. K+ leak channels allow K+ OUT of the cell more slowly than in skeletal muscle

b. Na+ slowly leaks into cell, causing membrane potential to slowly drift up to the threshold to trigger Ca++ influx from outside (-40 mV)

c. when threshold for voltage-gated Ca++ channels is reached (-40 mV), fast calcium channels open, permitting explosive entry of Ca++ from of the cell, causing sharp rise in level of depolarization

d. when peak depolarization is achieved, voltage-gated K+ channels open, causing repolarization to the "unstable resting potential"

e. cycle begins again at step a.

C. Anatomical Sequence of Excitation of the Heart

1. Autorhythmic Cell Location & Order of Impulses

(right atrium) sinoatrial node (SA) -> (right AV valve) atrioventricular node (AV) ->atrioventricular bundle (bundle of His) ->right & left bundle of His branches -> Purkinje fibers of ventricular walls

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(from SA through complete heart contraction = 220 ms = 0.22 s)

a. sinoatrial node (SA node) "the pacemaker" - has the fastest autorhythmic rate (70-80 per minute), and sets the pace for the entire heart; this rhythm is called the sinus rhythm; located in right atrial wall, just inferior to the superior vena cava

b. atrioventricular node (AV node) - impulses pass from SA via gap junctions in about 40 ms.; impulses are delayed about 100 ms to allow completion of the contraction of both atria; located just above tricuspid valve (between right atrium & ventricle)

c. atrioventricular bundle (bundle of His) - in the interATRIAL septum (connects L and R atria)

d. L and R bundle of His branches - within the interVENTRICULAR septum (between L and R ventricles)

e. Purkinje fibers - within the lateral walls of both the L and R ventricles; since left ventricle much larger, Purkinjes more elaborate here; Purkinje fibers innervate “papillary muscles” before ventricle walls so AV can valves prevent backflow

D. Special Considerations of Wave of Excitation

1. initial SA node excitation causes contraction of both the R and L atria

2. contraction of R and L ventricles begins at APEX of heart (inferior point), ejecting blood superiorly to aorta and pulmonary artery

3. the bundle of His is the ONLY link between atrial contraction and ventricular contraction; AV node and bundle must work for ventricular contractions

4. since cells in the SA node has the fastest autorhythmic rate (70-80 per minute), it drives all other autorhythmic centers in a normal heart

5. arrhythmias - uncoordinated heart contractions6. fibrillation - rapid and irregular contractions of the

heart chambers; reduces efficiency of heart7. defibrillation - application of electric shock to heart

in attempt to retain normal SA node rate8. ectopic focus - autorhythmic cells other than SA node

take over heart rhythm

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9. nodal rhythm - when AV node takes over pacemaker function (40-60 per minute)

10. extrasystole - when outside influence (such as drugs) leads to premature contraction

11. heart block - when AV node or bundle of His is not transmitting sinus rhythm to ventricles

E. External Innervation Regulating Heart Function

1. heart can beat without external innervation2. external innervation is from AUTONOMIC SYSTEM

parasympathetic - (acetylcholine) DECREASES rate of contractionscardioinhibitory center (medulla) -> vagus nerve (cranial X) -> heart

sympathetic - (norepinephrine) INCREASES rate of contractionscardioacceleratory center (medulla) -> lateral horn of spinal cord to preganglionics Tl-T5 -> postganlionics cervical/thoracic ganglia -> heart

IV. Electrocardiography: Electrical Activity of the Heart

A. Deflection Waves of ECG

1. P wave - initial wave, demonstrates the depolarization from SA Node through both ATRIA; the ATRIA contract about 0.1 s after start of P Wave

2. QRS complex - next series of deflections, demonstrates the depolarization of AV node through both ventricles; the ventricles contract throughout the period of the QRS complex, with a short delay after the end of atrial contraction; repolarization of atria also obscured

3. T Wave - repolarization of the ventricles (0.16 s)

4. PR (PQ) Interval - time period from beginning of atrial contraction to beginning of ventricular contraction (0.16 s)

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5. QT Interval the time of ventricular contraction (about 0.36 s); from beginning of ventricular depolarization to end of repolarization

V. The Normal Cardiac Cycle

A. General Concepts

1. systole - period of chamber contraction2. diastole - period of chamber relaxation3. cardiac cycle - all events of systole and diastole

during one heart flow cycle

B. Events of Cardiac Cycle

1. mid-to-late ventricular diastole: ventricles filled

* the AV valves are open* pressure: LOW in chambers; HIGH in aorta/pulmonary trunk * aortic/pulmonary semilunar valves CLOSED* blood flows from vena cavas/pulmonary vein INTO

atria* blood flows through AV valves INTO ventricles

(70%)* atrial systole propels more blood > ventricles

(30%)* atrial diastole returns through end of cycle

2. ventricular systole: blood ejected from heart

* filled ventricles begin to contract, AV valves CLOSE

* isovolumetric contraction phase - ventricles CLOSED

* contraction of closed ventricles increases pressure

* ventricular ejection phase - blood forced out* semilunar valves open, blood -> aorta & pulmonary

trunk

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3. isovolumetric relaxation: early ventricular diastole

* ventricles relax, ventricular pressure becomes LOW* semilunar valves close, aorta & pulmonary trunk

backflow* dicrotic notch - brief increase in aortic pressure

TOTAL CARDIAC CYCLE TIME = 0.8 second(normal 70 beats/minute)

atrial systole (contraction) = 0.1 secondventricular systole (contraction) = 0.3 secondquiescent period (relaxation) = 0.4 second

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VI. Heart Sounds: Stethoscope Listening

A. Overview of Heart Sounds

1. lub-dub, - , lub, dub, -2. lub - closure of AV valves, onset of ventricular

systole3. dub - closure of semilunar valves, onset of

diastole4. pause - quiescent period of cardiac cycle

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5. tricuspid valve (lub) - RT 5th intercostal, medial6. mitral valve (lub) - LT 5th intercostal, lateral7. aortic semilunar valve (dub) - RT 2nd intercostal8. pulmonary semilunar valve (dub) - LT 2nd

intercostalB. Heart Murmurs

1. murmur - sounds other than the typical "lub-dub"; typically caused by disruptions in flow

2. incompetent valve - swishing sound just AFTER the normal "lub" or "dub"; valve does not completely close, some regurgitation of blood

3. stenotic valve - high pitched swishing sound when blood should be flowing through valve; narrowing of outlet in the open state

VII. Cardiac Output - Blood Pumping of the Heart

A. General Variables of Cardiac Output

1. Cardiac Output (CO) - blood amount pumped per minute

2. Stroke Volume (SV) - ventricle blood pumped per beat

3. Heart Rate (HR) - cardiac cycles per minute

CO (ml/min) = HR (beats/min) X SV (ml/beat)

normal CO = 75 beats/min X 70 ml/beat=5.25 L/min

B. Regulation of Stroke Volume (SV)

1. end diastolic volume (EDV) - total blood collected in ventricle at end of diastole; determined by length of diastole and venous pressure (~ 120 ml)

2. end systolic volume (ESV) - blood left over in ventricle at end of contraction (not pumped out); determined by force of ventricle contraction and arterial blood pressure (~50 ml)

SV (ml/beat) = EDV (ml/beat) - ESV (ml/beat)normal SV = 120 m1/beat-50 ml/beat = 70 ml/beat

3. Frank-Starling Law of the Heart - critical factor for stroke volume is "degree of stretch of cardiac muscle cells"; more stretch = more contraction force

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a. increased EDV = more contraction force

i. slow heart rate = more time to fillii. exercise = more venous blood return

C. Regulation of Heart Rate (Autonomic, Chemical, Other)

1. Autonomic Regulation of Heart Rate (HR)

a. sympathetic - NOREPINEPHRINE (NE) increases heart rate (maintains stroke volume which leads to increased Cardiac Output)

b. parasympathetic - ACETYLCHOLINE (ACh) decreases heart rate

c. vagal tone - parasympathetic inhibition of inherent rate of SA node, allowing normal HR

d. baroreceptors, pressoreceptors - monitor changes in blood pressure and allow reflex activity with the autonomic nervous system

2. Hormonal and Chemical Regulation of Heart Rate (HR)

a. epinephrine - hormone released by adrenal medulla during stress; increases heart rate

b. thyroxine - hormone released by thyroid; increases heart rate in large quantities; amplifies effect of epinephrine

c. Ca++, K+, and Na+ levels very important;

* hyperkalemia - increased K+ level; KCl used to stop heart on lethal injection

* hypokalemia - lower K+ levels; leads to abnormal heart rate rhythms

* hypocalcemia - depresses heart function* hypercalcemia - increases contraction phase* hypernatremia - HIGH Na+ concentration; can

block Na+ transport & muscle contraction

3. Other Factors Effecting Heart Rate (HR)

a. normal heart rate - fetus 140 - 160 beats/minutefemale 72 - 80 beats/minutemale 64 - 72 beats/minute

b. exercise - lowers resting heart rate (40-60)

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c. heat - increases heart rate significantlyd. cold - decreases heart rate significantlye. tachycardia - HIGHER than normal resting

heart rate (over 100); may lead to fibrillation

f. bradycardia - LOWER than normal resting heart rate (below 60); parasympathetic drug side effects; physical conditioning; sign of pathology in non-healthy patient

VIII. Imbalance of Cardiac Output & Heart Pathologies

A. Imbalance of Cardiac Output1. congestive heart failure - heart cannot pump

sufficiently to meet needs of the bodya. coronary atherosclerosis - leads to gradual

occlusion of heart vessels, reducing oxygen nutrient supply to cardiac muscle cells; (fat & salt diet, smoking, stress)

b. high blood pressure - when aortic pressure gets too large, left ventricle cannot pump properly, increasing ESV, and lowering SV

c. myocardial infarct (MI) - "heart cell death" due to numerous factors, including coronary artery occlusion

d. pulmonary congestion - failure of LEFT heart; leads to buildup of blood in the lungs

e. peripheral congestion - failure of RIGHT heart; pools in body, leading to edema (fluid buildup in areas such as feet, ankles, fingers)

B. Heart Pathologies (Diseases of the Heart)1. congenital heart defects - heart problems that are

present at the time of birtha. patent ductus arteriosus - bypass hole

between pulmonary trunk and aorta does not close

2. sclerosis of AV valves - fatty deposits on valves; particularly the mitral valve of LEFT side; leads to heart murmur

3. decline in cardiac reserve - heart efficiency decreases with age

4. fibrosis and conduction problems - nodes and conduction fibers become scarred over time; may lead to arrhythmias

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Circulatory Physiology

I. Factors Involved in Blood Circulation

A. Blood Flow - the actual VOLUME of blood moving through a particular site (vessel or organ) over a certain TIME period (liter/hour, ml/min)

B. Blood Pressure - the FORCE exerted on the wall of a blood vessel by the blood contained within (millimeters of Mercury; mm Hg)

blood pressure = the systemic arterial pressure of large vessels of the body (mm Hg)

C. Resistance to Flow (Peripheral Resistance) - the FORCE resisting the flow of blood through a vessel (usually from friction)

1. viscosity - a measure of the "thickness" or "stickiness" of a fluid flowing through a pipe

a. V water < V blood < V toothpasteb. water flows easier than blood

2. tube length - the longer the vessel, the greater the drop in pressure due to friction

3. tube diameter - smaller diameter = greater friction

D. Relation Between Blood Flow, Pressure, Resistance

difference in blood pressure ( P)

Blood Flow (F) = peripheral resistance (R)

a. increased P -> increased flowb. decreased P -> decreased flowc. increased R (vasoconstriction) -> DECREASED

flowd. decreased R (vasodilation) -> INCREASED flow

II. Systemic Blood Pressure

A. Blood Pressure Near the Heart

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1. HEART produces blood pressure by pumping the blood2. Blood pressure decreases with distance from Heart3. systolic arterial blood pressure - pressure in

aorta (& major arteries) in middle of ventricular contraction (120 mm Hg in healthy adult)

4. diastolic arterial blood pressure - pressure in aorta (& major arteries) during ventricular diastole, when semilunar valves are closed (80 mm Hg in healthy adult)

5. mean arterial pressure (MAP) - the "average" blood pressure produced by the heart (93 mm Hg in healthy adult)

mean arterial pressure = diastolic pressure + 1/3 pulse pressure

** pulse pressure = systolic pressure - diastolic pressure

6. blood pressure decreases throughout system

L ventricle -->120 mm Hgarteries -->120 - 60 mm Hgarterioles -->60 - 40 mm Hgcapillaries -->40 - 20 mm Hgvenous -->20 - 10 mm HgR atrium -->10 - 0 mm Hg

7. venous return - venous blood pressure is so low, other factors contribute to venous blood flowa. respiratory pump - breathing action of thorax "squeezes" blood back toward the heartb. muscular pump - contraction/relaxation of skeletal muscles "milk" blood up veins to heart

III. Factors Affecting Blood Pressure

A. Cardiac Output ( = stroke volume X heart rate)CO =SV (ml/beat) x HR (beats/min)

=70 ml/beat x 60 beats/min = 4200 ml/min

1. increased cardiac output -> increased blood pressure

2. increased stroke volume -> increased blood pressure

3. increased heart rate -> increased blood pressure

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B. Peripheral Resistance

1. arteriole constriction ---> increased blood pressure

2. resistance inversely proportional to the "fourth power" of the radius change

C. Blood Volume1. hemorrhage - decrease in blood pressure2. salt/fluid - increase in blood pressure3. polycythemia - increase in blood viscosity4. RBC anemia - decrease in blood viscosity

IV. Regulation of Blood Pressure

A. Nervous System Control1. control of arteriole diameter2. directs blood flow to proper organs and tissues

that need it3. REFLEX PATHWAY:

baroreceptors/chemoreceptors/brain --> afferent nerve fibers --> medulla (vasomotor center) --> vasomotor (efferent) nerve fibers --> smooth muscle of arterioles

B. Vasomotor Fibers to Smooth Muscle of Arterioles1. sympathetic fibers that release norepinephrine

(NE); cause vasoconstriction of arterioles

C. Vasomotor Center of the Medulla

1. sympathetic neuron cell bodies in the medulla2. receive input from baroreceptors, chemoreceptors,

and brain3. vasomotor tone - general constricted state of

arterioles set by vasomotor center

D. Baroreceptors

1. blood pressure receptors large arteries (carotid sinuses, aortic arch, neck/thorax arteries)

2. send blood pressure information to vasomotor center of medulla

increased pressure --> decreased pressure --> inhibits vasomotor center --> stimulates vasomotor center -> vasodilation vasoconstriction

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E. Chemoreceptors

1. located in aortic arch and carotid arteriesa. carotid and aortic bodies

2. monitor OXYGEN and pH levels of the bloodlow OXYGEN or low pH -------> increase blood pressure, return blood to lungs quickly

F. Higher Brain Centers Control on BP1. hypothalamus & cortex also effect vasomotor area

G. Chemical Controls of Blood Pressure

1. hormones of adrenal medulla - "fight-or-flight" response to fear; release of norepinephrine and epinephrine from adrenal medulla; causes vasoconstriction and increased BP

2. atrial natriuretic factor (ANF) - secreted by the atria of the heart, promotes general decline in blood pressure kidney releasing more Na+ and water, reducing fluid volume

3. antidiuretic hormone (ADH) - released by the hypothalamus, causes increase in blood pressure by getting the kidneys to conserve water in the body; e.g. during hypotensive situations

4. endothelium derived factorsa. endothelin - strong vasoconstrictorb. endothelium derived relaxing factor -

vasodilation5. alcohol - causes vasodilation

H. Renal (Kidney) Regulation1. direct regulation - fluid loss through urine

a. low pressure/volume --> conserve waterb. high pressure/volume --> release more water

2. renin-angiotensin mechanismlow blood pressure --> release of renin --> formation of angiotensin II--> vasoconstriction Release of aldosterone --> Na+/water reabsorption by kidney)

V. Variations in Blood Pressure

A. Measuring Blood Pressure

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1. vital signs - blood pressure, pulse, respiratory rate, and body temperature

2. auscultory method of blood pressure measurement

a. “sphygmomanometer” wrapped around upper armb. inflate above systolic pressure of brachial c. pressure released, first sounds - systolic d. disappearance of sounds - diastolic pr.

B. Hypotension (below normal blood pressure, < 100/60)

1. factors - age, physical conditioning, illness2. orthostatic hypotension - generally in elderly,

drop in blood pressure during postural changes3. chronic hypotension - ongoing low blood pressure

a. low blood protein levels (nutrition)b. Addison’s disease (adrenal cortex malfunction)c. hypothyroidismd. also sign of various types of cancer

C. Hypertension (above normal blood pressure at rest, > 140/90)

1. factors - weight, exercise, emotions, stress2. chronic hypertension - ongoing high blood pressure

a. prevalent in obese and elderlyb. leads to heart disease, renal failure, strokec. also leads to more arteriosclerosisd. primary hypertension - unidentified source

i. high Na+, cholesterol, fat levelsii. clear genetic component (in families)iii. diuretics - promote water removaliv. NE blockers - slow vasoconstriction

e. secondary hypertension - identifiable disorderi. kidney disordersii. endocrine (hormone) disordersiii. arteriosclerosis

VI. Blood Flow in the Body

A. General Features

1. delivery of oxygen and removal of carbon dioxide2. gas exchange in the lungs

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3. absorption and delivery of nutrients from GI tract4. processing/waste removal in the kidneys5. normal blood flow at rest

abdominal organs 24%skeletal muscle 20%kidneys 20%brain 13%heart 4%other 15%

B. Velocity of Blood Flow1. velocity directly related to the TOTAL cross-

sectional area of the vessel(s)

FASTEST aorta 40-50 cm/sarteries 20-40 cm/sarterioles 1-20 cm/s

SLOWEST capillaries 0.1-1 cm/s

C. Local Regulation of Blood Flow1. autoregulation - regulation of blood flow by

altering arteriole diametera. oxygen and carbon dioxide levelsb. prostaglandins, histamines, kininsc. needy areas --> more blood flow

2. myogenic response - change in flow through arteriole in response to stretch of smooth muscle

3. reactive hyperemia - increase in blood flow to area where an occlusion has occurred

4. increased vasculature - results from prolonged lack of oxygen/nutrients to an area (eg. heart)

D. Blood Flow to Skeletal Muscles

1. active (exercise) hyperemia - increased blood flow to muscles during heavy activitya. decreased oxygen and increased lactic acidb. visceral organ blood flow is decreased

E. Blood Flow to The Brain

1. MUST maintain constant blood flow (750 ml/min)2. sensitive to low pH and high carbon dioxide3. blood pressure tightly regulated in the brain

a. fainting -> below 60 mm Hgb. edema (brain swelling) -> above 180 mm Hg

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F. Blood Flow to The Skin

1. intimately involved in temperature regulation

increased body temperature -> hypothalamic inhibition of vasomotor area -> vasodilation of vessels in skin -> increased blood flow -> sweating -> (bradykinin -> more vasodilation)

G. Blood Flow to the Lungs

1. short pathway from heart, less pressure required2. low oxygen level --> vasoconstriction

H. Blood Flow to the Heart

1. blood to coronary arteries during diastole2. vasodilation from ADP and carbon dioxide

VII. Blood Flow in the Capillaries

A. Exchange of Gases and Nutrients

1. diffusion - all molecules move DOWN the concentration gradient (from HIGH to LOW) into or out of the blood

2. oxygen/nutrients (blood ----> body cells)carbon dioxide/ wastes(body cells ----> blood)

B. Fluid Movements1. hydrostatic pressure - force from the capillary

wall on the blood itselfa. filtration pressure - the pressure forcing

fluid and solutes through capillary clefts2. osmotic pressure - force driving fluid in the

direction of HIGHER solute concentration3. movement out: Hydrostatic pressure > Osmotic

differencemovement in : Hydrostatic pressure < Osmotic difference

4. normal fluid movement 1.5 ml/min in the entire body

C. Circulatory Shock

1. circulatory shock - blood pressure gets so low that blood will not flow adequately

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2. hypovolemic shock - circulatory shock resulting from loss of fluid (bleeding, diarrhea, burn)a. heart rate increases rapidlyb. general vasoconstriction of vessels

3. vascular shock - extreme vasodilation causes sudden drop in blood pressurea. snake and spider bites with NE blockersb. septicemia - bacterial infection

4. cardiogenic shock - heart is unable to provide sufficient blood pressure

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The Immune System: Innate and Adaptive Body Defenses

 

I. Innate Defenses

A.  Surface Barriers: Skin and Mucosae

1.   Skin, a highly keratinized epithelial membrane, represents a physical barrier to most microorganisms and their enzymes and toxins.

2.   Mucous membranes line all body cavities open to the exterior and function as an additional physical barrier.

3.   Secretions of the epithelial tissues include acidic secretions, sebum, hydrochloric acid, saliva, and mucus.

 B.  Internal Defenses: Cells and Chemicals

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1.   Phagocytes confront microorganisms that breach the external barriers.

a. Macrophages are the main phagocytes of the body.b. Neutrophils are the first responders and become phagocytic when they encounter infectious material. c. Eosinophils are weakly phagocytic but are important in defending the body against parasitic worms.d. Mast cells have the ability to bind with, ingest, and kill a wide range of bacteria.

2.   Natural killer cells are able to lyse and kill cancer cells and virally infected cells before the adaptive immune system has been activated.

 

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Inflammation is a bodily response to cell damage (physical trauma, intense heat, irritating chemicals, or infection by viruses, fungi, or bacteria).

The four cardinal signs of inflammation, as described by the Roman physician and science writer Celsus, are:

Rubor - redness Tumor - swelling Calor - heat Dolor - painThe fifth sign, which is sometimes present, is loss of

function, or functio laesa - this was originally described and added to the four signs described by Celsus by another Roman physician and science writer, Galen, but was popularized in the 1800s by Rudolph Virchow, the "Father of Modern Pathology". Functions:

To destroy and remove pathogens and debris. To confine pathogens; prevent spread of infection. To repair or replace damaged tissue (sets stage for wound

repair).The release of inflammatory chemicals causes vasodilation,

which increase blood flow to the area, increased vascular permeability, which allows fluid containing clotting factors and antibodies to enter the tissues, sensitize and even directly stimulate pain receptors, and act as chemotactic factors for phagocytes (neutrophils and macrophages).

A brief explanation of how some of this inflammation/ phagocytosis /complement activation gets started:

Pattern recognition receptors (PRRs) are receptors that recognized conserved (common) molecular sequences associated with a number of different pathogens (PAMPs - pathogen associated molecular patterns). PRRs are found on the surface and in the cytoplasm of macrophages, dendritic cells, mucosal epithelial cells, endothelial cells, and lymphocytes. Some secreted molecules recognize PAMPs and act as PRRs as well.Secreted PRRs:Circulating acute phase proteins, like C-reactive protein, mannose-binding lectin, and complement proteins C3b and C4 bind to PAMPs on the surface of a number of different pathogens. This causes opsonization and phagocytosis of the pathogen and activation of the complement cascade.

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Cytoplasmic PRRs:Intracellular receptors recognize nucleic acid sequences,

cell wall components of gram-positive and gram-negative bacteria, and a number of other pathogen associated molecules. Interaction with their ligands activates cytokine production and HLA upregulation.Phagocytosis Receptors:

Macrophages have cell-surface receptors that recognize certain PAMPs, including, those containing mannose. When a pathogen displays a cell surface polysaccharide containing mannose it is engulfed into a phagosome. Toll-Like Receptors (TLRs):

Surface membrane receptors that recognize a number of different PAMPs. There are at least 10 different TLRs.

Binding of the pathogen to the PRRR initiates a signaling pathway leading to the activation of the transcription factor NF-κB. NF-κB turns on cytokine genes, such as those for tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and chemokines, which attract white blood cells to the site. All of these effector molecules lead to inflammation at the site.

Mast cells, injured tissue cells, neutrophils, lymphocytes, and basophils all release inflammatory mediators as well.

The release of histamine, kinins, and prostaglandins causes vasodilation and increased permeability of blood vessels.

Histamine causes vasodilation, increases vascular permeability, and is chemotactic for eosinophils.

Kinins cause clotting, vasodilation, increased vascular permeability, and pain.

Factor XII (Hageman Factor) is activated by endotoxin, uric acid, calcium pyrophosphate, and basement membrane proteins (collagen).

XIIa activates Factor XI to initiate clotting and cleaves prekallikrein to kallikrein.

Kallikrein converts plasminogen to plasmin, HMW kininogen to bradykinin, and cleaves C5 to release C5a and C5b.

C5a stimulates inflammationArachidonic acid metabolitesCyclooxygenase products

Prostaglandins: PGE2 increases vascular permeability, sensitizes to pain,

and is pyrogenic.

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PGI’s cause vasodilation. Thromboxanes cause vasoconstriction.

Lipooxygenase products Leukotrienes are produced by mast cells, basophils,

macrophages, and eosinophils. LTB4 (SRS-A) is chemotactic, causes vasoconstriction, and

increases endothelial stickiness. LTC and LTD cause bronchoconstriction, allergy, increase

vascular permeabilityBlood clots can form around an abscess to prevent dissemination of the infection. Epithelial mucosal cells increase their release of b- defensins (broad spectrum antimicrobial proteins) when the epithelial barrier has been breached and the underlying connective tissue is inflammed. Chemotaxis of PhagocytesPhagocytes have the ability to stick to the lining of the blood vessels (margination, pavementing).

They also have the ability to squeeze through blood vessels (emigration or diapedesis).

PMNs show up first and release ROI (reactive oxygen intermediates), like superoxide anions, hydroxyl ions, hydrogen peroxide, and the enzyme myeloperoxidase, which converts hydrogen peroxide to hypochlorous acid (HOCl, which dissociates to H+ and OCl-, the hypocholorite anion, basically bleach). PMNs also release defensins and are phagocytic.

Pus is the accumulation of damaged tissue and dead microbes, granulocytes, and some macrophages. Generally macrophages show up late to clean up the cellular debris (debride the wound) and set the stage for wound healing.

 

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A tissue is repaired when the stroma (supporting tissue) or parenchyma (functioning tissue) produces new cells.

Stromal repair by fibroblasts produces scar tissue.

 

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4.   Antimicrobial proteins enhance the innate defenses by attacking microorganisms directly or by hindering their ability to reproduce.

a. Interferons are small proteins produced by virally infected cells that help protect surrounding healthy cells.

b. There are three types of human interferon: alpha-IFN, beta-IFN, and gamma-IFN. Recombinant interferons have been produced.

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* The mode of action of alpha-IFN and beta-IFN is to induce uninfected cells to produce antiviral protein (AVPs) that prevent viral replication.

* Once produced and released from virus-infected cells, IFN diffuses to uninfected neighboring cells and binds to surface receptors, inducing uninfected cells to synthesize antiviral proteins that interfere with or inhibit viral replication.

* Interferons are host-cell-specific but not virus-specific.

* INFs also enhance the activity of phagocytes and natural killer (NK) cells, inhibit cell growth, and suppress tumor formation; they may hold promise as clinical tools in AIDS and cancer treatment once they are more fully understood.

* Gamma-IFN activates neutrophils and macrophages to kill bacteria and activates Th1 cells, which stimulate cell-mediated reactions.

* Lack of gamma-IFN results in activation of Th2 cells, which are humoral mediators.

* Very high levels of gamma-IFN stimulates NK cells and CTLs.

c. Complement refers to a group of about 20 plasma proteins that provide a major mechanism for destroying foreign pathogens in the body.

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5.   Fever, or an abnormally high body temperature, is a systemic response to a bacterial or viral infection.

Bacterial endotoxins and interleukin-1 can induce fever.

A chill indicates a rising body temperature; crisis (sweating) indicates that the body’s temperature is falling.

  II. Adaptive Defenses

A.  Aspects of the Adaptive Immune Response

1.  Specific: The adaptive defenses recognize and destroy the specific antigen that initiated the response.

2.   Systemic: The immune response is a systemic response; it is not limited to the initial infection site.

3.   Has Memory: After an initial exposure the immune response is able to recognize the same antigen and mount a faster and stronger defensive attack.

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4.   Humoral immunity is provided by antibodies, which are produced by plasma cells and are present in the body’s “humors” or fluids.

Plasma cells arise from B-lymphocytes after B-cell activation.

5.   Cellular immunity is associated with T-lymphocytes and has living cells as its protective factor.

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B.  Antigens are substances that can mobilize the immune system and provoke an immune response.

1.   Complete antigens are able to stimulate the activation process that leads to proliferation of specific lymphocytes and antibody production; they are recognized by activated lymphocytes and the antibodies they have stimulated production of.

2.   Haptens are incomplete antigens that are not capable of stimulating the immune response, but if they interact with proteins of the body they may be recognized as potentially harmful.

3.   Antigenic determinates or epitopes are a specific part of an antigen that are immunogenic and bind to free antibodies or activated lymphocytes.

C.  Cells of the Adaptive Immune System: An Overview

1.   Lymphocytes originate in the bone marrow and when released become immunocompetent in either the thymus (T cells) or the bone marrow (B cells).

2.   Antigen-presenting cells engulf antigens and present fragments of these antigens on their surfaces where they can be recognized by T cells.

 

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III. Humoral Immune Response

A.  The immunocompetent but naive B lymphocyte is activated when antigens bind to its surface receptors.

1.   Clonal selection is the process of the B cell growing and multiplying to form an army of cells that are capable of recognizing the same antigen.

2.   Plasma cells are the antibody-secreting cells of the humoral response; most clones develop into plasma cells.

3.   The clones that do not become plasma cells develop into memory cells.

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B.  Immunological Memory

1.   The primary immune response occurs on first exposure to a particular antigen with a lag time of about 3–6 days.

2.   The secondary immune response occurs when someone is reexposed to the same antigen. It is faster, more prolonged, and more effective.

C.  Active and Passive Humoral Immunity

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1.   Active immunity occurs when the body mounts an immune response to an antigen - effector cells and memory cells are generated.

a. Naturally acquired active immunity occurs when a person suffers through the symptoms of an infection.

b. Artificially acquired active immunity occurs when a person is given a vaccine.

2.   Passive immunity occurs when a person is given preformed antibodies - no lymphocyte activation, no effector cells, no memory cells.

a. Naturally acquired passive immunity occurs when a mother’s antibodies enter fetal circulation.

b. Artificially acquired passive immunity occurs when a person is given preformed antibodies that have been harvested from another person.

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D.  Antibodies or immunoglobulins are proteins secreted by plasma cells in response to an antigen that are capable of binding to that antigen.

1.   The basic antibody structure consists of four looping polypeptide chains linked together by disulfide bonds.

2.   Antibodies are divided into five classes based on their structure: IgM, IgG, IgA, IgD, and IgE.

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3.   Embryonic cells contain a few hundred gene segments that are shuffled and combined to form all of the different B cells that are found in the body.

4.   Antibody Targets and Functions

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a. Complement fixation and activation occurs when complement binds to antibodies attached to antigens, and leads to lysis of the cell.

b. Neutralization occurs when antibodies block specific sites on viruses or bacterial exotoxins, causing them to lose their toxic effects.

c. Agglutination occurs when antibodies cross-link to antigens on cells, causing clumping.

d. Precipitation occurs when soluble molecules are cross-linked into large complexes that settle out of solution.

5.   Monoclonal antibodies are commercially prepared antibodies specific for a single antigenic determinant.

IV. Cell-Mediated Immune Response

A.  The stimulus for clonal selection and differentiation of T cells is binding of antigen, although their recognition mechanism is different from B cells.

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1.   T cells must accomplish a double recognition process: they must recognize both self (an HLA molecule of a body cell) and nonself (antigen) at the same time. (HLA molecules are Human Leukocyte Antigens , you may be more familiar with the term MHC)

2.   T-cells bind and recognize their specific antigen through an antigen receptor, which is known as the T-cell receptor (TCR). 

The TCR will bind to the antigen it is specific for  only when the antigen is bound to an HLA molecule on the surface of some other cell.

Human Leukocyte Antigens, or tissue antigens, are glycoproteins that are present on almost every cell in the body. HLA molecules have a groove along the top of the molecule (the peptide binding site) that binds a small piece of protein, typically between 8 and 15 amino acids long.

The presence of peptide in the peptide binding site of an HLA molecule such that T-cell receptors can bind to the HLA-peptide complex is known as antigen presentation.

There are two classes of HLA molecules, Class I and Class II.

Class I HLAs are coded for by three different genes, Class I A, Class I B, and Class I C. Class I molecules are present on all nucleated cells in the body and are recognized by CD8+ T-cells.

Class I HLAs present "internal foreign antigens" like viral antigens and tumor antigens (which look foreign because they are mutant normal peptides).

Class II HLAs are coded for by three different genes as well, the DR, DP, and DQ genes. Class II molecules are present on antigen presenting cells (APCs), which include macrophages, dendritic cells, and B-cells.

Class II HLAs are recognized by CD4+ T-cells.

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Class II HLAs present "exogenous foreign antigens", things that have been phagocytized and broken down within APCs. 

Normally, HLA molecules have a small piece of endogenous self-peptide, a piece of some normal self protein that has "worn out" and been recycled, bound to their antigen binding site.

T-cells "dock" with the HLA-peptide complex, recognize it as "self", and go on about their business.  This is called immune survellience. 

If a foreign peptide is bound to the antigen binding site of the HLA molecule the T-cell will recognize the complex as "foreign" and respond appropriately.

But - In order to respond to an antigen, the T-cell has to be activated first.

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T Cell Activation

a. The first step in T-cell activation is binding of the T-cell to HLA-antigen complex it is specific for on the surface of an APC (thats why they're called antigen presenting cells). 

b. The second step is the requirement for the T-cell to recieve a co-stimulatory signal.  Co-stimulation may be the result of interaction of the CD28 protein on the surface of T-cells and B-7 proteins on the surface of APCs or stimulation of the T-cells by cytokines, in particular IL-2, or a number of other interactions (this is somewhat simplified, but go with it).

Without co-stimulation the T-cell won't respond to its antigen - it becomes anergized or tolerized.

Since non-antigen presenting cells don't have co-stimulatory molecules, like B-7, on their surface they can't activate T-cells.

The bottom line here is this: In order to become activated, naive T-cells must contact their specific antigen by binding between their T-cell receptor and the appropriate HLA-antigen complex on the surface of an APC.

c. Once activated, a T cell enlarges and proliferates to form a clone of cells that differentiate and perform functions according to their T cell class.

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3.   Cytokines include hormonelike glycoproteins released by activated T cells and macrophages.

B.  Specific T Cell Roles

1.  Helper T-cells (CD4+)

Th1 secrete IL-2, IFN-g, TNF-ß

Drives cell-mediated responses (stimulates CD8+ T-cells and high levels of IFN-g will stimulate phagocytes to kill internal pathogens)

Th1 also secrete IL-3 and GM-CSF to stimulate bone marrow to produce more leukocytes

Th2 secrete IL-4, IL-5, IL-6, IL-10

Drives humoral responses (stimulates antibody production by activated B-cells)

Th1 and Th2 cytokines are antagonistic in activity.

The Th1 cytokine IFNg inhibits proliferation of Th2 cells, while IFNg and IL-2 stimulate B cells to secrete IgG2a and inhibit secretion of IgG1 and IgE.

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The Th2 cytokine IL-4 stimulates B cells to secrete IgE and IgG1; IL-10 inhibits Th1 secretion of IFNg and IL-2; it also suppresses Class II MHC expression and production of bacterial killing molecules and inflammatory cytokines by macrophages.

The balance between Th1 and Th2 activity helps drive the immune response in the direction of cell-mediated or humoral immunity.

Antigen presenting cells phagocytize external antigens, break them down in phagolysomes, and put peptide fragments in the peptide binding site of Class II HLAs. 

The Class II HLA-peptide complex is then moved to the surface of the APC where it can be recognized by an appropriate CD4+ T-cell.

The act of phagocytosis will stimulate macrophages to secrete IL-1, which will co-stimulate CD4+ T-cells when they bind to the HLA-peptide complex.

When CD4+ T-cells are activated in this way they secrete IL-2, which stimulates macrophages, stimulates CD8+ T-cells, stimulates B-cells, and self stimulates the activated CD4+ T-cells.  IL-2 works like a growth factor.

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2.  Cytotoxic T-cells (CD8+)

What about antigen presentation and activation of CD8+ T-cells?

Same deal, except the antigen is presented bound to a Class I HLA molecule.  APCs can take up viral particles by phagocytizing virally-infected host cells or through gap junctions between the APC and virally-infected cell.

B7 proteins on APCs bind CD28 on the T-cells and costimulate them to become activated.

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CD8+ T-cells kill virally infected cells and tumor cells when activated by secreting perforin, granzymes, and expressing a protein called FAS-ligand on their cell surface. 

 

Perforin creates channels in the target cell membrane.

Granzymes enter the target cell through the channels and turn on enzymes that induce apoptosis in the target cell.

FAS-ligand binds to a receptor protein on the target cell called FAS.  This interaction also stimulates the tartet cell to undergo apoptosis.

 3.   Regulatory T cells release cytokines that suppress the activity of both B cells and other types of T cells.

May be CD4+ or CD8+

4.   Gamma/delta T cells are found in the intestine and are more similar to NK cells than other T cells.

5.   Without helper T cells there is no adaptive immune response because the helper T cells direct or help complete the activation of all other immune cells.

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C.  Organ Transplants and Prevention of Rejection

1.   Grafts

a. Autografts are tissue grafts transplanted from one body site to another in the same person.

b. Isografts are grafts donated to a patient by a genetically identical individual such as an identical twin.

c. Allografts are grafts transplanted from individuals that are not genetically identical but belong to the same species.

d. Xenografts are grafts taken from another animal species.

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2.   Transplant success depends on the similarity of the tissues because cytotoxic T cells, NK cells, and antibodies work to destroy foreign tissues. Tissue typing for HLA matching and blood typing for ABO matching are important parts of preparing for transplantation. An example: Tissue typing for bone marrow transplantation.

V. Homeostatic Balances of Immunity

A.  Immunodeficiencies are any congenital or acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally.

1.   Severe combined immunodeficiency (SCID) is a congenital condition that produces a deficit of B and T cells.

2.   Acquired immune deficiency syndrome (AIDS) cripples the immune system by  interfering with helper T cells.

B.  Autoimmune diseases occur when the immune system loses its ability to differentiate between self and nonself and ultimately destroys itself. There is often involvement of HLA type in susceptibility to autoimmune disease.

C.  Hypersensitivities, or allergies, are the result of the immune system causing tissue damage as it fights off a perceived threat that would otherwise be harmless.

1.   Immediate hypersensitivities (Type I or anaphylactic) begin within seconds after contact and last about half an hour. IgE antibodies bind to the Fc receptor on basophils and mast cells and when allergen binds to the IgE molecules and crosslinks them they cause degranulation and release of histamine, leukotrienes and prostaglandins, which cause inflammation.

There are two basic kinds of reactions: systemic anaphylaxis and localized reactions.

Systemic anaphylaxis is anaphylactic shock and can be counteracted by epinephrine injection.

Localized reactions include allergic rhinitis (hay fever) accompanied by itchy and teary eyes, congestion, coughing

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and sneezing; asthma, accompanied by wheezing and shortness of breath; and hives, a skin rash usually due to food allergies.

Anaphylactic reactions can be prevented by determination of the specific allergens that a patient is sensitive to and injecting small amounts of the allergens over an extended period of time (desensitization). This causes the production of blocking antibodies, which are IgG.

The only other treatment is symptomatic, such as with antihistamines.

 

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2.   Subacute hypersensitivities (Types II and III) take 1–3 hours to occur and last 10–15 hours.

Type II, or cytotxic

Cytotoxic reactions are mediated by IgG or IgM and complement.

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The antibodies are directed toward cellular antigens on foreign cells or foreign antigens on host cells.

The antigen-antibody complexes cause complement fixation resulting in cell lysis and phagocytosis.

Examples include transfusion reactions and drug induced hemolysis.

Type III, or immune complex

Antigens involved are not part of host cells but soluble antigens.

The antigens are bound by IgM or IgG antibodies and the antigen-antibody complexes precipitate and lodge in basement membranes.

Complement fixation leads to inflammation and cell lysis.

Example: Glomerulonephritis

Inflammation of the glomeruli due to immune-complex disease.

Occurs as a sequel to a beta-hemolytic streptococcal infection (group A).

Antigen-antibody complexes cause inflammation and damage to the glomerular membrane.

Other Immune Complex Diseases:

Systemic lupus erythematosus

Rheumatoid arthriti

3.   Delayed hypersensitivity reactions take 1–3 days to occur and may take weeks to go away.

Delayed-type hypersensitivity (TDTH) T-cells are involved.

Sensitized T-cells secrete lymphokines in response to antigen.

Lymphokines attract macrophages and initiate tissue damage.

Examples:

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Tuberculin skin test

Allergic contact dermatitis

VI. Developmental Aspects of the Immune System

A.  Embryologic Development

1.   Stem cells of the immune system originate in the liver and spleen during weeks 1–9 of embryonic development; later the bone marrow takes over this role.

2.   In late fetal life and shortly after birth the young lymphocytes develop self-tolerance and immunocompetence.

B.  Later in life the ability and efficiency of our immune system declines.

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Commonly Asked Questions

What are the advantages of a closed, as compared with an open, circulatory system?

Two basic types of transport systems – the open and the closed circulatory systems- occur in the larger invertebrate animals. Smaller animal do not need transport systems, for all of their body cells are near internal cavities or the external environ, In an open circulatory system, the blood is not completely enclosed with the vessels, the hearts pump blood through arteries into large cavities or sinuses, where it mixes wit interstitial fluid and bathes the cells of the body. The blood is slowly return to the heart through small pores, called ostia. And bathes the cell of the body. The blood is slowly returned to the heart s through small pores called ostia. In a closed circulatory system, the blood remain within a completely enclose system of vessel and never comes in a direct contact with the body cells Material move between the blood and interstitial fluid through the thin walls of capillaries.

Circulation is slower in an open system, because with some of the blood pooled in sinuses, the hearts cannot build up enough pressure to make the blood flow rapidly. In an open

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system cannot achieve high rates of oxygen transport that active animals requires animals with open system are either quite small and sluggish of use the open system only for transport of food and wastes and use a different system for transport of gases. Insects for opens system only transport of food and wastes and use a different system for transport of gases, Insects of example, have a separate system of vessels- the tracheal system – for gas transport, the insects circulatory system is composed of five muscular hearts which slowly pump the blood, which contains food and wastes (except carbon dioxide, hominess and other material though a system of vessels and open cavities in a forward and downward direction. the blood bathes the cells of he body in open cavities below the vessel. Providing the necessary materials (except oxygen) for cellular activities and accumulating waste products 8 except carbon dioxide from the cells. The blood then moves slowly form these cavities backward and upward to the hearts. Transport is accelerated during physical activity, when the skeletal l muscles contact rhythmically, squeeze the cavities and forcing the blood back toward the hearts.

Invertebrate animals that have open circulatory systems include the arthropod (such as insects, spiders, crabs and lobsters, and most mollusks (such as snails, oysters and clams. Invertebrates with a closed circulatory system include the annelids such as earthworms and some mollusks (such as squids)

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How can a frog or a lizard be very active if its oxygen-rich blood mixes with oxygen-poor blood before becoming available to the body cells?

A frog or a lizard has a single ventricle, which receives oxygen-poor oxygen –poor blood from the body as well as oxygen-rich blood form the lungs, and in the case of a frog, from the skin. Blood from the ventricle is pumped via one artery to the lungs (and skin, in the case of a frog) and via another artery to the rest of the body. In neither animal, however, is there’s complete mixing of the two types of blood in the ventricle, a

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frog has ridge of heart tissue hat partially segregates the ventricle into a left and right side. The ridge divert unoxygenated blood fro the right atrium to he artery leading to the lungs and skin and oxygenated blood from the left atrium to the artery leading to the rest of the body. A lizard has septum, or wall, in its ventricle that perform the same function, but perform it much better that the ridge in frog’s ventricle. The septum almost completely separates the ventricle into a left and right side there is a very; little mixing of oxygenated and unoxygenated blood in a lizard’s heart. The active cells of both a frog and a lizard receive highly oxygenated ventricles. A bird or mammals, however, has a greater need for oxygen, because of the high metabolic demands of endothermy.

What controls heart rate?The rate at which the heart muscles contract is regulated in

several ways, the main controls is the sino-atrial node or pacemaker, which’s a small piece of specialized hat muscle located in the wall of the right atrium. Electrical impulses emitted at regular interval by this tissue stimulate muscle contraction the four chambers of the heart. Each impulse travels through both atria, causing them to contract almost simultaneously, and on to another specialized region – the atrio-ventricular node – which transmits the impulse to both ventricles simultaneously, the slight delay in the signal produces a sequence of contrition first the two aria, the then two ventricle.

A second regulator of heart rate is an area within the medulla oblongata of the rain. The cardio-inhibitory center in this area communicates with the Sino trial node via the vagus nerves, which contain both afferent and efferent axons. The afferent nerve axons, which originate in the node and terminate in the cardio-inhibitory center and extend to the sinoatrial node, can time the node to decrease the rate of heart-muscle contractions. The cardio-inhibitory center functions to restrains the Sino Arial node, to hold the heart rate in check.

In addition to feedback from the sinoatrial mode, the cardio-inhibitory center receiver information from sensory surfaces and higher brain centers. Sensory cells on the internal and external body surfaces transmit information t the center

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about such conditions as indigestion, inhalation of irritating fumes sudden cold temperatures and blood pressure, when the center receiver the information, it stimulates the efferent axons of the vagus nerves, which diminish the heart rate certain emotional l state also stimulate the cardio-inhibitory centers, many areas of the brain are involved in the regulation of emotion, but the critical pathway that influences heat rate form the limbic system to the cardio-inhibitory center.

The cardio-accelerating with the medulla oblongata of the brain is stimulated by many factors; including the pain sensations form the skin and anticipation of exercise. Efferent neurons form the cardio-accelerating center terminate in the heart muscle themselves, rather than in the sinotarial node. When the stimulated, these neurons release a neurotransmitter (norephineprine) that increase both the heart rate and the stroke volume (amount of blood pumped with each contraction

Hormones also affect the heart rate. Thyroxin, the hormone secreted by thyroid gland, increases the heart rate, Epinephrine. A hormone secreted by the adrenal medullas, increases both the rate and the stroke volume.

What regulates the rate a blood flows though the circulatory system.

Animals must be able to adjust the rate of blood flown in response to changing conditions when cellular activity is low, as during sleep, the ea of blood flow is lowered to conserve energy. During strenuous activity, the rate of blood flow must b e rapid enough to meet the increased demand for exchange of material between the bloods and more active cells.

The cardiac output, or quantity of blood the heart pumps per minute, is about 5-liter sin a resting human. Cardiac outputs is the product of two factors, - the heart rate (number of contractions per minute) and Stroke volume (amount of blood ejected from the heart during each contraction)

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Heart rate is controlled primarily by Sino Arial node, but also by cardio-inhibitory and cardio-accelerating center within the medulla oblongata of the brain and by hormones secreted by the thyroid and adrenal glands.

Stroke volume is controlled by artery diameter. Because the vessels and the heart form a closed circulatory system, net volume of blood expelled form the heart during each contraction can only be increase if the rate at which blood is returned to the heart undergoes a corresponding increase. As the volume of blood returning per minute to the heart increases, the muscles conditions that force blood through the heart becomes stronger. Blood is returned other heart more rapidly when the blood pressure is higher i.e. when arteries are more constricted.

Artery diameter is controlled by vasomotor center in the medulla oblongata in response to carbon dioxide levels in the blood and by brain centers that control emotions Higher concentrations of carbon dioxide, a waste product of cellular respiration, reflect high levels of cellular activity, the amount of carbon dioxide in the blood detected by neurons in two vasomotor center, one on each side of the medulla oblongata, which send electrical-chemical impulses along vasomotor nerves to the muscles of the arties. High levels of carbon dioxide cause constriction of the arterial walls, and thus and increase in blood pressure and amore rapid flow of blood thorough the circulatory system. Low levels of carbon dioxide product the opposite effect: the arteries become dilated blood pressure drops, and blood flow becomes slower.

Finally blood flow is controlled by the brain center that control the emotions, including the cerebral cortex in the limbic system, which emits electrochemical impulses that travel to the vasomotor center of ht medulla oblongata, Certain emotional states can accelerate the heart rate and constrict the arteries, other emotion stress can inhibit the heart rate and dilate the arteries to though the point that the individual faints, Information is I transmitted from the vasomotor center to the arterial walls, which either constricts of dilates vessels.

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Applications

1. The ECGAs the heart goes through its contraction-relaxation cycle,

waves of depolarization and repolarization pass from the atria to the ventricular tissue. These waves produce a measurable electrical current and associated voltage changes. Since alterations in heart function due to disease are often reflected units electrical activity patterns, analysis of the patterns has considerable diagnostic use.

The instrument used to measure heart electrical activity is called an electrocardiogram, where electrodes are attached to the body. These lead to an amplifier where the tiny voltages are magnified and fed into a recorder. An example of a normal tracing is shown in the figure. There are five distinct alterations in voltage, called P,Q,R,S and T for reference. Notice that the measured voltages are very small, approximately a thousandth of a volt. In the heart the voltage changes are nearly a hundred times larger, but the electrocardiograph can only measure the voltages that reach the surface of the body.

The first small change, the P wave is produced when the atria depolarize, the depolarization wave travels to the ventricle where a much larger change occurs, called the QRS region. The final T wave is produced by the repolarization of the ventricles. Now, compare the normal tracing with the one made form a fibrillating heart. Fibrillation occurs when the heart muscle contractions are irregular and uncoordinated and often sets in after a severe heart attack. In fact, fibrillation is the usual cause of death. The ECG clearly shows the random patterns associated with the fibrillating heart. Of course, this is an extreme case, the ECG is more often used to diagnose heart disease sickness subtle changes in the ECG pattern can be related to specific kinds of heart damage form disease.

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An example of such an abnormal patter in is called an atrioventricular block and results when the tissue that normally conducts the electrical waves from the atria to the ventricles is damaged by disease to the extent that conduction is impaired. In a block leak, there is no coordination of contraction between atrial and ventricles and the heart’s efficiency as a pump is greatly impaired.

The Pacemaker

Artificial pacemakers. As we age, the heart may lose control of its beat, the most common cause of this condition is that conduction between the atria and ventricles is blocked. The atrium may contract normally at 70 to 80 times per minute, driven by the pacemaker tissue, but the ventricles beat at their own rate at 40 to 50 times per minute.

In many instances, it is possible to implant an artificial pacemaker near the heart. this is a device that delivers a small electrical shock to the heart at timed intervals, the purpose of the shock is not so much to initiate heart beat as to coordinate the atrial and ventricular contractions. For instance, the pacemaker can be set so that it produces ventricular contractions. For instance, the pacemaker can be set so that it produces a ventricular contraction whenever the atria contract.

A relates application of our knowledge is the defibrillator, now found in most hospitals, during fibrillation, waves of contraction are moving randomly in heart muscle and the problem is to coordinate them. The defibrillator does this by sending a single strong electrical shock through the chest wall into the heart. the heart muscle responds by contracting completely, then often begins to beat normally under the influenced of its pacemaker tissue.

Sphygmomanometers.

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Blood pressure is an important indicator of vascular function and most of us have had our blood pressure measures. The instrument is called a sphygmomanometer, and consists of an inflatable cuff that is calibrated so that a air pressure in the cuff reads out in millimeters of mercury to operate the devise, the cuff is wrapped around the upper arm while a stethoscope is placed at the inner elbow near the artery that supplied blood to the heart. As the cuff is inflated, the blood pressure in the artery is overcome so that the artery collapses. Pressure through the artery in spurts. At this point , a thumping is heard in the stethoscope as the artery fills and collapses this is a good estimate of systolic blood pressure. More pressure is then released and at a second point the thumping sound disappears when the artery stays open even during diastole. This pressure is equivalent to the diastolic blood pressure.

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