Biol 1724 Lecture Notes (Ziser) Exam IV:  nonspecific immunity

The Endocrine System

no clear distinction between nervous and endocrine systems

they are intimately interrelated  complement each other

Similarities

Both: coordinate and control produce biologically active chemicals in some cases use same chemical affect nervous system/nervous sytem affects releases one may override normal effects of the other: eg Bld sugar: normal = 80-120 mg/100ml  regulated by hormones stress  sympathetic stimulation  increases blood sugar levels

Differences: Nervous localized effects targets: other neurons, muscle cells, glands, transmits long range information by nerve impulses uses chemical signals (=) only to cell only produced by neurons immediate response short lived (ms – minutes)

Endocrine widespread effects targets: all tissues transmits long range information as chemical signals only = hormones, through circulatory system gradual response (seconds – hours) longer – lived effects (minutes – days)

1 Chemicals shared between Nervous and Endocrine Systems Functions as Neurotransmitter as Hormone Endorphins binds to pain receptors in brain released from hypothalamus during times of stress Enkephalins blocks pain perception adrenal medulla – blocks pain sensations Dopamine “feel good” NT in limbic system & inhibits secretion of prolactin midbrain Estrogen,Progesterone affects appetite center & body temp gonads and adrenal cortex - initiate in hypothalamus and stimulates secondary sex characteristics, follicular sexual arousal pathways development & menstrual cycle Testosterone stimulates sexual arousal pathways gonads and adrenal cortex - initiate and orgasm reflex secondary sex characteristics & spermatogenesis Norepinephrin, “feel good” NT in limbic system adrenal medulla – maintains Epinephrin and sympathetic branch of ANS sympathetic response Prolactin NT in brain anterior pituiitary – milk production Leutinizing Hormone NT in brain Anterior Pituitary - maturation and development of reproductive system most if not all organs produce hormones the endocrine system consists of several major glands and many minor glands are ductless glands (endocrine vs exocrine glands)

all endocrine glands are richly supplied with blood capillaries

most are fenestrated capillary beds their secretions affect virtually every aspect of physiology at any one time there may be up to 40 major hormones and other minor hormones circulating in body some general effects of hormones on body: a. enhance or moderate neural control of effectors b. affects overall metabolic rate c. helps to maintain homeostasis of body’s internal environment by regulating concentrations of salts, nutrients, hormones, and fluids d. helps body cope with and respond to environmental changes that can cause infection, trauma, thirst, hunger e. contributes to all aspects of the reproductive process f. provides smooth, sequential integration of all 2 factors involved in growth and development g. affect moods and behavior

Physiology of Hormones

1. secreted from ductless glands directly into blood

2. secreted in response to specific stimuli

3. hormones can be secreted independently of one another

4. Many endocrine glands secrete more than one hormone

5. effective in minute quantities

6. major hormones are of two basic types: a. derived hormones i. amines (acetylcholine, thyroid hormone, epinephrine, norepinephrine ii. polypeptides and glycoproteins ( ADH, Insulin, TSH) b. steroid hormones (cortisol, testosterone, estrogen)

7. hormones are often derived from less active precursor in gland cells eg. long chain “prohormone”  cut and spliced to form active hormone

8. hormones circulate in blood are often attached to carrier protein (inactive)

eg testosterone circulates in inactive form  must be activated by target cell

9. may be secreted for long periods of time

10. effects are highly specific to “target organ”

target cells respond only to specific hormones  requires specific binding site ( proteins)

even though every hormone comes in contact with every cell

3 11. Most cells have receptors for more than one type of hormone

hormones can interact with each other  synergistic effects = presence of 1 enhances effects of other  antagonistic effects = 1 counteracts effects of other  permissive effects = one hormone “primes” target organ for another hormone;

eg estrogen then progesterone on uterus

12. At the cellular level each hormone can affect a target cell in only a few ways: a. change in permeability b. protein synthesis stimulated or inhibited c. enzymes activated or inactivated d. change in secretory activity of a cell

13. Each hormone can affect each target cell in >1 way

14. Maybe different effects in different target cells for same hormone

15. Hormones don’t accumulate in blood

those that bind to target cells are destroyed  half-life ~ seconds – 30 minutes excess are continually cleared by liver and kidney

typical duration of hormones effects: = 20 min to several hours

effects may disappear rapidly as blood levels drop or may persist even thought blood levels are low

therefore for prolonged effect  hormones must be continuously secreted

16. the extend of target cell activation can depend on: a. blood levels of hormones b. relative # of receptor proteins on target cells c. affinity of binding

4 Hormones effects are concentration dependent overstimulation can cause desensitization hyper and hypo secretion  much of our knowledge of hormones effects comes from study of abnormal production

similar problems if too little or too many receptor proteins or target cells

Mechanism of Hormone Action on Target Cell

depends on hormone structure and location of receptors on target cell

A. Steroid Hormones

are nonpolar and fat soluble

and thyroid hormone which is also nonpolar)

receptors are located inside cytoplasm and nucleus  intracellular receptors

hormone enters cell and binds to receptor and activates it

hormone/receptor complex inters nucleus  binds to a protein on chromosome  triggers transcription

therefore: steroid hormones have a direct effect on DNA activity

B. Amino Acid Derived Hormones

are polar

cannot enter cell

use “second messenger” to produce effect on target cells

hormones attaches to specific receptor site on target cell

triggers enzyme “adenylate cyclase” (via G protein) to make “cyclic AMP” from ATP

cyclic AMP diffuses throughout cell and mediates target cell response to hormone

5 mainly by activating one orm more different enzymes called “protein kinases”

each protein kinase hs a specific substrate that it acts on:  enzyme activation or inactivation  cellular secretion  membrane permeability  gene activation or inhibition

the time required for the onset of hormone effects varies greatly

 some hormones provoke immediate response

 others (eg steroid ) may require hours to days before their effects are seen

Control of Hormone Release

The synthesis and release of most hormones are regulated by some type of negative feedback system

three major mechanisms: 1. Humoral 2. Neural 3. Hormonal

some endocrine glands respond to multiple stimuli

1. Humoral

hormones secreted in direct response to changing blood levels of certain chemicals in blood

affect endocrine gland directly

eg. parathyroid gland cells directly monitor conc of Ca++ions when Ca++ decline they respond by secreting PTH

eg. pancreas insulin and secreted in response to blood sugar concentrations

eg. adrenal cortex aldosterone

6 2. Neural hormones secreted due to direct nervous stimulation

eg. adrenal gland directly stimulated by sympathetic fibers of ANS produces same effects as Sympathetic NS but lasts 10 times longer: ∆ cardiac output ∆ heart rate ∆ alertness ∆ respiratory rate

eg. Posterior Pituitary secretes oxytocin and ADH in direct respnse to nerve impulses from hypothalamus

3. Hormonal

Anterior Pituitary = master gland secretes several hormones that control the secretion of other endocrine glands  Tropic Hormones each tropic hormone has a target gland which it stimulates to produce its characteristic hormones

eg. TSH, ACTH, FSH LH

The release of trophic hormones is controlled by hypothalamus:

hypothalamus receives nerve impulses from all areas of brain

no direct neural connection between anterior pituitary and hypothalamus

they are connected by dense capillary bed

no blood brain barrier between them

hypothalamus contains neurosecretory cells

these cells serve as link between nervous and

7 endocrine systems

neurosecretory cells are activated by nerve impulses and reat by secreting = releasing hormones

produces specific Releasing Hormones for each tropic hormone eg. TSH-RH

releasing hormones travel in capillary bed to anterior pituitary

trigger release of appropriate tropic hormone

 translates nerve impulses into hormone secretions

sensory information in form of nerve impulses can be interpreted and acted on by the release of hormones =Neuroendocrine Reflex

eg. rapid response to stress

eg. thoughts and emotions affect body’s hormone levels

Hormones are switched off by negative feedback mechanisms require receptor – CNS – effector eg. Negative Feedback for Hormonal Regulation

hypothalamus contains chemoreceptors for hormones switched on by tropic hormones

when levels get too high this inhibits the production of releasing hormones

stops production of tropic hormones

stops production of specific hormone

8 Minor/Temporary Endocrine Glands

Pineal Gland

located behind the midbrain and 3rd ventricle not sure of all its functions in lower animals it helps regulate cyclic activities: hibernation estrous migration is light sensitive  monitors photoperiod

in lower animals is called “3rd eye” some reptiles actually have 3rd eye in skull directly above pineal gland

main hormone it secretes is melatonin light suppresses production dark stimulates production

light exposure suppresses melatonin secretion

In humans:  inhibits LH  inhibits ovarian function at night  may help regulate menstrual cycle  inhibits onset of puberty in males

seems to degenerate in adult??

Thymus

behind sternum, below thyroid

large in fetus and child maximum size at puberty degenerates in adult (replaced with fat)

functions as endocrine gland and as part of immune system

secretes thymosin  induces maturation and development of WBC’s

9 Skin

produces cholecalciferol an inactive form of Vit D3

activated by UV

increases absorption of calcium by intestine

Kidneys

secrete erythropoietin  stimulates RBC production in bone marrow

Heart

atria contain some specialized muscle cells that secrete Atrial Natriuretic Peptide (ANP)

 reduces blood volume, pressure, Na+ conc

does this by: signaling kidney to increase productio of salty urine and inhibiting aldosterone

Placenta

acts as temporary endocrine gland during pregnancy

releases 3 hormones:

a. chorionic gonadotropic hormone (CGH)

 maintains hormonal activity of ovary

pregnancy test

b. estrogens & progesterone

Stomach & Duodenum

mucosal lining secretes hormones to help control digestion:

10 enterogastrone regulates secretion of: gastric juices pancreatic enzymes bile

Adipose Tissue

releases leptin

after uptake of glucose and lipids which is converted to fat

leptin binds to CNS neurons in hypothalamus

 produces sensation of satiety

Somatostatin

seems to be a local hormone

peptide of 14 amino acids

secreted by digestive epithelium and thyroid

has inhibitory effects on secretion of: GH insulin calcitonin PTH

also inhibits secretion of immuniglobins

inhibits secretion of renin

inhibits secretion of bicarbonates and disgestive enzymes from pancreas

Somatomedin (IGF = Insulinlike )

affects many tissues

produced by liver

secondary hormone

11 Anterior Pituitary monitors blood levels of IGF to control GH production

in men GH causes liver to produce IGF which stimulates cartilage development

 in women estrogen stim secretion of IGF causing uterine enlargement  in women: in cartilage of long bones, estrogen interferes with IGF causing bones to be shorter than in men

12 Other Chemical Regulators so far have studied two major types of regulatory molecules: neurotransmitters & neuromodulators hormones defined mainly by function, location, and action a 3rd class of regulatory molecules are distinguished by the fact that they are produced in many different organs generally active in same organ that produces them

= paracrine regulators

Paracrine Regulators

= produced in almost every organ and tissue of body except RBC’s not officially part of endocrine system biologically active lipids (modified fatty acids, not steroids)

local regulators (= tissue hormones) made in small quantities short lived

mainly and leukotrienes have wide variety of effects in various systems: immune response regulate inflammatory process  role in pain, fever cardiovascular system role in blood pressure vasomotor system = distribution of bloodflow reproduction ovulation  role in corpus luteum, endometriosis, PMS induce labor digestion  inhibit gastric secretions  intestinal peristalsis respiration  constriction/dilation of blood vessels  role in asthma

13 clotting eg thromboxane constricts blood vessels promotes platelet aggregations urinary function fat metabolism

Hormone Interactions

while each hormone has a specific function

hormones rarely act alone to maintain homeostasis

homeostasis usually involves several hormones working together in complex ways to regulate metabolic levels: synergists  hormomes which tend to cause the same effect

eg. ADH & aldosterone

antagonists  hormones which produce opposite effects

eg. insulin & glucagon

permissive  hormones which only affect “preprimed” tissues

eg. progesterone eg. Growth

Hormones that generally stimulate growth: growth hormone stimulates growth of cartilage at epiphyseal plates  stimulates growth in all tissues (except brain & reproductive organs) maintains adult tissues thyroid hormones regulates the amount of energy available for protein synthesis esp skeleton and nervous sytem and brain

low TH: retards growth, childlike proportions high TH: excessive growth, short stature, demineralization in adults

14 mineralocorticoids testosterone especially skeletal growth

Hormones that generally inhibit growth: glucocorticoids estrogen eg. Calcium Homeostasis: main hormones that maintain blood calcium levels:

PTH  stimulates osteoclasts  increases blood Calcium levels

Calcitonin  stimulates osteoblasts  decreases blood calcium

Estrogen & Testosterone  maintain bone density by slowing osteoclast activity and promoting osteoblast activity eg. Carbohydrate Metabolism one of best studied systems of hormone interactions glucose is most utilized carbohydrate in body circulates in blood until it is needed for any of several functions:

energy

glycogen glucose lipids

proteins

other carbohydrates (eg. ribose)

energy = with oxygen is converted to carbon dioxide and water

15 only energy source that the brain can use

storage = converted to glycogen synthesis of other carbohydrates, proteins, lipids several hormones from various glands play a direct role in glucose homeostasis

1. Insulin (Pancreas-Islet Cells)

accelerate transport of glucose into body cells increases rate of utilization of glucose by body cells

 lowers blood glucose levels

2. Glucagon (Pancreas-Islet Cells)

stimulates breakdown of glycogen in liver and release of glucose into blood also stimulates synthesis of glucose from lactic acid, glycerol, etc (=gluconeogenesis)

 raises blood glucose levels

3. ACTH (Anterior Pituitary)

tropic hormone that affects glucocorticoid production

4. glucocorticoids (Adrenal Cortex)

converts amino acids and fats to glucose in liver cells excess glucose is released into blood

 raises blood glucose levels

5. growth hormone (Anterior Pituitary)

shifts from glucose catabolism to fat catabolism increases oxidation of fats; spares glucose

unused glucose is converted to glycogen to maintain normal glycogen stores

16 excess glucose spills into blood

 raises blood glucose levels

6. TSH (Anterior Pituitary)

tropic hormone that stimulates release of thyroid hormone

7. Thyroid Hormones (Thyroid)

may accelerate catabolism of glucose to cause lowered blood glucose levels

or

or have other effects that raise blood glucose levels

8. Epinephrin (Adrenal Medulla)

stimulates breakdown of glycogen to glucose in muscle and liver cells and release of glucose into blood

 raises blood glucose levels

[but can also stimulate release of insulin by pancreas] of all hormones listed only insulin is major “hypoglycemic hormone” all others are mainly “hyperglycemic hormones”

Diabetes diabetes is a general name for a group of diseases two major varieties: diabetes insipidus diabetes mellitis (Types I & II)

Diabetes insipidus

17 a disease associated with Posterior Pituitary

deficiency in ADH causes low reabsorption of water

large volumes of dilute urine are produced:

(up to 10 gallons/day vs normal 1 qt/day)

leads to electrolyte imbalances etc

Diabetes mellitis

10 Million diabetics in US

40,000 die anually as result of disorder

effects: reduces life expectancy by ~1/3rd 25 x’s greater rate of blindness 17 x’s greater rate of kidney disease 17 x’s greater rate of gangrene 2 x’s greater chance of heart attack

diabetes is a group of disorders

may be triggered by: genetic factors environmental factors autoimmune disease pregnancy obesity

two kinds: 10% = Juvenile Onset Diabetes (Type I) 90% = Maturity Onset Diabetes (Type II)

Type I Diabetes

develops before the age of 20 years

is result of malfunction of Islet cells in pancreas

dramatic decrease in the number of beta cells

insulin is not produced in sufficient quantities

18 in all body cells: decreased glucose utilization  cells can take in only ~ 1/4th normal amount of glucose levels of glucose build up in blood  3-10 times normal = hyperglycemia since glucose can’t be used alternate fuels are mobilized:

increased fat mobilization fats in blood rise to up to 5x’s normal as cells shift to fat catabolism  produce ketone bodies  lower blood pH = acidosis  acetone breath  increased risk of atherosclerosis

without insulin to stimulate protein synthesis they are instead broken down and converted to glucose in cells  tissue wasting

high levels of glucose in blood lead to large quantities of glucose spilling into urine  diagnostic test for disease (used to taste it, now have chemical indicators)  this draws large amts of water into urine

Type II

adult onset diabetes

body produces insulin but target cells don’t respond

receptor problem

related to obesity

possibly overstimulation of receptors they decline in numbers until cells don’t respond

treatment mainly by dietary changes

Blood & Hematology

The human body is made up mostly of water;

19 ~60 - 65% (40 L)

Where is this water located?

This water can be visualized as occurring in several “compartments”: intracellular 62% 40% (25 L) extracellular 38% 20% (15 L) interstitial 30% 16% (12 L) [80% of ecf] intravascular 8% 4% (3 L) [20% of ecf]

Intracellular

most of the fluid in the body = 2/3rd’s inside all body cells

Extracellular

all fluid outside cells ~1/3rd of body water some is in tissue spaces between cells = interstitial (= intercellular) 30% of total fluids some is circulating in vessels = intravascular (blood and lymphatic systems) 8% of total fluids

These compartments are interconnected:

outside intravascular interstitial intracellular

maintaining water and salt balance in each compartment means maintaining a balance in body as a whole

they interact with the environment by specialized organ systems: respiratory system excretory system digestive system

Fluid inputs: digestive tract 2000ml metabolism 500ml TOTAL: 2500ml

Fluid outputs: kidneys 1300ml

20 lungs 450ml skin 650ml intestine 100ml TOTAL: 2500ml

Body’s transport system plays key role in balancing fluids in the body’s compartments  “river of life” Marieb

Transport system includes: Circulatory system (=cardiovascular system)  blood Lymphatic system  lymph

General Functions of these Transport Systems: Transport functions:

1. Pick up food and oxygen from digestive and respiratory systems and deliver them to cells

2. pick up wastes and carbon dioxide from cells and deliver to kidneys and lungs

3. Transport hormones, enzymes etc throughout the body

Homeostasis functions:

4. maintain fluid and electrolyte balances in tissues and cells

5. maintain acid/base balances in tissues and cells

6. help regulate temperature homeostasis transfers excess heat from core to skin for removal

Protective Functions:

7. Protect body from infection = “immune system”

------Average person (150lb) has 4.8 L of blood = 8% body weight

21 loss of 15-30% of blood  pallor and weakness loss of >30%  severe shock, death arterial blood: bright red = oxyhemoglobin venous blood: darker red viscosity = 4.5 - 5.5 pH = 7.35 – 7.45 temperature = 38º C (100.4º F) [thorax] the amount of blood varies inversely with amount of excess body fat  less fat = more blood/unit wt

Composition:

plasma 55% of volume formed elements 45%

Plasma

the liquid part of blood

clear straw colored fluid

serum = plasma with clotting factors removed

90% water;

10% solutes >100 different solutes salts, ions, gasses, hormones, nutrients,wastes most solutes are proteins

plasma proteins (8%): albumins 54-60% globulins 36-38% fibrinogen 4-7%

globulins = antibodies, part of immune system

albumins  (with other proteins) contribute to viscosity, osmotic pressure & blood volume

fibrinogen

22  (with some albumins) clotting most blood proteins synthesized by liver globulins produced by immune cells

Formed Elements

about 45% of whole blood erythrocytes (RBC’s) –most, 45%, of formed elements leukocytes (WBC’s) thrombocytes (Platelets)

all three are produced by stem cell = hemocytoblast

1. Erythrocytes

main job is to carry oxygen to cells

also deliver some carbon dioxide to lungs

most abundant of the three types of formed elements 99% of formed elements 5.5 mil/mm3 males 5.1 – 5.8 mil/mm3 females 4.3 – 5.2 mil/mm3

equivalent to 2.5 trillion blood cells in whole body

7.5 µm diameter

biconcave disc thin center, thick edges  high surface/volume ratio 30% more surface area than sphere with same diameter greater efficiency of gas exchange area of all RBC’s in body = >football field for gas exchange  flexible easily deforms to fit through narrow capillaries affects speed of bloodflow regulated by prostaglandins

in each RBC are 200-300 Million hemoglobin molecules

men’s RBC’s typically contain more hemoglobin than womens RBC’s

23 males: 13-20 g/100ml women: 12-16 g/100ml each hemoglobin consists of: a protein = globin combined with 4 pigment molecules = heme each heme contains 4 Iron atoms each iron atom can combine with 1 O2 molecule

each hemoglobin molecule can combine with 4 oxygen molecules

= oxyhemoglobin therefore, each RBC can carry ~1 Billion O2 molecules hemoglobin can also combine with and transport carbon dioxide

RBC Formation

Erythropoiesis (hematopoiesis)

RBC’s are formed from stem cells in bone marrow these stem cells divide and go through several stages of development hemoglobin require iron (65% of body’s iron is in blood) [the rest is in liver, spleen] [free iron is toxic to cells]

Iron is absorbed through digestive tract if not used immediately can be quickly lost: average intake of iron: 1.0-1.5 mg/day (12-15 mg intake; 5-10% absorbed) average daily loss of iron: less than 1mg lost/day males= .9 mg/day females = 1.7 mg/day requires B vitamins for absorption also B12 & Folic Acid for DNA synthesis and cell proliferation

24 nucleus becomes smaller and is eventually lost as cell leaves marrow and enters blood it is 20% larger than older RBC’s = reticulocyte (~1-2% of RBC’s) can monitor number of reticulocytes to get estimate of rate of erythropoiesis kidneys produce hormone = erythropoietin that regulates erythropoiesis: hypoxic  secretes more erythropoietin excessive O2 inhibits hormone production

testosterone enhances kidney production of erythropoietin estrogen and progesterone have no effect average RBC lives 100-120 days they are destroyed by fragmentation as they squeeze through capillaries cells lining blood vessels (esp in liver spleen and bone marrow) phagocytize the fragments hemoglobin components are recycled after death:  biliverdin (green) & bilirubin (yellow/orange)  bile  iron stored in liver both are transported to liver each day > 100 million RBC’s are replaced

Erythrocyte Disorders

1. Anemias symptoms: pale lack energy low hematocrit: males 5.1 – 5.8 mil/mm3 females 4.3 – 5.2 mil/mm3 low hemoglobin males: 13-20 g/100ml women: 12-16 g/100ml

kinds: hemorrhagic (bleeding) hemolytic (disease, parasites, drug reactions, genetic) aplastic (cancer) Iron deficiency

25 Pernicious (no B12)

2. Abnormal Hemoglobin

anemia like symptoms

kinds: thalassemias thin and delicate blood cells sickle cell

3. Polycythemia

too many RBC’s 8-11 million/mm3 hematocrit = 80%

increased viscosity

causes: overstimulation of stem cells high altitude prolonged physical activity fluid loss genetic factors

2. Leucocytes

4000-11,000/mm3 or 1% of blood volume

numbers are misleading since they do most of their work outside the blood vessels

mainly function in protection of body as part of immune system

WBC’s are motile by amoeboid motion they squeeze out of capillaries into tissue spaces attack and destroy bacteria and pathogens remove dead cells and tissues

slightly larger than RBC’s = 8µm diameter

large, irregular, lobed nucleus

live for a few hours to a lifetime

26 5 different kinds of WBC’s:

the numbers of each type per unit of blood are clinically important = differential WBC count

ID depends on presence and staining characteristics of granules and nucleus:

neutrophils 40-70% granulocyte attracted to sites of lifespan: hours - days especially bacteria and some fungi indicate: acute infections and appendicitis

eosinophils 1-4% granulocyte especially abundant in pulmonary mucosa and dermis counteract inflammatory chemicals eat proteins, not “bugs” lifespan: days indicate: worms and protozoan parasites

basophils <1% granulocyte least abundant of WBC’s tissue basophils = Mast Cells bind to Ig E  release of heparin and  leaky vessels enhance migration of WBC’s to site lifespan: hours - days

lymphocytes 20-45% agranulocytes only few in “blood” T and B cells lifespan: hours to years

monocytes 5-8%

27 agranulocytes only few in blood in tissue become macrophages lifespan: months increases: chronic infections, eg TB and viruses mononucleosis

Formation

Leucopoiesis:

granular WBCs usually formed from stem cell s in bone marrow

agranular WBC’s are formed from stem cells in lymphatic tissue

sitmulated by hormone, CSF (colony stimulating factor) from macrophages and T lymphocytes exposed to antigens and toxins

lifespan: hours to lifetime

Leukocyte Disorders

1. Leukocytosis total WBC count >10,000/mm3 indicate: acute infections, eg appendicitis vigorous exercise excessive loss of body fluids

2. Leukopenia total WBC count <5,000/mm3 indicate: influenza measles mumps chickenpox poliomyelitis anemias lead poisoning

3. Leukemia cancer characterized by uncontrolled production of leucocytes

but large numbers are usually nonfunctional

28 crowd out functioning WBC’s

may become anemic as normal marrow is crowded out

myeloid leukemia > granulocytes

lymphoid leukemia > lymphocytes

3. Thrombocytes (Platelets) small, irregular shape cell fragments

2-4 µm diameter usually 250,000 – 500,000/mm3

no gender differences

short life span: ~10 days

formed in marrow, lungs and spleen by fragmentation of large cells (=megakaryocyte)

their production is controlled by thrombopoietin

play important role in hemostasis and blood clotting

Hemostasis

stoppage of blood flow

include: vascular spasm reduces blood loss platelet plug 1-5 seconds after injury platelets become sticky

29 platelets swell develop spiky processes become sticky  adhere tenaceously degranulate  release & throboxane  enhance vascular spasm aggregating agens attract more platelets

prostaglandins may be involved

Blood Clotting

if injury is extensive clotting cascade is initiated

mechanism must be rapid to stop bleeding

involve over 30 different chemicals

each is activated in a rapid sequence = cascade (positive feedback)

1. trigger: rough spot in lining of slow blood flow (also, bedridden)

2. clumps of platelets adhere to site (1-2sec) 3. platelets release serotonin and thromboxane  constricts blood vessels at site of injury 4. platelets and damaged tissues release chemical (=thromboplastin, = prothrombin activator) 5. prothrombin (an inactive albumin)  becomes thrombin 6. thrombin converts fibrinogen to fibrin (fibrinogen – soluble protein) (fibrin – insoluble protein)

fibrin is a protein forming fine threads that tangle together forming a clot clot retraction 30-60 minutes draws edges of clot together fibrinolysis = clot dissolution 30 occurs continuously plasmins & fibrolysin = clot busters

Thrombocyte Disorders body has mechanism that prevent spontaneous clotting without vessel damage: - normal lining of vessels is smooth  platelets do not adhere

- blood also contains antithrombins  inactivate thrombin eg. heparin (a natural blood constituent)

1. sometimes clots are triggered by internal factors two conditions favor clots: rough spots on blood vessels atherosclerosis may trigger clotting

abnormally slow flow of blood bedridden or imobilized patients

these may be caused by: atherosclerosis severe burns inflammation slow flow

thrombus – a fixed persistant clot embolism – a traveling clot

2. Bleeding Disorders (=Hemophilias) inability of blood to clot in normal amount of time may be caused by decreased # of platelets liver disease inability to form various clotting factors

prothrombin and fibrinogen are produced in liver require vitamin K (absorbed from intestine) vitamin K requires bile to be digested and absorbed

if bile ducts becfome obstructed results in vitamin K deficiency  liver cant produce prothrombin at

31 normal rate

eg. factor VII comprises 83% of cases eg. factor X a sex linked condition

Blood Types blood type refers to the kinds of antigens found on the surface of blood cells (esp RBC’s) related to immunity and how the body protects itself from pathogens:

our immune system recognizes and distinguishes between “self” and “nonself”:

self = all proteins and other chemicals that are part of our bodies; that belong there

nonself = any proteins or chemicals that don’t belong

antigen = any foreign substance that enters our body

antibody = special proteins made by our immune system to remove foreign substances many antigens are present on surface of blood cells only a few are important in transfusions: ABO system Rh system

If these antigens are attacked by our antibodies it causes agglutination (clumping) of cells [antibodies are agglutinins: cause clumping] leads to: heart attack stroke kidney failure etc most important consideration in transfusions:

32 don’t want recipient’s antibodies to react with donor’s antigens

Blood Antigens antibodies can donate can receive Type produced blood to blood from A anti B A, AB A, O A B anti A B, AB B, O B AB A & B neither AB A, B, AB, O (universal recipient) O none both A, B, AB, O O (universal donor)

% Frequency in US Population Blood White Black Asian Native Group American A 40 27 28 16 B 11 20 27 4 AB 44 5<1 O 45 49 40 79

even type O donors must be cross matched since many other antigens are present and some may cause reactions

Rh incompatability:

RhoGAM blocks the mothers immune systems response and prevents her sensitization to Rh+ blood of child.

RhoGAM is a serum containing anti-Rh agglutinins that agglutinate the Rh factors that get into her blood

Circulatory System large, multicellular organisms need good transport system to supply all cells with nutrients and oxygen, to get rid of carbon dioxide and wastes, and to distribute hormones major connection between external and internal environment:

33 everything going in or out of body must go through the circulatory system to get to where its going two major transport systems in body: circulatory (cardiovascular) system lymphatic system circulatory system works in conjunction with lymphatic system = an open system circulatory system consists of “plumbing” and “pumps”: 1. blood travels within a closed system of vessels; never leaves vessels circuit of blood first described by W. Harvey, 1628 idea was vigorously opposed 2. has muscular pump that helps to move it is one of first organ systems to appear in developing embryo  heart is beating by 4th week

The Heart about size and shape of closed fist beats >100,000 x’s/day lies in mediastinum, behind sternum lower border of heart (=apex) lies on diaphragm heart is enclosed in its own sac, = pericardium (=pericardial sac)(parietal pericardium) composed of tough fibrous outer layer and inner serous membrane outer surface of heart is also covered with serous membrane (= visceral pericardium) (=epicardium) continuous with the pericardium between the 2 membranes is pericardial fluid lubrication wall of heart: epicardium = visceral pericardium thin & transparent serous tissue myocardium = cardiac muscle cell

34 most of heart branching, interlacing contractile tissue acts as single unit (gap junctions) endocardium = delicate layer of endothelial cells continuous with inner lining of blood vessels [endocarditis] interior of heart is subdivided into 4 chambers: atria = two upper chambers with auricles smaller, thinner, weaker ventricles = two lower chambers larger, thicker, stronger left ventricle much larger and thicker than right ventricle

There are 4 major vessels attached to heart: 2 arteries (take blood away from heart): aorta - from left ventricle pulmonary trunk - from right ventricle 2 veins (bring blood back to heart): vena cava (superior & inferior) - to right atrium quickly splits into 2 pulmonary arteries pulmonary veins (4 in humans) - to left atrium

There are also 4 one-way valves that direct flow of blood through the heart in one direction: 2 Atrioventricular (AV) valves held in place by chordae tendinae attached to papillary muscles  prevent backflow (eversion) keeps valves pointed in direction of flow bicuspid (Mitral) valve - separates left atrium and ventricle - consists of two flaps of tissues tricuspid valve - separates right atrium and ventricle - consists of three flaps of tissues 2 Semilunar valves at beginning of arteries leaving the ventricles aortic SL valve

35 at beginning of aorta pulmonary SL valve at beginning of pulmonary trunk

Histology of Heart cardiac muscle fibers: striated 1 nucleus branched cells T tubules and SR less developed than skeletal mm

separated by intercalated discs  myocardium behaves as single unit but atrial muscles separated from ventricular muscles by conducting tissue sheath  atria contract separately from ventricles

mitochondria account for 25% of cardiac muscle cells (compared to 2% of skeletal muscle cells)  greater dependence on oxygen than skeletal muscles  can’t build up much oxygen debt

more adaptable in nutrient use; can use: glucose fatty acids (preferred) lactic acid

refractory period lasts 250 ms almost as long as contraction phase (vs 1-2 ms in skeletal muscle)  prevents tetanus

Conducting System

heart has some specialized fibers that are modified cardiac muscle cells

don’t contract; fire impulses that coordinate contraction of heart muscle

innervated by autonomic NS

consists of: SA Node intrinsic rhythm 70-75 beats/min

36 initiates stimulus that causes atria to contract (but not ventricles directly due to separation) AV Node picks up stimulus from SA Node if SA Node is not functioning it can act as a pacemaker =ectopic pacekmaker (usually slower intrinsic rhythm) AV Bundle (Bundle of His) connected to AV Node takes stimulus from AV Node to ventricles Purkinje Fibers takes impulse from AV Bundle out to cardiac mucscle fibers of ventricles causing ventricles to contract the heart conducting system generates a small electrical current that can be picked up by an electrocardiograph =electrocardiogram (ECG; EKG)

ECG is a record of the electrical activity of the conducting system body is a good conductor of electricity (lots of salts) potential changes at body’s surface are picked up by 12 leads

ECG is NOT a record of heart contractions

R

P T

Q S

P wave = passage of current through atria from SA Node atrial depolarization

QRS wave = passage of current through ventricles from AV Node – AV Bundle – Purkinje Fibers ventricular depolarization

T wave = repolarization of ventricles (atrial repolarization is masked by QRS) by measuring intervals between these waves can get idea of how rapidly the impulses are being conducted

37 amplitude of waves also gives info on condition of conducting system and myocardium

Abnormalities of ECG’s = arrhythmias

1. bradycardia (<60 bpm) decrease in body temperature some drugs (eg digitalis) overactive parasympathetic system endurance athletes

2. tachycardia (>100 bpm) increased body temperature  fever emergencies, stress activation of sympathetic NS some drugs may promote fibrillation

3. flutter short bursts of 200-300 bpm but coordinated

4. fibrillation rapid, uncoordinated contractions of individual muscle cells atrial fibrillation is OK (since it only contributes 20% of blood to heart beat) ventricular fibrillation is lethal electrical shock used to defibrillate and recoordinate contractions

5. AV Node Block normal P - Q interval = 0.12 – 0.20 seconds changes indicate damage to AV Node  difficulty in signal getting past AV Node

1st º block: >0.20 seconds 2nd º block: AV Node damaged so only so wave passes through ventricles only after every 2-4 P waves 3rd º block: (complete block) no atrial waves can pass through ventricle paced by different ectopic pacemaker therefore beat abnormally slow

Cardiac Cycle

1 complete heartbeat (takes ~ 0.8 seconds)

38 consists of: systole  contraction of each chamber

diastole  relaxation of each chamber two atria contract simultaneously as they relax, ventricles contract ventricular systole (atrial diastole) = 0.3 sec ventricular diastole = 0.5 sec contraction and relaxation of ventricles produces characteristic heart sounds lub-dub lub = systolic sound contraction of ventricles and closing of AV valves dub = diastolic sound shorter, sharper sound ventricles relax and SL valves close abnormal sounds: “murmurs”  defective valves congenital rheumatic (strep antibodies) septal defects relationship of cardiac cycle, ECG, heart sounds

Cardiac Output

CO = Heart RateX Stroke volume = 75b/m X 70ml/b = 5250 ml/min (=5.25 l/min) ~ normal blood volume

A. Heart Rate: innervated by autonomic branches to SA and AV nodes control center in medulla receives sensory info from: baroreceptors (stretch) in aorta and carotid sinus increased stretch  slower chemoreceptors monitor carbon dioxide and pH

39 more CO2 or lower pH  faster

Other Factors that Affect Heartrate: 1. hormones epinephrin  faster thyroxine  faster acetylcholine ? 2. ions low Calcium  slower high Calcium  faster spastic heart contracitions high Sodium  blocks Ca++  slows high Potassium  faster may cause cardiac arrest 3. temperature heat increases heart rate 4. age younger = faster, slows with age 5. gender women = faster (72-80 bpm) men = slower (64-72 bpm) 6. exercise increases during exercise also heart beats slower in physically fit 7. emotions fear, anxiety, anger  increase HR depression, grief  reduce HR any marked, persistent changes in rate may signal cardiovascular disease

B. Stroke Volume: healthy heart pumps ~60% of blood in it normal SV = ~70 ml

SV = EDV (end diastolic vol) – ESV (end systolic vol)

affected by: mean arterial pressure back pressure heart contractility indicates amt of damage amount of stretch Starling’s Law: within physiological limits the heart pumps all the blood that returns to it without undue damming of blood in veins.

40 intrinsic regulatory mechanisms permit adaptation of the heart to varying rates of venous return.

>stretch = >strength of contraction

venous return viscosity (>RBC’s, dehydration, blood proteins)

Blood Pressure

measured as mmHg

blood flow in arteries depends on: 1. pressure gradient created by heart beat 2. resistance - counteracts pressure

Blood Flow = Difference in pressure Peripheral resistance blood circulates by going down a pressure gradient:

Pulse Pressure: Pulse Pressure = Systolic Pr – Diastolic Pr

eg. 120/80; then PP = 40 mmHg

Mean Arterial Pressure: represents the average of Sys & Diast BP’s MAP = Diastolic Pr + 1/3rd x Pulse Pressure

arteries variable systolic = 130-5 mmHg diastolic = 85-90 mmHg

capillaries 35 – 15 mmHg

veins 6 – 1 mmHg larger veins near 0 mmHg

41 Pulmonary Blood Pressure

heart pumps ~5l of blood per minute  5 liters in systemic circuit  5 liters in pulmonary circuit

change in pressure: systemic circuit: averages 100 0 difference = 100 mmHg

high resistance

pulmonary circuit: averages 15 5  difference = 10 mmHg

low resistance  no pulmonary edema

Measuring Blood Pressure use sphygmomanometer usually use brachial artery procedure: a. increase pressure above systolic to completely cut off blood flow in artery b. gradually release pressure until 1st spurt (pulse) passes through cuff = systolic pressure c. continue to release until there is no obstruction of flow sounds disappear = diastolic pressure

normal BP = 110-140 / 75-80 [mm Hg]

top number = systolic pressure force of ventricular contraction

bottom number = resistance of blood flow may be more important indicates strain to which vessels are continuously subjected also reflects condition of peripheral vessels

Normal Blood Pressure varies with:

42 age kids 90/60; adults 120/80; old 150/82 gender race socioeconomic status mood physical activity posture etc sclerosis  high diastolic pressure

Main factors affecting blood pressure: 1. cardiac output 2. peripheral resistance 3. blood volume  a change in any of these could cause a corresponding change in blood pressure

1. Cardiac Output physical condition of the heart already discussed cardiac output

2. Peripheral Resistance factors that affect peripheral resistance are mediated by autonomic nervous sytem Peripheral resistance is also affected by the condition of the vessels themselves and by blood-born chemicals

a. Vasomotor Control Center (medulla) works in conjunction with cardiac centers

both arteries and veins can dilate

mainly sympathetic control  activation can cause constriction eg. in skin or dilation eg in muscles

b. Condition of vessels eg atherosclerosis inhibits flow  raises blood pressure

eg. obesity leads to many additional vessels that blood must pass through  raises blood pressure

c. Blood Borne chemicals

43 numerous blood-borne chemicals influence short term control of blood pressure

act directly on vascular or on vasomotor system

eg. NO secreted by endothelial cells localized vasodilation lowers BP very brief effect, quickly destroyed is the major antagonist to sympathetic vasoconstriction

eg. viagra stim production of NO

eg. inflammatory chemicals , kinins, etc potent vasodilators  lower BP increase capillary permeability

eg. nicotine intense vasoconstriction  raise BP simulates sympathetic release of NE

eg. alcohol depresses VMC inhibits ADH release vasodilation (esp of skin vessels) raises BP (also flushing of face)

3. Blood Volume blood pressure is directly affected by the volume of fluids retained or removed from body:

greater volume  increases BP eg. excessive salts promote water retention lower volume  decreases BP eg. dehydration eg. internal bleeding

factors that regulate blood volume are mainly renal factors and are slower to change  long term controls

44 these factors can act as a system wide control over whole body blood pressure

mainly involve control by the kidneys

baroreceptors quickly adapt to long term (chronic) changes in blood pressure

renal mechanisms step in to restore homeostasis by regulating blood volume

kidneys act both directly and indirectly to regulate arterial pressure:

a. Direct Renal Control of Blood Volume involves regulation of blood volume by kidneys greater BP: more filtration from kidney  greater urine output lower BP: more reabsorption of water by kidney  lower urine output

b. Indirect Renal Control of Blood Volume = Long Term Controls renin-angiotensis mechanism lower BP:  kidneys release enzyme = renin  renin triggers production of II  angiotensin causes: vasoconstriction  raises BP release of ADH  conserves water to raise BP

Hypotension low BP  systolic <100 usually not a cause for concern  often associated with long healthy life but. in some may produce dizziness when standing up too quickly (esp in older patients) may be due to severe bleeding and lead to circulatory shock may hint at poor nutrition eg.

45 Hypertension if transient is normal: adaptation during fever, exercise, strong emotions if persistent is a cause for concern 30% of those >50 yrs old suffer from hypertension usually asymptomatic for first 10-20 yrs = silent killer prolonged hypertension is a major cause of: heart failure vascular disease kidney failure stroke

Blood Vessels & Circulation

blood flows in closed system of vessels over 60,000 miles of vessels (mainly capillaries)

arteries  capillaries  veins (25%) (5%) (70%)

arteries & arterioles – take blood away from heart to capillaries capillaries -actual site of exchange venules & veins – bring blood from capillaries back to heart

arranged in two circuits: pulmonary: heart  lungs  heart rt ventricle pulmonary arteries (trunk)lungspulmonary veinsleft atrium systemic: heart  rest of body  heart left ventricleaortabodyvena cavart atrium

heart is a double pump oxygen deficient blood in pulmonary vein and vena cava  usually blue on models

walls of arteries and veins consist of three layers: tunica adventitia outer fibrous connective tissue tunica media middle smooth muscle

46 tunica intima (=interna) inner endothelium

Characteristics of Blood Vessels

Arteries contain ~ 15% of all blood pressure is variable MAP ~ 93 varies from 100 – 40 mmHg three layers: thick layer of connective tissue for strength heavily muscular to withstand pressure large lumen most organs receive blood from >1 arterial branch provides alternate pathways

vasa vasorum = blood vessels within walls of large arteries sympathetic innervation

Arterioles ~ 10% of all blood average pressure ~40 –25 mmHg pressure decreases drastically in arterioles  most resistance is here ~ 1/2 of whole system muscle tissue makes up major bulk of walls innervated by vasomotor nerve fibers of autonomic NS major role in controlling the distribution of blood in body sympathetic stimulation  vasoconstriction

Capillaries most of 62,000 miles of vessels usually no cell >.1 mm away from a capillary each capillary <1mm long but only contains ~5% of blood in body variable pressure 35 – 15 mm Hg; ave=25-12 mmHg thin walled - single cell layer thick extremely abundant in almost every tissue of body 1 inch3 of muscle = 1.5 million capillaries

A. density of capillaries varies with metabolic rate

47 eg. cartilage and cornea have no capillaries eg. tendons and ligaments are poorly vascularized eg. cartilage and epithelial cells lack capillaries eg. muscle, liver, lungs, kidneys have rich blood supply

B. types of capillary structure: 1. continuous lining is uninterrupted adjacent cells joined by tight junctions but with intracellular clefts to allow passage of fluids and small solute most common type eg. skin, muscles, lungs, adipose special: CNS blood brain barrier no clefts

2. fenestrated similar to above but some cells are riddled with pores much greater permeability eg. kidneys, endocrine glands, intestinal mucosa 3. sinusoidal (discontinuous) highly modified “leaky” capillaries large clefts and fenestrae allows large molecuels and cells to pass eg. bone marrow, liver, spleen

C. capillary beds: functional groupings of capillaries = functional units of circulatory system

arterioles and venules are joined directly by metarterioles (=thoroughfare channels)

capillaries branch from metarterioles 1-100/bed

cuff of smooth muscle surrounds origin of capillary branches = precapillary sphincter

48 amount of blood entering a bed is regulated by: a. vasomotor nerve fibers b. local chemical conditions

D. Velocity of blood flow blood flows slowest in capillaries due to greater cross-sectional area of all capillaries combined: 600 – 1000 x’s cs of aorta

provides greatest opportunity for exchange to occur

most materials pass to tissues by diffusion: fat soluble, CO2, O2 go through cell membrane ions and small molecules go through pores (passive ion channels) large molecules pass by exocytosis

Veins & Venules 60% of all blood is in veins ~10% in venules low pressure: 12 – 8 mmHg venules 6 – 1 mmHg veins larger veins near 0

generally have a greater diameter than arteries but thinner walls  more compliant

three layer are all thinner than in arteries tunica adventitia is thickest of three but not as elastic as arteries little smooth muscle

large veins also contain vasa vasorum  blood vessels in walls with sympathetic nerve innervation

Movement of Blood in Veins movement of blood in veins is not pressure driven by the heart

venous blood flows due to:

49 1. constriction of walls by ANS minor effect muscle layer is very thin, veins are very compliant 2. 1 - way valves prevent backflow most abundant in veins of limbs

quiet standing can cause blood to pool in veins and may cause fainting

varicose veins: “incompetent” valves esp. superficial veins may be due to heredity prolonged standing obesity pregnancy increased venous pressure

hemorrhoids: varicosities of anal veins due to excessive pressure from birthing or bowel movements

3. venous pumps muscular pump (=skeletal muscle pump) during contraction veins running thru muscle are compressed and force blood in one direction (toward heart) respiratory pump inspiration: intrapleural pressure falls from –2.5 mm Hg to –6 mmHg while abdominal pressure increases  creates pressure gradient in Inferior Vena Cava to move blood toward heart expiration increasing pressure in chest cavity forces thoracic blood toward heart veins function to collect blood and act as blood reservoirs with large lumens and thin walls they can accommodate relatively large volumes of blood

50 60-70% of all blood is in veins at any time

largest veins = sinuses eg. coronary sinus, dural sinus

most organs are drained by >1 venous branch even more common than alternate arterial pathways

 occlusion of veins rarely blocks blood flow

removal of veins during bypass surgery usually not traumatic

Vasomotor Control System

circulation involves differential distribution of blood to various body regions active body parts receive more blood than inactive parts blood volume must be shifted to parts as they become more active blood circulates because of pressure gradients pressure gradients are created through cardiac output peripheral resistance the greatest peripheral resistance is found in the arterioles 85 at beginning 35 at end 50 mmHg difference individual arterioles can increase or decrease their resistance to bloodflow by constricting or dilating mediated by autonomic nervous sytem vasomotor control center in medulla works in conjunction with cardiac centers mainly sympathetic control both arteries and veins can dilate

51 vasomotor control system can also shift blood to or from blood reservoirs in veins as needed: large veins sinuses skin liver spleen sensory input from:

baroreceptors in carotid sinus aortic arch

 stretch inhibits VMC  vasodilation

chemoreceptors monitor oxygen and pH in aortic arch and carotid sinus these receptors also help to control respiration

lower pH or O2  vasoconstriction

cerebral cortex and hypothalamus can affect VMC eg. hypothalamus fight or flight  vasoconstriction eg. cerebral cortex emotions

Local Regulation of Blood Distribution

in addition to vasomotor reflex,local regulation of specific arterioles can also direct blood to organs needing it most

individual tissues can control the amount of blood they receive through some autoregulation (=intrinsic controls) largely independent of systemic factors (VMC) noted above

Autoregulation involves: 1. Metabolic controls 2. Myogenic controls

52 1. Metabolic controls changes in the concentrations of specific nutrients or waste products can cause vasodilation and relaxation of precapillary sphincters in affected tissues eg. reduction in esp O2 eg. increases in potassium eg. increase in Hydrogen ions (lower pH), lactic acid

2. Myogenic controls inadequate blood flow to an organ can cause cell damage or death too much blood flow may rupture fragile vessels the physical effects of blood flowing to an organ causes direct local stimulation of its vascular tissue: passive stretch  triggers constriction  higher local BP  slows blood flow to tissue

reduced stretch  triggers dilation  reduces local BP  increases blood flow to tissue

Angiogenesis

if short term changes cannot supply adequate oxygen or nutrients the body can respond by increasing the number of blood vessels supplying the area

the number of blood vessels to a high demand area will increase

eg. heart with occluded vessels grows new ones

eg. people at high altitudes have greater number of vessels in tissues throughout their bodies

Body Defenses & Immunity

immunity = resistance to disease

the immune system provides defense against all the microorganisms and toxic cells to which we are exposed  without it we would not survive till adulthood

our body has many ways to prevent or to slow infections

53 Many factors affect an individual’s overall ability to resist infections: Genetics: human diseases, zoonoses, etc Age: mainly an immune response Health: eg. protein deficiency  less phagocytic activity eg. stress  lower resistance to disease Hormones: eg. cortisone (a glucocorticoid) reduces inflammatory response the immune system is a functional system rather than a system with discrete organs  parts of many organs contribute to body defense almost all organs in body play some role in immunity  dispersed chemicals, cells and tissues  dispersal and transport via circulatory and lymphatic systems two major mechanisms that protect the body: 1. Innate, nonspecific system of a. physical and chemical barriers b. internal cells and chemicals 2. Adaptive system that fights specific pathogens or, can view the immune system as a three tiered system of defense a. physical and chemical barriers b. chemical and cellular barriers c. specific defense mechanisms

Innate, Nonspecific Resistance

Physical Barriers

1st major level of protection from invasion and infection nonspecific – treats all potential pathogens the same way attempt to prevent entry of pathogens into body

1. Intact Skin

tightly packed cells filled with waxy keratin

thick, multiple layers of dead keratinized cells

54 shed regularly

rarely, if ever, penetrated while intact only a few parasitic worms (cercariae) can do this

if skin is broken: staphs and streps are most likely to get in

sebaceous glands provides protective film over skin

acidity of skin secretions ('acid mantle') inhibit bacterial & fungal growth; also contains bacteriocidal chemicals

but if skin is moist, not cleaned frequently enough may permit yeasts and fungi already present to become a problem

2. Mucous Membranes

line all systems that open to outside of body nasal hairs trap pathogens mucous thick, sticky, traps pathogens cilia in resp sys move mucous out of system (‘ciliary escalator’  1-3 cm/hr) coughing and sneezing speed up process gastric juices secreted by lining of stomach contains HCl and enzymes; highly acidic (pH~1.2-3.0) kill and dissolve most bacteria and toxins except S. aureus and C. botulinum

but: Helicobacter pylori neutralizes acids to grow in stomach may cause gastritis or ulcers Lacrimal Apparatus continual blinking flushes and wipes away pathogens lysozyme kills and dissolves some bacteria

55 (most G+ and some G- bacteria) (lysozyme also found in sweat, saliva, and nasal secretions) Saliva continual flushing of bacteria to stomach lysozyme kills and dissolves some bacteria Urine continual flushing of bacteria entering urethra  low flow  bladder infection acidity also inhibits bacterial growth Vaginal Secretions flushing and trapping pathogens in mucous acidity inhibits bacterial growth

but: some pathogens thrive in moisture and if they occur in large enough numbers they are able to penetrate eg. Treponema

Internal Cellular and Chemical Defenses

1. blood has nonspecific, antimicrobial chemicals that help to fight invaders:

eg. transferrins – bind to Fe to inhibit bacterial growth

2. Simple Phagocytosis many WBC’s travel through blood and tissues and gobble up bacteria and foreign material mostly neutrophils and macrophages (formed from monocytes) migrate to area of infection monocytes enlarge on way to become macrophages engulf and destroy circulating pathogens especially bacteria some macrophages are “fixed macrophages” that screen blood as it passes by  esp in liver, bronchial tubes of lungs, nervous system, , spleen, lymph nodes, bone marrow peritoneal cavity [referred to as the reticuloendothelial system] eosinophils  can produce toxins and are most active against parasitc worms

mechanism of phagocytosis:

56 1. Chemotaxis chemical attraction to invaders, microbial products, components of WBC’s or damaged cells 2. Adherence attachment to surface of foreign material may be hampered by capsules (eg. S. pneumonia, H. Influenza) or M proteins (eg. S. pyogenes)  must trap them against rough surface (eg. blood vessel wall, clot, etc) also can be more readily phagocytized if 1st coated with certain plasma proteins that promote attachment (=opsonization) 3. Ingestion plasma membrane of phagocyte extends around microorganism or cell 4. Digestion forms food vacuole inside WBC fuses with lysozomes takes 10-30 minutes to kill most bacteria enzymes: lysozyme  hydrolyzes peptidoglycan of cell wall lipases, proteases, ribonucleases  hydrolyzes other cellular components some enzymes also produce toxic oxygen products: eg. O2-, H2O2, OH- residual body discharges wastes not all microorganisms are killed once phagocytized eg. Staph and Actinobacillus actually produce toxins that kill phagocytes eg. Chlamydia, Shigella, Mycobacterium, Leishmania (protozoan), and Plasmodium can survive inside phagocyte  they can prevent fusion of lysozome eg. other microbes can remain dormant for months

phagocytosis also plays a role in specific immunity

3. Natural Killer Cells the “pit bulls” of the defense system another kind of WBC police the body in blood and lymph promote cell lysis of virus infected cells or cancer cells not phagocytic

57 4. Inflammatory Response larger response that prevents spread of infection from localized area damage to body’s tissues causes: redness, pain, heat and swelling sometimes loss of function overall, has beneficial effect: a. destroys injuring agent b. removes it and its byproducts or limits its effects c. repairs or replaces damaged tissues occurs in three major stages: a. vasodilation b. phagocyte migration and phagocytosis c. tissue repair

a. Vasodilation and Increased Permeability damaged tissues release histamines and kinins blood vessels dilate in area of damage increased blood flow to area causes swelling (edema), redness and heat this allows defensive chemicals and clotting factors and cells to move to the area clot forms around area to prevent spread of infection b. Phagocyte Migration and Phagocytosis within an hour phagocytes begin to accumulate at the site as the flow of blood decreases, phagocytes stick to lining of blood vessels then squeeze out into tissue spaces chemical attractants, eg. kinins, draw WBC’s to site neutrophils arrive first, monocytes predominate during later stages as WBC’s die  pus accumulates c. Tissue Repair cant be completed until all harmful substances have been removed or neutralized

5. Fever systemic rather than local response hypothalamic thermostat is reset to eg. 102.2 ºF produced by pyrogens secreted by macrophages when exposed to certain pathogens

58 fever symptoms: blood vessels constrict metabolism increases shivering helps maintain high temp skin remains cold – chills

slight increase in temperature: a. inhibits growth of some pathogens b. speed metabolism for repair of body cells and to enhance phagocytosis c. cause liver and spleen to store zinc and iron both are nutrients needed by bacteria d. intensifies effects of other chemicals eg interferon

6. Complement Reactions: foreign substance may trigger cascade which activates complement proteins =complement fixation ~5% of all blood proteins (20 different ones) are complement proteins they can operate nonspecifically or specifically complement proteins formed from liver cells, lymphocytes, monocytes trigger a cascade reaction (inactive active)  initiation  amplification  effects

complement fixation can cause any of the following effects: a. cell lysis (cytolysis) membrane attack complex forms “transmembrane channels” ddigests a hole in bacterial cell, killing it b. opsonization makes pathogens stickier and easier for the leukocytes to phagocytize c. enhances infllammatory response helps trigger release of histamine and chemical attractants for WBC’s

the effects of complement activation are short lived  they are quickly destroyed malfunctions of system may result in some

59 hypersensitivity disorders

7. Interferon antiviral chemical secreted by infected cells they are host cell specific, not virus specific  different tissues in same host produce different interferons all interferons are small proteins stable at low pH heat resistant produced by infected cells and spread to uninfected cells  stimulate synthesis of antiviral proteins that disrupt various stages of viral multiplication effective for only short periods  good for acute, short term infections eg. colds, influenza

interferon is now produced in quantity by recombinant DNA technology has only very limited effects on cancer cells high doses have side effects: fatigue, fever, chills, joint pain, seizures experimentally used to treat HIV, Hepatitis, genital herpes, influenza, common cold might work better with other agents in combination

60