PSL301 Midterm 1

Functions of Blood

1. Regulates body temperature.

• If too hot → stay near surface

• If too cold → constrict blood vessels → stay near core.

2. Transport of gases, hormones, nutrients, and waste products.

3. Forms blood clots at injury sites to stop water loss.

4. Defense against pathogens and toxins.

5. Regulates composition of interstitial fluid.

• pH, water, ion concentration.

Blood Composition

Separated into plasma and formed elements

• Formed elements are all other cells and the platelets.

The amount of blood that is composed of RBC and WBC is called the hematocrit.

• Males have a higher % because of their testosterone.

Plasma Composition

Plasma is made of:

• Water

• Gases

  • CO2

  • O2 bound to hemoglobin

• Vitamins

• Ions that are very similar to the interstitial fluid.

• Organic molecules.

  • Albumin is responsible for generating osmotic pressure.

  • Transferrin is responsible for the transport of iron.

  • Alpha and Beta globulin are the enzymes, carriers, and clotting factors.

  • Gamma globulins are the antibodies.

  • Fibrinogen is cleaved into fibrin to form blood clots.

Formed elements composition

Made of RBC (erythrocytes), WBC (leukocytes), and platelets (thrombocytes).

These are formed in the bone marrow after birth.

Hematopoiesis

The process of blood cell formation.

• Starts with pluripotent hematopoietic stem cells in the bone marrow → some stay stem cells, some go through the process to become blood cells → in the circulation, they differentiate into the RBC, WBC, and platelets.

the process is regulated by cytokines.

• erythropoietin is made in the kidney cells and causes growth of RBC

• thrombopoietin is made in the liver and causes growth of megakaryocytes which break down into platelets.

• colony-stimulating factors, ILs, and stem cell factors are made in bone marrow fibroblasts and cause differentiation of all blood cells.

Red Blood Cells

Are basically bags filled with enzymes and hemoglobin with no nucleus.

• Have a disc shape that comes from the binding of the cytoskeleton with anchor proteins in the membrane.

• Main role is to transport oxygen and co2.

The hemoglobin in RBC is made of 2 alpha rings and 2 beta rings that are non-covalently bound to heme

• Heme is made of 4 porphyrin rings with an iron atom in the middle → iron binds oxygen for transport.

The number of RBC we have depends on maintaining balance between its production and removal.

• RBC have a short life span because they have no nucleus so no new proteins but also because as they squeeze through capillaries, they get worn out.

• Need to have constant RBC production to balance out this loss

RBC production

Called erythropoiesis

• When we have low oxygen in the blood, it is an indicator of not enough RBC carrying that oxygen → sensed by kidney cells → HIF1 alpha, a transcription factor, is produced → acts to turn on the erythropoietin gene → erythropoietin released by kidney cells → induces differentiation of progenitors → erythroblast → loses nucleus → reticulocyte → erythrocyte (RBC).

• The % of reticulocytes is an indicator of how much RBC synthesis is happening.

For this process to happen effectively, we need to have iron, vitamin B12, and folate in our diet.

RBC removal

The old and dead RBC need to be removed from our circulation.

• In the bone marrow, the RBC are produced → go through circulation → die → go to macrophages → broken down into heme and amino acids → the iron from heme is transported back to the bone marrow by transferrin because we have so little of it we can’t afford to just toss it. The porphyrin ring is broken down into bilirubin → goes to liver → intestines → excreted either as bile from the intestine (poo) or from the kidney (pee).

Blood-related issues

1. Jaundice

• Caused by too much RBC death → too much bilirubin

2. Anemia

• Caused by ineffective O2 transport because of low RBC concentration.

• Can come from either:

  • Low RBC production: drugs that kill stem cells, low nutrients, or low erythropoietin

  • High RBC death: genetic, infection, autoimmunity, drugs (hemolytic), or high blood loss (hemorrhagic).

• Symptoms:

  • Tired,Headaches,Weakness,Pain,Dizziness.

3. Polycythemia

• When the hemocrit concentration is too high (%RBC or WBC)

• Caused by low O2 delivery or wrong erythrocyte precursors.

Immune system roles

Has 3 main functions

1. Destroy pathogens

2. Detect and kill abnormal cells

3. Remove cell debris

Types of pathogens

Parasitic worms

Protozoa

Virus

Bacteria

Fungi

Immune system composition

Made of primary and secondary lymphoid tissues

Primary:

• Thymus → makes T lymphocytes

• Bone marrow → makes blood cells

• Lymphatic vessels → transport pathogens and DCs to the blood, take fat from the digestive system to the blood, and take excessive tissue fluid back to blood

Secondary:

• Tonsils

• Lymph Nodes → monitor lymph through immune cells

• Spleen → monitor blood. made of red pulp that has macrophages and white pulp that has lymphocytes.

• MALT

• Skin

Innate Immunity

The first response to an infection.

• Rapid but non-specific

Made of different components

1. Physical barriers

• Epithelium of skin + mucosa

• Mucus, enzymes, Ab → Trap enzymes.

• pH of stomach → ingested pathogens killed

2. Contains phagocytes

• PRRs bind PAMPs and DAMPs → engulf → Kill

• Macrophages, dendritic cells, and neutrophils.

3. Contains NK cells

• Normally, host cells have MHC I on them → viruses can remove expression of MHC I → NK cells look for cells without MHC I and kill them.

4. Has Antimicrobial peptides

• IFN alpha and beta stop replication

• IFN gamma activates macrophages and immune cells

• Complement proteins coat targets → cause inflammation, attract phagocytes, and form the MAC to create pores in the membrane and lyse the cell.

5. Causes inflammation

• Response to tissue damage

• Damage → Mast cells release histamine and heparin → blood vessel dilation → increased blood flow → swelling and blood clot formation. OR after release → phagocyte recruitment → repair.

6. Causes fevers

Adaptive Immune system features

1. Specificity

• BCRs and TCRs recognize specific antigen shapes and structures → only respond to those antigens

2. Memory

• B cells and T cells are long lasting → remember an antigen that was previously encountered

3. Versatility

• The B cells and T cells respond to different types of antigens → able to respond to any type of antigen at any time.

4. Tolerance

• Only respond to foreign things and ignore self-tissues cuz self-reactive B and T cells were deleted.

BCR

Made of 2 alpha chains and 2 beta chains with an antigen binding site

• ABS is what has variations and creates specificity.

Binds extracellular antigens.

TCR

Binds antigens presented on APCs.

Binds to both the viral antigen and the MHC.

Clonal Expansion

The B and T cells circulate the body looking for an antigen → when it is encountered, they go through clonal expansion.

• Process that produces a bunch of clones of B and T cells.

• Antigen presented to receptor → activated → proliferate → clonal expansion to make a bunch of clones of the same cell with specificity to the antigen.

From their first response, the produce antibodies slowly → second exposure to the same antigen → quick antibody production → memory

Also go through positive and negative selection to remove self-reactivitiy.

• B cell in bone marrow

• T cell in thymus.

B cell response

Aim of B cell response/Humoral immunity is to produce antibodies.

• Antigen binds BCR → internalized → combined with MHC → taken back to surface → recognized by Th cell → secretes cytokines → B cell proliferation → differentiation into either memory B cells or plasma cells that secrete antibodies

Antibodies

Have many different functions

• Clump antigens in one spot

• Inactivate toxins

• Act as opsonins

• Degranulation trigger

• Complement

• B cell activation.

IgA → Protects epithelial surfaces/mucosal tissues.

IgD → BCR

IgE → Allergic response

IgM → Complement activation

IgG → New born immune response

T cell Activation

T cells are activated through binding to an APC.

• MHC and antigen form a complex → bind to TCR → Signal transduction to activate T cell.

T cell types

Can be T helper cells if presented with MHC Class II → secrete cytokines to either activate or repress immune cells.

Can be T cytotoxic cells if presented with MHC Class I → kill target cells using granzyme and perforin, or activate the death receptor Fas.

MHC Class II

On DCs, macrophages, and B cells.

• Pathogen gets phagocytosed → lysosome binds → produces fragments of the antigen → ER produces MHC Class II → come together and form a complex → go to surface → antigen fragments presented by Class II MHC.

Used for exogenous antigens to activate Th cells.

MHC Class I

On all nucleated cells.

• Have an infection inside the membrane → produces peptides → goes to ER → Class I MHC incorporate the peptides into themselves → transport to cell membrane → peptides presented at surface by MHC Class I.

Used for endogenous antigens to activate Tc cells.

2 types of an immune response

If your immune response is deficient, different things happen.

1. Infectious agent → immune response = protection but deficient response = recurrent infection.

2. Innocuous substance → immune response = allergy :(

3. Unmatched blood and a grafted organ → immune response = rejection :(

4. Self organ → immune response = autoimmunity ☹

5. Tumor → immune response = tumor immunity 🙂 but deficient response = cancer

Allergies

A result of immune response to a nonpathogenic antigen.

2 types.

1. Immediate hypersensitivity

• Allergen exposure → ingested by APC → Th cell activated → Th activates B cell → B cells becomes memory and plasma cells → plasma cells secrete antibodies to fight the allergen → when you get re-exposed to the same allergen, memory cells remember and react more quickly → mast cells secrete histamine and T cells secrete cytokines → inflammation → allergic reaction.

2. Delayed hypersensitivity

Hemostasis

The process of clot formation.

Happens in 3 phases.

1. Vascular phase

• The goal of this phase is to stop bleeding.

• Injury/cut → smooth muscles constrict → lumen smaller → less blood loss.

  • This vasoconstriction is made longer by serotonin and thromboxane A2 that are secreted by platelets and by endothelia which is secreted by endothelial cells.

2. Platelet Phase

• The goal of this phase is to begin forming the plug/clot

• Tissue damage causes collagen to be exposed → Vonwillebrand factor secreted by endothelial cells → brings platelets to the collagen → bind to the collagen → secrete ADP, PAF, serotonin, and thromboxane A2 → more platelets attracted to wound site → aggregate → plug formed.

  • If there is no damage, endothelial cells secrete prostacyclin and NO → prevent platelet adhesion and cause vasodilation.

3. Coagulation phase

• Goal is to stabilize the clot formed in the platelet phase because it is very unstable, needs fibrin.

• There is an old school model.

  • In an extrinsic pathway, the damage causes tissue factor to be exposed and activates VII → VIIa and TF activate X in the common pathway.

  • In an intrinsic pathway, collagen activates XII → XIIa activates XI → XIa works with TF and VIIa to activate IX → IXa and VIIIa activate X in the common pathway.

  • In the common pathway, Xa works with Va to cleave prothrombin into thrombin → thrombin cleaves fibrinogen to fibrin and activates XIII → XIIIa causes fibrin monomers of the same type to cross link → solid structure formed → clot stabilized

• But this old school model was found to have gaps so now we use the cell-based theory

  • Initiation phase: Damage exposes tissue factor and activates VII → TF and VIIa activate X and IX → Xa causes a small amount of prothrombin to be cleaved into thrombin → thrombin spark.

  • Amplification Phase: this small amount of thrombin activates VIII, V, and XI.

  • Propagation Phase: XIa activates IX → IXa combines with VIIIa to create tenase → tenase activates X → Xa combines with Va to form prothrombinase → cleave a lot of prothrombin into thrombin → thrombin burst → thrombin cleaves fibrinogen to fibrin and activates XIII → XIIIa causes fibrin monomers of the same type to cross link → solid structure formed → clot stabilized.

Clot removal

After the skin has been healed, the clot needs to be removed.

• tPA is released by the damaged endothelium → cleaves plasminogen to plasmin → plasmin cleaves fibrin into fragments → clot removed.

Cardiovascular System

A closed loop.

• Everything is connected together through two circuits.

• Pulmonary Circuit

  • The goal is to move deoxygenated blood to the lungs where it can be oxygenated.

  • On the right side of the heart

  • Does not generate a lot of pressure.

• Peripheral Circuit: Oxygenated blood goes from the left ventricle → aorta → arteries → different organs.

  • Goal is to spread oxygenated blood to the organs.

  • On the left side of the heart.

  • Does generate a lot of pressure

Path of blood through the heart

Deoxygenated blood from the head and neck enter the heart through the superior vena cava, deoxygenated blood from the periphery enter heart from the inferior vena cava → right atrium → tricuspid valve → right ventricle → pulmonary semilunar valve → out of the heart from the pulmonary arteries → to the lungs where it gets oxygenated.

oxygenated blood re-enters through the left pulmonary vein → left atrium → bicuspid valve → left ventricle → aorta → organs.

Valves

There are 2 valves, separated into two groups.

• Semilunar valves are like cups that grab the blood to prevent back flow.

  • Include the pulmonary and aortic valves.

• Atrioventricular valves are in between the atria and ventricles.

  • Tricuspid and Bicuspid valves.

Heartbeat

We need a heartbeat for the blood to actually be moved.

• The heartbeat is produced by the generation and conduction of electrical signals through APs.

Type I autorhythmic cells of the intrinsic conduction system generate and rapidly conduct the electrical signals (Decide when the heart should beat).

• These cells are located in sinoatrial nodes and atrioventricular nodes.

• All the cells in the intrinsic conduction system are able to generate electrical signals, but the ones in the SA node are able to do it the fastest → as long as they are functioning, they decide when the heart beats.

• In the sinoatrial node, there are funny current channels → allow a small amount of Na into the cell and a small amount of K out the cell → gradual depolarization → brings the memrbane to threshold → an AP can begin.

  • Called the unstable resting membrane potential.

Type II contractile cells are responsible for spreading the signal produced and causing contractions that make the heart beat (Decide how hard the heart should beat).

• The contractile cells stay at rest until they receive a signal.

Autorhythmic cells generate an electrical signal → pours out of the SA node → comes in contact with the contractile cells → generate contractions.

Contractile cardiac muscle

The cells in the contractile cardiac muscle, the one responsible for making the heart contract and actually beat, form a synctial network.

• The myocytes in this network are connected through desmosomes and tight junctions.

  • The desmosomes allow for the force to get transferred between the cells.

  • The tight junctions allow for the electrical signals to be passed between the cells.

• These networks get organized into fibers and fiber bundles → aligned so all the contractile cells are able to uniform → maximum force can be generated.

There are two types of contractile cardiac cells.

• Skeletal cells → Have a shorter refractory period.

  • The short refractory period means that multiple APs can happen at the same time → if they summate, the muscles are going to lock → tetanus.

• Myocardial cells → have a longer refractory period to correspond with the stop of the heart contractions

In this muscle, there are deep invaginations of T-tubules and a sarcoplasmic reticulum with sacs of calcium.

Cardiac muscle activation

Happens through excitation-contraction coupling.

1. Depolarizing current passes through T-Tubule → opens the voltage-gated calcium channel (L-type channel) → high [Ca] outside → influxes into the cell → RyR on the sarocplasmic reticulum sense the calcium → opens briefly → calcium can leaves the SR →

Nodes

There are two nodes in the intrinsic conduction system

1. Sinoatrial node

• The primary pacemaker that is responsible for initiating and generating the electrical signal.

• Sets the pace of the heart beat.

• Functions through the sympathetic and parasympathetic system

2. Atrioventriuclar node

• The logic gate that controls the speed of the heartbeat and controls the direction of the electrical signals.

• Also responsible for delaying the transmission of action potentials.

  • Need to do this because you don’t want simultaneous contractions so you don’t get tetanus.

  • Also need to do this because the atrial contractions need to finish before the ventricles can contract.

Tracks of autorthytmic cells direct the SA node to the AV node → when they come together, they pause → split apart → one goes into the left bundle branch and one goes to the right bundle branch.

• The pausing allows for the atria to contract.

Parasympathetic control of heart rate

The parasympathetic activity aims to lower your heart rate.

• Parasympathetic nerves activate vagus nerve that goes into the SA and AV node → releases Ach → binds to M2R in the SA node → activation of alphai G protein → activates beta gamma G protein → activates GIRK → GIRK increases permeability to K so K can come out of cell and membrane can be hyperpolarized → slower SA node firing → slower heart rate

• Alpha i G protein also inhibits adenylyl cyclase → less cAMP released → less PKA activated → can’t phosphorylate funny current channel and calcium channel → threshold reached slower → slower heart rate.

Atropine is a drug that can be taken to increase heart rate.

• Binds to M2R instead of Ach to block the pathway.

The parasympathetic and sympathetic nervous system cannot be acting at the same time.

Sympathetic control of the heart rate

The goal of the sympathetic system is to increase your heart rate.

• Sympathetic nerves go into the SA node → release norepinephrine and epinephrine → binds to B adrenergic receptor → activates alpha s g protein → activates adenylyl cyclase → inhibits alpha i g protein activation and converts a bunch of ATP to cAMP → activate PKA → phosphorylates funny curent channel and calcium channels → threshold reached faster → increased heart rate.

Catecholamines from the adrenal gland are also released during this response to increase heart rate.

Complete process of electrical conduction in the cardiac cycle

SA node in the superior vena cava depolarizes through the funny current channel → electrical activity gets passed to the AV node in the right atira through the internodal pathways → Conduction slows at the AV node to allow atrial contraction to finish→ speeds up again as it goes through the ventricular conducting system → goes through left and right ventricles → apex of the heart → spreads upward

ECG

Measures the dipole moments created by the depolarization and repolarization of the heart.

Has 3 waves

1. P wave: SA node begins firing → the atria is slowly depolarizing → small incline.

2. P-Q: Signal passed to the AV node → pauses to allow atria to contract → small downward slope to flat

3. Q wave: signal is rapidly moving away from the electrodes as it passes down the septal tissue → a sharp spike down

4. R wave: electrical signal moves from the endocardial surface to the epicardial surface → rapid depolarization → sharp spike up

5. S wave: signal passes through the ventricles → sharp spike down again

6. S-T: ventricles contract and there is no more electrical activity → flatness.

7. T wave: repolarization → small slop upward.