Physiology 209

Physiology

The study of the normal functional activities in the healthy living organism

Milieu Intérieur

the internal environment surrounding individual cell

Basic Cell functions

Claude Bernard Belief

• Environment surrounding individual cells is vastly different from external environment

• Internal environment remains relatively constant under conditions of health

Homeostasis

a state of dynamic constancy

Fundamental Principle

“At all levels of organization, the functional activities are directed at maintaining optimal and relatively constant INTERNAL CONDITIONS”

What are the factors that must be homeostatically controlled?

• Concentration of Nutrient Molecules

• Concentration of O2 and CO2

• Concentration of Waste Products

• Concentration of Electrolytes

• pH

• Temperature

• Volume and Pressure

Failure to maintain homeostasis causes. .

disease

Body water is the medium in which…

• Solutes are dissolved

• Metabolic reactions take place

What accounts for the large variation in water content in different individuals?

• Fat (adipose tissue) varies in % in each individual based on factors unrelated to water

• fat contains only 10% water, unlike the 70-80% of other body tissues

What is a physiological reference individual? What should one adjust for when the subject varies from the reference individual?

• 21 yr old white 70 kg male

• age, gender, weight

  • babies are 70% water

  • mid-life women 50%, men 60%

  • elderly women 45%, men 50%

How do you calculate body water volume? How can this be important?

• (weight * %body water)/100

• important when administering water-soluble medication (helps calculate accurate concentration)

  • need to know how to convert between mili, micro, nano, and pico (look at attached photo PLS)

What are the intakes necessary to maintain dynamic water balance in the body?

• Oral fluid (drank fluids, they have water)

• Oral intake as food (stuff you eat has water)

• Oxidative water from metabolism (metabolic reactions produce water as a byproduct)

What are the main types of output necessary to maintain dynamic water balance in the body?

• 2 ways to categorize, insensible vs sensible and obligatory vs facultative, one can be insensible and facultative at the same time or any other combo between the different ways of categorization

• Insensible (automatic processes you cannot control, you can’t sense it, hard to measure)

  • Lungs (water molecules lost through breathing by accident, out of your control)

  • Skin (passive evaporation from pores, NOT SWEAT)

• Sensible (necessary processes that you do, like removing waste, you can sense it, you can measure it)

  • kidneys (urine)

  • stool (feces)

  • sweat (NOT OBLIGATORY OR FACULTATIVE, JUST SENSIBLE)

• Obligatory (a set, unchanging amount of water that must be lost each day to get rid of waste and maintain bodily function regardless of consumption)

  • lungs and skin (insensible)

  • urine and stool (sensible)

• Facultative ( a variable amount of water that is lost based on the given intake of that day to maintain homeostasis in the body)

  • urine (kidney is the main homeostatic organ for water balance)

What is the difference between insensible precipitation and sweat?

• Insensible precipitation

  • pure water

  • passive evaporation (no energy, not on purpose, just affected by ambient (surrounding) temperature and relative humidity

  • takes place on the entire skin surface, so it can occur in people that don’t have sweat glands

  • Continuous and classified as obligatory

• Sweat

  • electrolyte solution (not pure)

  • active secretion ( on purpose, requires energy and signals in the body)

  • requires sweat glands

  • activated by heavy work or high temperatures

What is the difference in body water turnover in24 hours as an adult vs a baby?

• Adults are much lower, 3-4% of body weight

• Baby’s much higher, 10% of body weight

What can cause a negative water balance? (Water Loss > Water Intake)

• reduced intake

• excessive loss from gut (vomiting)

• excessive sweating

• excessive loss in expired air (high altitude has dry air, increasing amount of water lost from skin pores)

• excessive loss in urine

What can cause water intoxication? (water intake > water loss)

• excessive water intake (difficult)

• renal system failure

Body water volume is remarkably constant under conditions of health (water intake = water loss) This helps maintain…

• normal solute concentrations

• normal blood volume and pressure

both of these together allow for adequate supply of O2 to tissues

What are the two major body water compartments?

• Intercellular Fluid (ICF)

  • Aggregate of fluid bound by internal surfaces of all cell membranes

  • true “Milieu Interieur”

  • The fluid which percolates between individual cells

  • 2/3rds of all body water

• Extracellular Fluid (ECF)

  • 1/3rd of all body water

  • divided into 2 Major ( Plasma and Interstitial Fluid) and 2 Minor (Lymph and Transcellular Fluid)

Hematocrit (Ht)

• The percentage of Blood Volume that is occupied by Red Blood Cells (erythrocytes)

• calculated by: (height of erythrocyte column/whole blood column)

Plasma

The fluid medium in which blood cells are suspended

Explain the Lymphatic system from the smallest piece to largest

• A network of blind-ended terminal tubules come together to form larger lymphatic vessels

• these converge to form large lymphatic ducts

• which in turn drain into the large veins in the chest

Transcellular fluid

• Aggregate of small fluid volumes secreted by specific epithelial cells that line some body cavities

• these small fluids have specialized function

• does not contribute significantly to overall water exchanges; local changes do not affect body fluid balance

• still plays an important role in function locally

What are the 3 important factors that are constant for bodily fluids?

• Total Volume in a compartment remains CONSTANT

• Relative Distribution between compartments remains CONSTANT

• Compartments are in a state of DYNAMIC equilibrium

What are the two types of methods to determine compartment volumes?

• direct

  • just straight up measure

  • ex: indicator dilution method

• indirect

  • via calculations

How does the Indicator Dilution Method Work?

1. Introduce known quantity (Q) of indicator into vein

2. Allow time to equilibrate

3. Remove known volume of blood, and centrifuge to obtain plasma

4. Measure concentration c in unit volume of plasma

5. Calculate

   V = Q/c

Need to know:

• The total quantity of test substance introduced

• The concentration of the substance/unit volume of fluid, after dispersion

What do you need to consider when choosing an Indicator for an Indicator Dilution Method?

• Indicator must be:

  • Non-toxic

  • Diffuse readily, distribute

    evenly throughout

    compartment(s) to be

    measured (must choose one that only diffuse as far as needed, not further, or shorter, see diagram for designated indicators for each compartment)

  • Induce no changes in

    distribution of water

    between compartments

  • Easy to measure its

    concentration

In a clinical situation, what would you have to account for in an Indicator Dilution Method that we do not in class?

• any amount of bodily fluid which has been removed from body by metabolism or excretion during the time allowed for mixing.

  
  

What is the difference in ion and protein concentrations between the ICF and ECF?

• ICF

  • High in K+ and Mg++

  • low in Na* and Cl-

  • high protein anions

• ECF

  • High in Cl- and Na+

  • low protein anions found only in plasma NOT ISF

What are the Barriers to transport between ICF and External Environment

• Cell (plasma)

  • membrane barrier between ICF and ECF

• Capillary wall

  • barrier between:

    • ECF and plasma

    • plasma and the external environment

Explain the simplified directional movement of materials between compartments

What does the viability of the cell depend on and require?

• depends on the relative constancy of the “Internal Environment” (the “Milieu Intérieur”)

• requires EXCHANGES with the internal and (ultimately) the external environment

Describe what the Cell membrane in permeable, impermeable, and partially permeable to?

• Highly Permeable to:

  • H2O

  • Lipid-soluble substances

  • Dissolved Gases (O2, CO2)

  • Small uncharged molecules

• Less Permeable to:

  • Larger molecules

  • Charged particles

• Impermeable to:

  • Very Large molecules

Cholesterol

• inserted into the phospholipid bilayer

• functions as a buffer (prevents extremes, keeps state near constant)

• prevents lower temperatures from decreasing cell membrane fluidity and higher temperatures from increasing fluidity too much

• involved in the formation of vesicles ( these pinch off the plasma membrane and in lipid rafts)

• Slightly amphipathic

Cell Membrane

• Bimolecular Phospholipid Layer ( Phosholipid Bilayer)

• Amphipathic

  • Polar head (outside) and Nonpolar tails (inside)

• comprised of 40-50% phospholipids by weight

Proteins

• Most diverse macromolecules

• 25-75% of cell membrane by weight

• Two types:

  • Integral

    • closely associated with phospholipids (found at least partly inside the layer), mostly cross the membrane (Trans-membrane, partly in membrane partly out of membrane)

  • Peripheral

    • more loosely associated (attached on the outside), can be found on both sides of the plasma membrane

Glycocalyx

• a gel-like, sugar-rich coating

• surrounds the cell membrane

• formed of:

  • glycans

  • glycoproteins

  • glycolipids

• contributes to cell-cell:

  • recognition

  • communication

  • adhesion

  • protection

How does the Fluid Mosaic Model of the Cell Membrane describe it?

• describes the cell membrane as a dynamic, fluid structure where a phospholipid bilayer acts as a "solvent" (like a moving river) for embedded and attached proteins, creating a "mosaic" of molecules that can move laterally (horizontally)

What are the different Cell Membrane Transport Mechanism?

• Passive (energy independent, doesn’t need it)

  • simple diffusion

  • facilitated diffusion

  • osmosis

• Active (energy dependent, needs energy)

  • Active Transport

    • Primary Transport

    • Secondary Transport

  • Endo and Exocytosis

Diffusion

• the movement molecules from one location to another as a result of random thermal motion

Flux

• Amount of a solute crossing a surface area per unit time

• Two types:

  • One-way flux:

    • Unidirectional rate of movement of a solute

  • Net flux:

    • Overall rate of movement of a solute

• At equilibrium, net flux is 0 and either direction one-way fluxes are equal

Explain equilibrium for intracellular concentration (inside a cell) vs extracellular concentration (outside of a cell)

• While there is equivalent exchange between the two fluids, the volume outside of the cell is so much larger than inside the cell that this exchange of solute between them does not alter the extracellular concentration. It remains constant.

• Intracellular fluid has a significantly lower volume than extracellular fluid, so as the exchange occurs, it’s concentration is greatly affected. Since the concentrations need to be equivalent for equilibrium, and extracellular concentration is unaffected by the exchange, intracellular concentration rises or falls to match the extracellular concentration

Explain Fick’s law of Diffusion, include the equation and the meaning of the variables

• Equation: J = PA (C0 – Ci)

• C0 – Ci: Concentration gradient of the diffusing molecule across the membrane

• J: Flux, Amount (moles) of solute crossing a surface area of membrane per unit time - rate of diffusion

• P: Permeability (or diffusion) coefficient, a constant based on the ease with which a molecule moves through a membrane

• A: Surface area of the membrane

Ion Channels

• transmembrane proteins that show ion selectivity

• The movement of an ion through it is determined by opposing electrochemical forces

• 1st by the electrical potential difference across the cell membrane (must balance charges on both sides, positive ions go toward negatively charged side, and vise versa)

• 2nd by the concentration gradient of that ion across the cell membrane (normal diffusion, goes toward lower concentration

• When both are balanced, its called an electrochemical equilibrium

  • note: electrical potential difference balances the concentration gradient

Channel Gating

• The ability of an ion channel to open and close

• 3 types:

  • Ligand Gating

    • channel changes conformation, pinches inside together to close

  • Voltage Gating

    • opens and closes based on the electrical potential difference across the membrane

    • ex: Na+, K+ and Cl- channels

  • Mechanical Gating

    • a separate attached gate plugs the pore of the ion channel

Mediated Transport

• the movement of ions and other molecules (glucose, amino acids) by integral membrane proteins called transporters, carriers or exchangers

• NOT diffusion

• slower than ion channels

• Can be passive or active, ex:

  • Facilitated Diffusion (Passive)

  • Primary Active Transport

  • Secondary Active transport

What are the characteristics of Mediated Transport?

• Specificity

  • transporter usually transports one particular type of molecule

• Competition

  • occurs when structurally similar substances compete for the same binding site on a membrane carrier

• Saturation

  • rate of transport reaches a maximum when all binding sites on all transporters are occupied

  • Thus, a limit – the transport maximum (Tm) – exists for a given substance across a given membrane

Facilitated Diffusion

• involves the presence of a “transporter” or “carrier” molecule

  • enables a solute to penetrate more readily than it would be expected to by simple diffusion

• How it works:

  • Solute binds transporter

  • Transporter changes configuration

  • Solute is delivered to other side of membrane

  • Transporter resumes original configuration

• transporter (carrier) mediated

• passive (no-energy)

• net flux from high to low concentration

• Hormones may increase the number and/or affinity of transporters in some membranes

  • Glut-4 transports glucose in muscle that is increased by insulin

Active Transport

• transporter mediated

• requires supply of chemical energy (usually derived form enzymatic hydrolysis of ATP)

• Susceptible to metabolic inhibitors

• Can transport solute against its concentration gradient (i.e., “uphill transport”)

Primary Active Transport

• involves the hydrolysis of ATP by a transporter (carrier)

• Phosphorylation of the transporter changes the conformation of the transporter and its solute binding affinity

• Changes in the binding site affinity for a transported solute are produced by phosphorylation and dephosphorylation of the Na+/K+-ATPase

• How it works (using Na+/K+-ATPase as an example):

  • 1. Na+ binds to a transporter outside the cell (where the Na+ concentration is high) allowing glucose or amino acid to bind to the same carrier (atp is used, bound to transporter)

  • 2. Through a change in configuration, the transporter “delivers” both Na+ and glucose or amino acid into the cell (configuration changes when atp is phosphorylized, used)

  • 3. The transporter then reverts to its original configuration, and the Na+ is extruded from the cell by the Na+/K+ -ATPase (when the attached phospho group leaves the shape reverts to original)

    • note: He writes it in this order where Na+ leaves somehow at the end after the transporter reverts back to its original position, but both his diagram and previous classes (biol 112, gr 12) say that Na+ stays in the cell after it is delivered stays in the cell and detaches with glucose or amino acid

• other examples of transporters:

  • Ca2+-ATPase

    • Maintain low intracellular Ca2+ levels

  • H+-ATPase, Vacuolar-type H+-ATPase (V-ATPase)

    • Maintain low lysosomal pH

  • H+/ K+- ATPase

    • Acidification of the stomach

      
      

Secondary Active Transport

• the movement of Na+ down its concentration gradient is coupled to the transport of another solute molecule (ion, glucose, amino acid)

  • uphill against its concentration gradient

• uses the energy stored in the electrochemical gradient to move both the Na+ and the transported solute

• The creation and maintenance of the electrochemical gradient depends on primary active transport

Symport/Cotransport

• when solute X is transported in the same direction as Na+ in Secondary Active Transport

• ex:

  • Na+/HCO3− cotransporter

  • (NBC) Na+/amino acid cotransporter (NAcT)

  • Na+/glucose cotransporter (SGLT)

Antipor/Countertransport/Exchange

• when solute X is transported in the opposite direction to Na+.

• ex:

  • Na+/H+ exchanger (NHE)

  • Na+/Ca2+ exchanger (NCX)

Endocytosis

• Active transport mechanism (energy-dependent) involving participation of the cell membrane itself

• the cell membrane invaginates (opens a pore to let outside solute in) and pinches off to form a vesicle

• 3 types:

  • Pinocytosis

    • also known as fluid endocytosis

  • Phagocytosis

    • the process by which cells bind and internalize particulate matter (>0.75 μm, solids, particles) such as small-sized dust particles, cell debris and microorganisms

  • Receptor-mediated Endocytosis

    • molecules in the extracellular fluid (ligands) bind with high affinity to specific protein receptors

      on the plasma membrane

Exocytosis

• Active transport mechanism (energy-dependent) involving participation of the cell membrane itself

• the process of moving material from the inside to the outside of the cell

• 2 Types

  • Constitutive Exocytosis

    • Non-regulated

    • replaces plasma membrane

    • delivers proteins to the cell membrane

    • secretes collagen and other substances from the cell.

  • Regulated Exocytosis

    • triggered by extracellular signals and the increase ofcytosolic Ca2+

    • secretes of hormones, digestive enzymes, and neurotransmitters

Pinocytosis

• also known as fluid endocytosis

• an endocytotic vesicle engulfs the extracellular fluid including whatever solutes are in it

• nonspecific and constitutive (always active)

• vesicles travel into the cytoplasm and fuse with other vesicles such as endosomes or lysosomes

Phagocytosis

• the process by which cells bind and internalize particulate matter (>0.75 μm, solids, particles) such as small-sized dust particles, cell debris and microorganisms

• specific and triggered

• Extensions of the cell membrane called pseudopodia fold around the particle and fully engulf it

• The pseudopodia fuse to form large vesicles, called phagosomes, that pinch off the membrane

• Phagosomes migrate to and fuse with lysosomes where the contents of the phagosome are degraded

• Defends against infection and scavenge senescent and dead cells (macrophages, neutrophils and dendritic cells)

Receptor-Mediated Endocytosis

• molecules in the extracellular fluid (ligands) bind with high affinity to specific protein receptors

  on the plasma membrane

• 2 Types:

  • Clathrin-dependent

    • When the ligand binds the receptor undergoes conformational change and clathrin is recruited to the plasma membrane

  • Potocytosis

    • the process by which small molecules are sequestered and transported by tiny vesicles called caveolae

    • clathrin-independent

How does the LDL receptor work with cholesterol?

• Cholesterol is transported in the blood in low-density lipoprotein (LDL) particles (vesicles).

• The lipoprotein particles bind to PM LDL receptors

• Endocytosis occurs right after

• This a clathrin-dependent receptor-mediated endocytosis

• The endocytized vesicles fuses with early endosomes where LDL dissociates from the receptor protein

• The LDL continues to late endosomes and then lysosomes where cholesterol is released

Clathrin Dependent Receptor-Mediated Endocytosis

• When the ligand binds the receptor undergoes conformational change and clathrin is recruited to the plasma membrane

• Adaptor proteins link the ligand-receptor to the clathrin

• The complex forms a cagelike structure that leads to the aggregation of ligand bound receptors

• A clathrin coated pit is formed which then invaginates and forms a “clathrin-coated vesicle”

• Once the vesicle pinches off it sheds the clathrin coat and vesicles can fuse with the membrane of cellular organelles such as endosomes and lysosomes

• Or, they can sometimes fuse with the membrane on another side of the cell (transcytosis)

• Receptors and clathrin protein are recycled back to the cell membrane

• ex: LDL receptor

Potocytosis/ Clauveola-Dependent Receptor-Mediated Endocytosis

• the process by which small molecules are sequestered and transported by tiny vesicles called caveolae

• clathrin-independent

• The caveolae concentrate molecules within their lumen by releasing receptor-bound species, using enzymes to convert or detach extracellular substances from soluble carriers

• Caveolae can deliver their contents directly into the cell cytoplasm, to the endoplasmic reticulum (ER) and other organelles or to the plasma membrane on the opposite side of the cell (transcytosis).

• suggested they’re used in consumption of low molecular weight molecules such as vitamins

Osmosis

• the net diffusion of H2O across a semipermeable membrane (i.e., permeable to solvent, but not to all solute)

• Note: Water diffuses though cell membranes via water permeable channels called aquaporins

Osmotic Pressure

• The pressure required to prevent the movement of water across a semi-permeable membrane

• equal to the difference in the hydrostatic pressures of the two solutions across the membrane

• proportional to osmolarity (Osm)

• Calculated by using the Van’t Hoff Equation (π = MRT)

  • M (Osmolarity)

  • R (Gas constant) 0.0821 L ! atm/mol * K

  • T (Temperature) Absolute temperature in Kelvin

Osmolarity (Osm)

• the total solute concentration of a solution

• 1 mol of solute particles = 1 osmol

• Ex:

  • 1 mol glucose = 1 osmol of solute

    1 mol NaCl = 1 mol Na+ + 1 mol Cl- = 2 mol = 2 osmol

  • 1 mol glucose/L = 1 osmol/L = 1 Osm solution

• proportional to osmotic pressure

• Calculate by:

  • First find the Molarity (concentration)

  • Determine Osmolarity (account for each ion that would show in aqueous solution)

    • ex

    • 0.15 M NaCl solution = 0.15 moles/L Na+ + 0.15 moles/L Cl-

      • = 0.15 osmol/L + 0.15 osmol/L = 0.30 osmol

      • = 0.30 osmol/L H2O = 0.30 Osm = 300 mOsm (miliosmol)

Isosomotic

• Solutions that have the same osmolarity (concentration

  of osmotically active particles) as normal extracellular or

  intracellular solution

• must be 300 mOsm or 0.30 Osm

Hypoosmotic

• Solutions which have an osmolarity lower than 300 mOsm

• Lower osmolarity than normal extracellular or intracellular solution

Hyperosmotic

• Solutions which have an osmolarity greater than 300 mOsm

• Higher osmolarity than normal extracellular or intracellular solution

Extracellular Na+ behaves as a nonpenetrating solute because . . .

• the Na+ that moves into the cell is pumped out by the Na-K ATPase

What kind of particles are effective in exerting sustained osmotic pressure?

• nonpenetrating molecules that cannot cross the membrane

Isotonic

• =300 mOsm

• extracellular solution has a concentration of 300 mOsm of nonpenetrating solute particles

• no net shift of water

Hypotonic

• <300 mOsm

• extracellular solution has a concentration of nonpenetrating solute particles less than 300 mOsm,

• water enters the cell

• cell swells

Hypertonic

• >300 mOsm

• extracellular solution has a concentration of nonpenetrating solute particles greater than 300 mOsm

• water leaves the cell

• the cell shrinks

Capillaries

• An adult has ~40 km

• contains ~5% of total circulating blood

• ~1mm long

• inner diameter ~8 μm

Capillary Wall

• A single layer of flattened endothelial cells and a supporting basement membrane

• Means of transportation:

  • 1, 2- (labeled for attached diagram) DIFFUSION

    • most important means of transport

    • also occurs through water filled channels (intercellular clefts and fused vesical channels)

  • 3. Transcytosis

    • Endocytosis on the luminal side followed migration of the vesicle across the cell and then exocytosis on the interstitial side

    • Simplifies: Endocytosis on one end of the cell membrane, then exocytosis on the opposing end

  • 4. BULK FLOW

    • distributes the extracellular fluid volume between the plasma and ISF

    • Magnitude of bulk flow is proportional to the hydrostatic pressure difference between the plasma and the ISF

• acts as a filter that permits protein free plasma to move from capillaries to the ISF (through BULK FLOW)

Blood

• a highly dynamic tissue, part of the cardiovascular system

• supporter of life – “lifeblood”

• associated with emotions – “bad blood”

• reflective of relationship – “blood brothers”

• Ancient Chinese Medicine –blood flow linked to energy flow

• Medieval Western Medicine – blood inhabited by good and evil spirits

• Modern Time – blood as a carrier of disease

• Ancient Greece – bleeding as treatment for disease

• Functions:

  • Transport

    • Nutrients

    • Respiratory Gasses

    • Wastes

    • Hormones

    • Temperature Regulation

  • Acid-Base Balance

    • Normal pH range 7.35 - 7.45

  • Protection

    • White Blood Cells (WBCs)

    • Plasma Proteins

• Contains:

  • After centrifuge: 55% plasma (ECF) 45% red blood cells (ICF, also called erythrocytes) and very thin BUFFY LAYER (white blood cells + platelets)

• accounts for ~7-8% of Body Mass

NORMOVOLEMIA

normal blood volume, “norm”

HYPOVOLEMIA

lower than normal blood volume, “hypo”

HYPERVOLEMIA

Higher than normal blood volume, “hyper”

Composition of Plasma

• Similar to ISF but with proteins

• >90% water

• Ions: Na+, K+, (Ca++, Mg++), Cl-, HCO3-, (PO4--)

May be approximated by physiological saline 0.9 % NaCl (= 300 mOsm, 6.7 atmospheres or ~ 5100 mm Hg) since most of it is Na+ and Cl-)

• Nutrients, Respiratory Gasses, Wastes

  • Glucose, Amino Acids, Lipids, O2, CO2, Urea, Lactic Acid

• Proteins (colloids) = 7 %

  • Albumins

  • Globulins

  • Fibrinogen

* Proteins are ONLY FOUND IN PLASMA, NOT in ISF

Electrophoresis

• a method of separating plasma proteins

• fractionation method based on movement of charged particles along a voltage gradient

• The rate of migration is influenced by the number and distribution of charges and by the molecular weight, MW, of each protein

• Each protein migrates at its own characteristic rate

What is the origin of plasma proteins

• Liver

  • Albumin

  • α1, α2, β Globulins

  • Fibrinogen

• Lymphoid Tissue - Gamma (Y) Globulin

• Since most in liver, if liver is diseased plasma protein levels decrease

Plasma Protein Properties + Importance

• Albumin is most abundant (highest []) and the smallest

• oval

• Fibrinogen is the largest and least abundant (lowest [])

  • elongated thin oval

• Globulin has the most variety in shape and size

• They play a major role in determining the distribution of fluid between the plasma and the ISF compartments by controlling transcapillary dynamics

How is the different bodily fluids distributed in the body (fractions) and what membranes separate them?

• ICF - 2/3

• ECF - 1/3

  • Of that 1/3:

    • ISF - 3/4

    • Plasma - 1/4

• ICF and ECF separated by cell membrane (relatively impermeable to ions)

• ISF and Plasma separated by capillary wall (freely permeable to H2O and ions but impermeable to proteins)

What can or cannot contribute to the effective Osmotic Pressure of a solution?

• Diffusible solutes do NOT contribute, because they become equally distributed on the 2 sides of the membrane

• Plasma Proteins are Non-Diffusible therefore, they can exert an osmotic effect

• This effect is known as the Colloidal Osmotic (Oncotic) Pressure (C.O.P.) of Plasma = 25 mm Hg

• For a net flow of water between compartments (ISF and Plasma) there must be a difference in osmotic pressure

  • Hence:

    • If the COP increases, more water will flow into plasma

    • If the COP decreases, more water will flow into ISF

• PLS LOOK AT DIAGRAM IT HELPS

Transport across the Capillary Wall

• two major forms of fluid transport across – osmotic flow and filtration

• 1. The C.O.P. of plasma (osmotic flow)

  • determines how much water will flow into or out of capillaries

  • plasma proteins, tend to “pull in” or retain fluid inside the capillaries

• 2. Filtration / Bulk Flow / Filtration

  • BULK FLOW – flow of molecules subjected to a pressure difference

    • Magnitude of bulk flow α hydrostatic pressure difference

  • FILTRATION = bulk flow across a porous membrane which acts as a “sieve” (strainer) withholding some particle

  • because fluid in the blood vessel is under pressure, it tends to “push out” fluid from the capillaries into ISF

• 1 AND 2 TOGETHER ARE CALLED THE STARLING FORCES

• The balance between Colloidal Osmotic Pressure and Hydrostatic Pressure will determine how water moves between these two compartment

Diffusion VS Starling Forces

• DIFFUSION is responsible for the exchange of nutrients, gases, and wastes across the capillary wall

• STARLING FORCES determine the distribution of ECF volume, the movement of water between the Plasma and ISF

Capillary Exchanges

• Nutrients, wastes, O2, CO2 move by simple diffusion

• Starling’s Transcapillary Dynamics

  • Exchanges filtration and absorption take place along the whole length of the capillary bed not just at the 2 ends

  • determines the distribution of ECF volume between Plasma and ISF

  • Filtration – tends to “push fluid out” from inside the capillaries

  • Osmotic Flow – tends to “pull fluid into” or retain fluid in the capillaries

• Only ~90% of the fluid filtered out of the capillaries is reabsorbed into the capillaries ~ 10% is drained from the tissues by the lymphatic vessel

Lymphatic System + Vessels

• System:

  • A network of blind-ended terminal tubules

  • which coalesce to form larger lymphatic vessels

  • which converge to form large lymphatic ducts,

  • which drain into the large veins in the chest

• Vessels

  • The walls are made up of a single layer of endothelial cells

  • highly permeable to all ISF constituents (including proteins which may have leaked into the ISF from the plasma)

Which proteins contribute the most to C.O.P.?

• The osmotic pressure of a solution depends on the NUMBER of osmotically active particles/unit volume

• NOT their configuration, size, or charge

• Each protein fraction exerts an osmotic pressure which is

  • directly related to its [] in the plasma

  • inversely related to the Molecular Weight of that protein

• Hence need a light and abundant protein - ALBUMIN

• Diagram gives metaphor to help

Daily Lymphatic & Blood Flow Volumes

• Total Blood Flow 6,000L

• Volume filtered into ISF 20L

• Volume returned by absorption 17L

• Volume returned by lymph drainage 3L

Edema

• accumulation of excess fluid in the interstitial spaces

• Caused by decreased venous fluid return (less fluid returned to veins from lymphatic drainage and absorption)

• Conditions that can lead to it:

  • Increased Hydrostatic Pressure

  • Decreased Plasma Protein (lower C.O.P.)

    • In extreme cases:

    • due to failure to synthesize plasma proteins e.g., Liver disease (since they are made there)

    • or severe protein malnutrition

      • can lead to swelling of the abdomen (Kwashiorkor)

  • Increased Capillary Permeability

    • Normally, there is very little protein in ISF.

    • If the capillary wall becomes more permeable, some plasma proteins escape into the ISF where they can exert oncotic pressure (colloid osmotic pressure), this pulls water out of the capillaries

  • Obstruction of Lymphatic Drainage

    • Extreme case: Elephantiasis. blockage of lymphatic drainage resulting from parasite infestation (Filaria nematode)

• Typical Symptoms: swollen ankles and feet

Roles of Plasma Proteins

• Determine the distribution of fluid between the plasma and the ISF compartments

  • the Starling Forces control transcapillary dynamics

• Contribute to the viscosity of plasma

  • Viscosity contributes to blood pressure

• Contribute to the buffering power of plasma

  • Normal pH range ~7.4

• Fibrinogen and some globulins are essential to clotting

• Gamma (γ) - globulins (Immunoglobulins/Antibodies) provide specific resistance to infection

• Albumin and some globulins act as carriers for lipids, minerals, hormones

What are the different cells in the blood?

• Red Blood Cells (Erythrocytes)

  • Diameter: 7.2 μm

  • Lifespan: 120 days

  • Number: 5 x 106/μL

• Platelets (Thrombocytes)

  • Diameter: 2-3 μm

  • Lifespan: 7-8 days

  • Number: 250,000-400,000/μL

• White Blood Cells (Leukocytes)

  • Diameter: 10-18 μm

  • Lifespan: hours-years

  • Number: 8,000-10,000/μL

• Note: Slide shows them coming from the Blood Progenitors, this is just their “ancestor” its a “blood ancestor” not a specific term you need to know

Hematopoiesis

• The process through which all blood cells are derived from a common, multipotential (pluripotential) hematopoietic stem cell in the bone marrow

• is a general pattern

• Examples for different cells:

  • Erythropoiesis is the production of Red Blood Cells (Erythrocytes)

  • Thrombopoiesis production of Platelets (Thrombocytes)

  • Leukopoiesis production of White Blood Cells (Leukocytes)

• How it works (according to diagram)

  • An inducer stimulates a Pluripotential Multipotential Stem Cell to self replicate (Division)

  • The self-replicating stem cell becomes a committed stem cell (committed to becoming a specific type of cell, from the options above, think about it like committing to a career path) (Differentiation)

  • The committed stem cell interacts with a stimulant and goes through the specific process (from options listed above) of production to become the specific cell type they have committed to

Cytokines

• substances (proteins or peptides) which are released by one cell and affect the growth, development, and activity of another cell

• those that influence the proliferation and differentiation of blood cell precursors are known as Hematopoietic Growth Factors (HGFs)

Sites of Hematopoiesis

• Pre-natal:

  • Yolk Sac til 3 months

  • Liver & Spleen from 1 month to 9 month

• Post-Natal (mainly, starts off in prenatal at ~4 months): Axial Skeleton

  • Flat bones of skull

  • Shoulder blades

  • Sternum

  • Vertebrae

  • Ribs

  • Pelvis

• Proximal epiphyses of long bones: over time (as shown in diagram) sites move to the epiphyses (long end, cap area) of long bones (femur, those in the arms, etc, not ribs!)

  • ex: moves to the top joint bone area of femur

Red Blood Cells (RBC)

• FUNCTION: facilitate transport of respiratory gases

• “biconcave” disk shape due to the presence of “spectrin” (a fibrous protein, forms a flexible network linked to cell membrane)

• Shape is advantageous

  • Maximal surface area and minimal diffusion distance

    • Increases the efficiency of O2 and CO2 diffusion

  • High degree of flexibility

    • Allows them to squeeze through narrow capillaries

• Cell Size

  • Normocytic (normal size)

  • Microcytic (smaller than normal)

  • Macrocytic (larger than normal)

• Cell Shape

  • Sickle Cell (looks like a sickle, half moon when its not supposed to

  • Spherocyte (completely circular no ovality or dip, also an illness, not normal)

• Rate of production = Rate of destruction ~2 x 106/second

• Numbers (MvsF)

  • determined by the O2 requirements by the body and the O2 availability

  • Increases with decreased O2 (higher altitudes)

  • Males: 5.1 – 5.5 x 106/μL (more than women)

  • Females: 4.5 - 4.8 x 106/μL

• Components:

  • contain no subcellular organelles (No Nucleus, No Mitochondria)

  • Glycolytic Enzymes to generate energy anaerobically

  • Carbonic Anhydrase for CO2 Transport

    • Converts CO2 to bicarbonate which is easier to transport

  • 33% deoxyhemoglobin (Hb), called hemoglobin when O2 is actively being carried (HbO2)

    • Each molecule of Hb can bind a maximum of 4 O2 molecules

Hemoglobin

• 200-300 x 106 molecules/RBC

• In lungs, becomes saturated with O2

  • blood appears bright red

• In tissues, O2 dissociates (no longer has O2)

  • blood appears dark red

• LOOK AT BOTH ATTACHED DIAGRAMS FOR DETAILS IN STRUCTURE + COMPONENTS

• Functions

  • Transport of O2 (Hb + O2 reversibly reacts to produce HbO2)

  • Transport of CO2

  • Acts as a buffer

• Despite O2 solubility being super low in plasma, due to Hb in RBC O2 solubility in overall Blood is very high ( 0.3 ml O2/100 ml plasma vs 20 ml O2/100 ml blood)

• Values in Blood (MvsF)

  • Males: 16 g/100 ml blood

  • Females: 14 g/100 ml blood

  • When Hb is fully saturated with O2 each gram of Hb holds 1.34 ml O2

    • Therefore, the O2 carrying capacity of blood is: 20 ml O2/100 ml blood (15 grams x 1.34 ml = 20)

Why have Hb inside the red blood cell rather than dissolved in plasma?

• Increases Plasma Viscosity (hard for the heart to pump, tougher to diffuse in)

• Plasma C.O.P.

  • adding yet another non-diffusing substance would increase osmotic pressure higher than normal, too much flow of water into veins

• Would lose them via the kidney