CS 2015
Introduction to Vascular Filtration
Christian StrickerAssociate Professor for Systems Physiology
ANUMS/JCSMR - ANU
[email protected]://stricker.jcsmr.anu.edu.au/Vasfilt.pptx
THE AUSTRALIAN NATIONAL UNIVERSITY
CS 2015
CS 2015
Aims
At the end of this lecture students should be able to
• appraise the capillary organisation and specialisation;
• describe the concepts of vascular diffusion and permeation;
• recognise factors determining capillary permeability;
• explain how blood flow determines solute transfer;
• show how Starling “forces” determine fluid exchange; and
• demonstrate how fluid balance in tissue is maintained.
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Contents
• Microcirculation and solute exchange– Organisation and histology of capillaries
– Diffusion and permeation of solute
– Blood flow and solute transfer
• Fluid circulation between plasma, interstice and lymph– Starling’s principle of fluid exchange
• Capillary pressure (Pc) and its regulation
• Colloid osmotic pressure in capillary (πp)
• Interstitial colloid osmotic pressure (πi)
• Interstitial fluid pressure (Pi)
– Tissue fluid balance
– Lymph
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1. Microcirculation and
Solute Exchange
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Organization of Capillaries
• Capillaries account for majority of solute and fluid exchange: 0.5 – 1 mm
long and 4 – 8 µm thick; are “porous” (see later).
• Originate as a module of capillaries from terminal arterioles.
• Reunite to form pericytic venules (~15 µm thick), which have smooth
muscle and are highly water permeable.
• Capillary density highly adapted to tissue function: 300-1000 / mm2 in
muscle; 3’000 in brain and heart; highest in lung → diffusional distance↓.
Le
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Vasomotion
• Capillary flow tends to fluctuate: wax and wave every ~ 15 s (vasomotion).
• Can stop for a while in “closed” capillaries.
• Capillary transit time governs time available for gas and fluid exchange.
• Upstream and downstream regulation (see later in Block 2).
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Three Types of Capillary• Continuous capillary: “standard”
– Lined out by endothelial cells with basal membrane delineating.
– Pericytes between basal membranes.– Transcapillary diffusion distance ~ 0.3 µm.– Features for solute exchange:
• Intercellular cleft• Glycocalyx• Caveola-vesicle system
• Fenestrated capillary: fluid filtration– In kidneys, intestines, synovia, choroid plexus.– Very permeable to water.– Diaphragm of 4 – 5 nm thick (cartwheel); form due
to vascular endothelial growth factor (VEGF).
• Discontinuous capillary: Blood cell turnover – Found in liver, spleen and bone marrow.– Sinusoidal capillaries.– Endothelial gaps over 100 nm wide; discontinuity
in basal membrane.
Levick, 5th ed., 2010
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Vascular Permeability• Vessels with semiperm. membrane
– only parts of solute can permeate (size).
• Permeability [cm/s] = capillary “diffusion” * concentration difference
• Depends on properties of both membrane and solute.– Lipid soluble molecules: O2, CO2, general
anaesthetics.• Transcellular diffusion across endothelial membrane
– Small, lipid-insoluble molecules: salts, glucose, AA, most drugs, etc.• Diffusion through aqueous path (intercell. cleft and
fenestrations; slow permeation due to limited space)
– Large, lipid-insoluble molecules: proteins• Diffuse slowly via large pore system (endothelial gaps,
vesicular transport and transendothelial channels)
• Mostly, specific transporters contribute little to transcapillary exchange.– Exchange via intercellular clefts ≫
transport capacities.
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Fibre Matrix on Endothelial Surface• Glycocalyx covers fenestrae,
endothelium, intercellular junctions:
sieves out plasma protein.– Proteoglycans and sialoglycoproteins bind
to + charged arginines on albumin creating
a 3D sieve reflecting cells and protein.
– Reflection governed primarily by glycocalyx
mesh size, secondarily by negative charge
on proteoglycans.
• Large pore system represented via
multivesicular transcellular channel
(MVC) and vesicles (V).– Caveolins, proteins that interact with
cholesterol and polymerize to build caveolae
forming invaginations for macromolecular
exchange across endothelium.
• Cap. permeability given by number of
open junctions and fenestrae.
Le
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Gu
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Solute Transfer and Blood Flow• Effect of increased blood flow
depends on whether solute
exchange is– flow limited: if diffusion capacity >
solute delivery rate, blood (Ca)
equilibrates with pericapillary fluid
(Ci) before capillary end.
• Transfer rate ~ blood flow (O2
uptake in lung; see later).
– diffusion limited (permeation ↑):
if diffusion capacity < solute
delivery rate, no equilibration
before capillary end (Cv).
• Transfer rate ~ constant (glucose
uptake in exercising muscle).Le
vick
, 5
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d.,
20
10
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2. Fluid Circulation between
Plasma, Interstitium and Lymph
Starling’s principle of fluid exchange
Ultrafiltration across semipermeable membrane
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Starling Principle of Fluid Exchange
• Pressures determine solute flow (simple formulation).• Hydrolic push = Pc – Pi
• Osmotic suction = πp – πi
• Cap. filtration rate ∞ (hydrolic push – osmotic suction)– If hydrolic push > osmotic suction: filtration into interstitium: normal.– If hydrolic push < osmotic suction: fluid absorption from interstice.
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Regulation of PC
• Measured using micropipettes
• Capillary blood pressure (PC):
– Most variable Starling parameter• Vascular resistance (see last lecture)
• Arterial pressure
• Venous pressure
• Gravity (hydrostatic pressure)
• Distance along capillary axis
• Blood pressure ↓ along capillary– at inflow: ~35 torr
– middle: ~25 torr
– at outflow: ~12 torr
• In glomerular capillary ~60 torr.
Levick, 5th ed., 2010
CS 2015
Interstitial Fluid Pressure (Pi)• 3D network of negatively charged biopolymer
fibres, a solid phase and a space-filling solution
of electrolytes and escaped plasma proteins.
• Quite difficult to measure.
• Determined by fluid volume and compliance of
tissue.
• Slightly negative (subatmospheric) in many
tissues: ~ -3 torr (loose subcutaneous tissue,
eye lid).– Holds certain tissues together.
• Slightly positive (~ 6 torr) in tightly encased
tissues (kidney, brain, sclera, around muscle),
but still more negative than capsule pressure.
• In most tissues, Pi is directly exposed to gravity
and, therefore, scales with hydrostatic level
(like Pc).
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Plasma Colloid Osmotic Pressure (πp)
• Colloid osmotic pressure (COP)
caused by impermeable protein in
plasma.
• Is about ~ 28 torr; 80% is caused by
albumin.
• Albumin contributes dyspropor-
tionately (19% protein and 9% Gibb-
Donnan, i.e. net negative charge of
protein attracts Na+).
• Other proteins contribute little (20%).
• Variable as solute is filtered along
capillary.Levick, 5th ed., 2010
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Interstitial COP (πi)• Impossible to measure; is
inferred value.
• Is typically about ⅓ of plasma
COP due to escaped plasma
protein via pores and
transcytosis.– Significant protein content in
interstice.
• Average value ~8 torr.
• Not a fixed quantity; i.e. drops
with capillary filtration rate
(“dilution”).Levick, 5th ed., 2010
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Fluid Balance Along Capillary
• Arterial end: net outward force
(~13 torr) as Pc is high.
• Mid-capillary: net outward force
(0.3 torr).
• Venous end: net inward force
(~7 torr) for absorption as Pc small.
• In most capillaries, amount of
filtration ~ volume returned by
absorption.
• ~90% of fluid is reabsorbed,
remainder in lymphatics
(~ 2 mL/min).
Modified from Boron & Boupaep, 2th ed., 2009
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Lymph
• Formation as filtrate (~2 - 3 L/d); almost like interstitial fluid; protein rich.
• Composition variable in different areas: high fat content in GI tract.
• Specialisation of lymph vessels: anchoring filaments can keep pores
open; valves direct flow.
• Lymph flow increases if Pc ↑, πp ↓, πi ↑, capillary permeability ↑.
• Lymph flow limited by Pi : > Patm vessel diam.↓ (compression) → R ↑.
Gu
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Overview of Microcirculation• 3 convective loops to fluid
circulation:– 1st loop: circulation proper
• 7200 L/d as CO and VR
– 2nd loop: interstitial exchange• Filtered in capillaries: 20 L/d
• Reabsorbed: 16 – 18 L/d (very little
protein)
– 3rd loop: lymph flow• 2 – 4 L/d
• Achieves fluid homeostasis
Modified from Boron & Boupaep, 2th ed., 2009
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Take-Home Messages• Vasomotion determines capillary flow.
• 3 type of different capillaries.
• Vascular permeability << diffusion (100x).
• Vascular permeability different for various solute
properties (lipid soluble, -insoluble, large and small).
• Solute transfer across capillary can be flow- or
diffusion-limited.
• In most capillaries, amount of filtration is about
volume returned by absorption.
• Pi is slightly negative in many tissues.
• Lymph is produced as a consequence of filtration.
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Barbara Jones, a 39 year-old has radiation therapy for breast
cancer of the right axillar region. She is concerned about
peripheral oedema as a consequence of radiation. Which of
the following changes favours filtration at the arteriolar end of
the capillary bed?
A. Decrease in hydrostatic pressure of capillaries.
B. Increase in hydrostatic pressure of capillaries.
C. Decrease in oncotic pressure of interstitium.
D. Increase in oncotic pressure of capillaries.
E. Increase in capillary flow.
CS 2015
That’s it folks…
CS 2015
Barbara Jones, a 39 year-old has radiation therapy for breast
cancer of the right axillar region. She is concerned about
peripheral oedema as a consequence of radiation. Which of
the following changes favours filtration at the arteriolar end of
the capillary bed?
A. Decrease in hydrostatic pressure of capillaries.
B. Increase in hydrostatic pressure of capillaries.
C. Decrease in oncotic pressure of interstitium.
D. Increase in oncotic pressure of capillaries.
E. Increase in capillary flow.
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