CS 2015

Introduction to Vascular Filtration

Christian StrickerAssociate Professor for Systems Physiology

ANUMS/JCSMR - ANU

Christian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Vasfilt.pptx

THE AUSTRALIAN NATIONAL UNIVERSITY

CS 2015

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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↓.

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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.

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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

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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

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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 ↑.

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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.

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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.