Lecture 6 Transcapillary Exchange

From Iusmphysiology

(Difference between revisions)
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*stopped here on 01/25/11 at 12PM.
*stopped here on 01/25/11 at 12PM.
 +
*started here on 01/27/11 at 8AM.
===II. The rules for capillary exchange of solutes===
===II. The rules for capillary exchange of solutes===
-
*A.  Concentration difference from blood plasma to interstitial fluid is the energy source for diffusion
+
*Concentration difference from blood plasma to interstitial fluid is the energy source for diffusion
 +
*Translating molar concentrations into equivalents of energy is tricky.
 +
**A 1 mM difference across a capillary, there is a force of about 17 mmHg, about the force of a quarter in your palm.  Not much energy.
 +
*Most concentration differences across capillaries are low
 +
**1-50 microM, really tiny forces.
 +
**So very small forces drive these solutes across the capillary
 +
*What gets moved:
 +
**Glucose (5 mM, lots of it)
 +
**aas (40-100 mM)
-
    For each 1 mM difference in 
+
====Area====
-
  concentration, energy equivalent to 17 mmHg
+
*Caps have lots of surface area; the more area the more exchange.
-
      MOST CONCENTRATION DIFFERENCES ABOUT 1-50 µ.  
+
*Area is regulated by changing how many caps have perfusion at a given moment.
-
      Glucose 5 mM in plasma --- interstitial fluid concentration???
+
**30-60% are in use at a given time
-
  Js = solute transferred per minute
+
**Very dinamic
-
  Cp = Plasma concentration
+
**Most used most of the time in brain and heart
-
  Ct = Tissue concentration
+
*Lipid soluble stuff can use the entire area as long as their is fresh plasma
-
+
*Water solubles can only go through pores, but htat's still lots.
-
Js ~ (Ct - Cp) 
+
*We could change capillary length to change SA
-
 
+
**Doesn't happen much
 +
**These are epithelial cells so they don't change diamter or length unless they are unheathtl
 +
*Number of caps can change
 +
**Doesn't happen much, though.
 +
*Number of caps used
 +
**Yes, epi, norepi can change this
 +
*Grow more caps
 +
**Yes, can start new caps in just one day
 +
**In obesity / diabetes, caps die, same with other diseases.
-
capillary structure cartoon
 
-
  B.  Surface area available  = A
+
*Calculating how diffusion changes
-
  (1). Lipid soluble - virtually entire capillary surface area
+
**Js = the amount of stuff moved
-
  (2).  Water soluble - only pore surface area
+
**Cp = concentratin in the plasma
-
  (3).  Surface area influenced by
+
**CP = concentration in the tissue
-
    a. Surface area of a capillary: capillary diameter and length changes?
+
**A = area.
-
    b.  Number of perfused capillaries:
+
**JS = A * (Cp - Ct)
-
      1. Active control perfuse different percentage of                  available capillaries
+
-
      2.  Grow new capillaries or lose capillaries by normal or disease
+
-
        processes 
+
-
Js ~  A (Ct - Cp)  
+
-
capillaries three for area
 
-
capillary structure cartoon
 
-
capillaries pores enlarged
+
====Permeability====
-
C.  Permeability of molecule to the capillary wall structure  P
+
*Lipids have no problems
-
  (1).  Lipid soluble materials are hundreds to thousands times more         permeable than water soluble materials
+
**Hundreds and thougsands of times more permeable
-
  (2).  Permeability for water soluble materials is regulated by tightness of     junctions between endothelial cells  
+
**Very easy to get them where they belong
-
  a.  Histamine can cause endothelial cells to “contract” and widen        “pores”   
+
*Water soluble:
-
  b.  Hypoxia and anoxia increase permeability either by damage or cell       shape changes  
+
**depends on tightness of jxns between endothelial cells
-
+
***This is usually fixed
-
P = moles / minute / area
+
**We can play with it, though
-
+
***Histamine:
-
Js ~  P A (Cp - Ct)
+
****Vessels dilate, more pressure in caps, more flow in caps
-
+
****Endothelial cell actin cytoskeleton changes such that clefts open and more leaks out of the blood into the tissue.
 +
**ischemia
 +
***endothelial cells change shape and lose tight junctions
 +
*Measure permeability in moles / minute / surface area
 +
*Permeability is fixed until:
 +
**Injury
 +
**skeletal muscle working very hard
 +
**underperfused hearts / brains / any vascular bed
 +
====Distance between caps====
 +
*How far apart caps are apart determines how far the molecules have to diffuse and therefore how likely it is that it will get used by a cell.
 +
*The greater the distance, the lower th enet amount of stuff given to the tissue.
 +
*Smaller the distance, the higher the oxygen concentration in the cell.
 +
*Change distance inthe same way we change area:
 +
**grow more caps
 +
**perfuse more caps
-
D.  Distance the molecules must diffuse into the tissue
+
====Regulation====
-
  (1) Primarily determined by the amount of tissue each capillary must serve
+
*Permeability can be increased via hypoxia, cytokines (TNF), and reperfusion injury.
-
  (2) Greatly influenced by the number of capillaries in service and perfused
+
*Cytokines can
-
+
*Reperfusion injury:
-
Js = (P A (Cp - Ct)) / D
+
**Having low blood flow isn't so bad, actually.
 +
**We must avoid reperfusion injury, though.
 +
**Lacking oxygen means ATP is really low and we generate inosine and hypoxanthine.
 +
**The hypoxanthine can react with hypoxanthine dehydrogenase and xanthine oxidase.
 +
**This reaction is ready to go and is waiting for oxygen.
 +
**Oxygen becomes available upon reperfusion.
 +
**Urate is generated and an oxygen radical.
 +
***The radical destroys (oxidizes) whatever it touches next.
 +
**Hydrogen peroxide is also generated which also releases a radical.
 +
***In the presence of Fe, they make hydroxylradicals.
 +
***These can get out of cells easily and therefore tear up cell neighbors and ECM.
 +
**Then cytokines are released and enuts start eating everything up including the microvessels and the tissue cells.
 +
**Then endothelial cells swell and the caps become clogged and leaky.
-
oxygenation by capillaries to sk muscle
+
===Rules for Capillary Exchange of Water===
 +
*We have to have water to generate plasma.
 +
*The capillary membranes are little molecular sieves.
 +
*Arteriole and capillary pressure is always pushing stuff out of the microvessels.
 +
**Mean arteriole pressure is around 90 to 100.
 +
**Cap pressure is usually around 15-35.
 +
***Higher within range in skeletal muscle.
 +
***Lower in intestine mucosa.
 +
*This is enough to push fluid out of the capillary through interstitial spaces between endothelial cells.
 +
*Standing increases cap pressures to high levels in the legs.
 +
**This can cause swelling.
 +
**We don't notice much because our hormones are good and our vavles are good.
 +
*Two forces oppose this edema:
 +
**Albumin
 +
**Globular proteins made by the liver.
 +
***Globulins
 +
*These two exert an osmotic pressure; they hold water in the plasma.
 +
**They can generate a pressure around 25, near to the fluid pressure of the cap (hydrostatic pressure).
 +
**This balance keeps water from leaving the blood.
 +
**Albumin proivdes 60% of this pressure.
 +
*Because there is a low concentration of big proteins in the ECF, there is about 3-6 mmHg osmotic pressure pulling water out into the ECF.
 +
**Albumin leaks into the tissue a little bit, too.
 +
**Then the molecule will pull water from the blood into th ECF.
 +
*There is also a pressure to pull water out of the blood called "tissue pressure".
 +
**This provides a force pulling water out.
 +
**This pressure is generated by a negative pressure in the ECF.
 +
**So as these many liters of water rush by in the caps, the ECF wants some of that water action.
-
E.
 
-
Rules for regulation of capillary permeabilty:  Primarily an issue of  decreasing the contact proteins between adjacent endothelial cells.  1.  Common causes of increased capillary permeability    a.  Hypoxia – inadequate blood flow provides too little oxygen for endothelial cells to maintain contacts between cells.  Fortunately, endothelial cells tolerate hypoxia and even anoxia quite well    b.  Reperfusion injury – formation of oxygen radicals when blood flow restored to a tissue. 
 
-
 
+
*stopped here at around 17:55.
-
 
+
-
 
+
-
 
+
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                                                      MICROVASCULAR CELL INJURY
+
   
   
-
LACK OF OXYGEN      OXIDANTS      PROTEASES
 
-
 
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ATP                                                          ACTIVATE NEUTROPHILS
 
-
 
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ADP                                                            INFLAMMATORY CYTOKINES
 
-
                                XANTHINE
 
-
AMP                  DEHYDROGENASE        TISSUE DAMAGE
 
-
 
-
ADENOSINE    -OH*
 
-
 
-
INOSINE  XANTHINE    Fe+3
 
-
                                    OXIDASE
 
-
HYPOXANTHINE                                    URATE + O2* + H2O2
 
-
                                                  REPERFUSION
 
-
                                                                OXYGEN
 
-
 
-
             
 
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+
  2.  Attempts to reabsorb water from tissue spaces  
-
 
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III. Rules for Capillary Exchange of Water
+
-
   
+
-
A. Capillary blood pressure attempts to push water out of capillary      through pores
+
-
  1.  Pc = Capillary Pressures are 15-35  mmHg.
+
-
  Intestinal mucosa 14-17 mmHg
+
-
  Brain  20-25 mmHg
+
-
  Muscle  23-30 mmHg
+
-
+
-
  2.  When standing, capillary
+
-
  pressures in lower body could be 80-150 mmHg
+
-
 
+
-
capillary albumin and Pcapillary
+
-
 
+
-
B. Plasma albumin and globulin large proteins resist having water removed from its sphere of influence: 
+
-
  1.  Plasma Oncotic Pressure = Plasma Colloidal Osmotic Pressure = COPp 
+
-
  About 22-27 mmHg is normal
+
-
+
-
  2.  Attempts to reabsorb water from tissue spaces  
+
   
   
   3.  Albumin accounts for about 60% of the oncotic pressure  
   3.  Albumin accounts for about 60% of the oncotic pressure  

Revision as of 01:08, 28 January 2011


  • test questions will come from objectives and clinical examples.

Contents

Capillaries

Objectives

  • How is movement through the capillary wall much different for water soluble versus lipid soluble molecules?
  • Be able to describe a typical small water filled pore in the capillary wall in terms of its size, contents, and number of pores over the capillary surface and the role of the glycocalyx surface proteins.
  • How does the concentration difference of solutes across the capillary wall and the surface area of capillaries influence the rate of exchange of solutes?
  • What are two ways the capillary permeability can be pathologically increased?
  • How would the number of capillaries in an area of tissue and their distance apart influence the concentration of a solute within the tissue?
  • What are the two primary sources of force or pressure which determine the amount of water filtered or reabsorbed across capillaries?
  • How do tissue hydrostatic pressure and tissue oncotic pressure normally influence the amount of water filtered or reabsorbed across capillaries?
  • What does the term edema mean and how is edema generated?
  • Be able to describe how a lymph vessel uses external compression or contraction of its endothelial cells to move water from the interstitial spaces.

The capillaries

  • Easy for lipids to go right through the endothelial cells.
  • Huge surface areas for exchange.
    • 1 gram of tissue has over 1000 square feet of SA.
  • Lungs have even higher surface area
  • Skeletal muscle caps have lowest SA for exchange.
  • What gets across:
    • Gasses
    • FAs, TAG
    • cholesterol-based hormones

Image

  • There are tight jxns to link cells together so there is no leakage.
  • There are also lots of invaginations.
  • There are vacules
    • Form on lumen of capilary and move outward (mostly).
    • These are useful for things that can't get across the capillary.

Higher mag

  • Glycocalyx sticks off endothelial cell into the plasma
    • polysacc strands
  • The tight jxns are longitudinally long between endothelial cells.
    • There are small spots where they break so that things like glucose can get through.
  • Small pore system:
    • lets 3-4 nanometer things thorugh: glucose, mannose, arginine, etc.
      • Na and K just go through.
    • Billions and billions of pores.
    • Don't take up much of the SA.

2. Materials leaving the capillary blood have many barriers to pass before passing between adjacent endothelial cells through physical holes known as pores.

  • Glycocalyx is negatively charged as are most molecules int he body.
    • So most things are repelled.
  • The glycocalyx can be damaged.
    • This can increase permeability.
  • a. Glycocalyx is proteineous structure of glycosaminoglycans, proteoglycans, and glycolipids
  • b. Glycocalyx is negatively charged and repels negatively charged molecules
  • c. Glyocalyx acts as a molecular sized filter to limit larger molecules reaching the physical pores between cells
  • d. The physical pores are generally very small and would limit even most small proteins


3. What is a capillary pore

  • a. Cleft between adjacent capillary endothelial cells
  • b. Pore is not a straight tube but circuitous due to tight junctions
  • c. Pore filled with fiber matrix mucopolysaccharide gel
    • This generates an electrical barrier
    • (1). Acts as partial barrier
    • (2). Electrical charge (-) acts as barrier
  • d. Basement membrane
    • (1). Dense collagen and elastin material act as a filter for large molecules
    • (2). May be barrier to lipid soluble materials: WATER FILLED BARRIER??
  • e. The single greatest barrier is the extensive system of tight junctions between adjacent cells but the glycocalyx is a close second.
    • (1). Areas between tight junctions are the water filled pores
    • (2). In the brain and testes, tight junctions encircle the endothelial cells.

4. Endocytosis of macromolecules: caveolae form vesicles that move from the blood to tissue side of the endothelial cell

  • A. Energy requiring system: hypoxia drastically decreases vesicle formation
  • B. A major molecule moved by endocytosis is albumin and all the many materials attached to albumin.
    • 1. albumin binding glycoprotein
      • a. receptor type protein to attach albumin
      • b. located predominately in caveolae
      • c. binds or associates with caveolin-1 when albumin attaches
      • d. vesicle forms, moves across endothelial cell, releases albumin
    • 2. Many hormones and fatty acids are associated with albumin
      • a. potential pathway for selective, controllable transport of hormones??
      • b. diseases that influence caveolae formation likely impair this process - for example, mice with no caveoli have minimal albumin in lymph


  • stopped here on 01/25/11 at 12PM.
  • started here on 01/27/11 at 8AM.


II. The rules for capillary exchange of solutes

  • Concentration difference from blood plasma to interstitial fluid is the energy source for diffusion
  • Translating molar concentrations into equivalents of energy is tricky.
    • A 1 mM difference across a capillary, there is a force of about 17 mmHg, about the force of a quarter in your palm. Not much energy.
  • Most concentration differences across capillaries are low
    • 1-50 microM, really tiny forces.
    • So very small forces drive these solutes across the capillary
  • What gets moved:
    • Glucose (5 mM, lots of it)
    • aas (40-100 mM)

Area

  • Caps have lots of surface area; the more area the more exchange.
  • Area is regulated by changing how many caps have perfusion at a given moment.
    • 30-60% are in use at a given time
    • Very dinamic
    • Most used most of the time in brain and heart
  • Lipid soluble stuff can use the entire area as long as their is fresh plasma
  • Water solubles can only go through pores, but htat's still lots.
  • We could change capillary length to change SA
    • Doesn't happen much
    • These are epithelial cells so they don't change diamter or length unless they are unheathtl
  • Number of caps can change
    • Doesn't happen much, though.
  • Number of caps used
    • Yes, epi, norepi can change this
  • Grow more caps
    • Yes, can start new caps in just one day
    • In obesity / diabetes, caps die, same with other diseases.


  • Calculating how diffusion changes
    • Js = the amount of stuff moved
    • Cp = concentratin in the plasma
    • CP = concentration in the tissue
    • A = area.
    • JS = A * (Cp - Ct)


Permeability

  • Lipids have no problems
    • Hundreds and thougsands of times more permeable
    • Very easy to get them where they belong
  • Water soluble:
    • depends on tightness of jxns between endothelial cells
      • This is usually fixed
    • We can play with it, though
      • Histamine:
        • Vessels dilate, more pressure in caps, more flow in caps
        • Endothelial cell actin cytoskeleton changes such that clefts open and more leaks out of the blood into the tissue.
    • ischemia
      • endothelial cells change shape and lose tight junctions
  • Measure permeability in moles / minute / surface area
  • Permeability is fixed until:
    • Injury
    • skeletal muscle working very hard
    • underperfused hearts / brains / any vascular bed

Distance between caps

  • How far apart caps are apart determines how far the molecules have to diffuse and therefore how likely it is that it will get used by a cell.
  • The greater the distance, the lower th enet amount of stuff given to the tissue.
  • Smaller the distance, the higher the oxygen concentration in the cell.
  • Change distance inthe same way we change area:
    • grow more caps
    • perfuse more caps

Regulation

  • Permeability can be increased via hypoxia, cytokines (TNF), and reperfusion injury.
  • Cytokines can
  • Reperfusion injury:
    • Having low blood flow isn't so bad, actually.
    • We must avoid reperfusion injury, though.
    • Lacking oxygen means ATP is really low and we generate inosine and hypoxanthine.
    • The hypoxanthine can react with hypoxanthine dehydrogenase and xanthine oxidase.
    • This reaction is ready to go and is waiting for oxygen.
    • Oxygen becomes available upon reperfusion.
    • Urate is generated and an oxygen radical.
      • The radical destroys (oxidizes) whatever it touches next.
    • Hydrogen peroxide is also generated which also releases a radical.
      • In the presence of Fe, they make hydroxylradicals.
      • These can get out of cells easily and therefore tear up cell neighbors and ECM.
    • Then cytokines are released and enuts start eating everything up including the microvessels and the tissue cells.
    • Then endothelial cells swell and the caps become clogged and leaky.

Rules for Capillary Exchange of Water

  • We have to have water to generate plasma.
  • The capillary membranes are little molecular sieves.
  • Arteriole and capillary pressure is always pushing stuff out of the microvessels.
    • Mean arteriole pressure is around 90 to 100.
    • Cap pressure is usually around 15-35.
      • Higher within range in skeletal muscle.
      • Lower in intestine mucosa.
  • This is enough to push fluid out of the capillary through interstitial spaces between endothelial cells.
  • Standing increases cap pressures to high levels in the legs.
    • This can cause swelling.
    • We don't notice much because our hormones are good and our vavles are good.
  • Two forces oppose this edema:
    • Albumin
    • Globular proteins made by the liver.
      • Globulins
  • These two exert an osmotic pressure; they hold water in the plasma.
    • They can generate a pressure around 25, near to the fluid pressure of the cap (hydrostatic pressure).
    • This balance keeps water from leaving the blood.
    • Albumin proivdes 60% of this pressure.
  • Because there is a low concentration of big proteins in the ECF, there is about 3-6 mmHg osmotic pressure pulling water out into the ECF.
    • Albumin leaks into the tissue a little bit, too.
    • Then the molecule will pull water from the blood into th ECF.
  • There is also a pressure to pull water out of the blood called "tissue pressure".
    • This provides a force pulling water out.
    • This pressure is generated by a negative pressure in the ECF.
    • So as these many liters of water rush by in the caps, the ECF wants some of that water action.


  • stopped here at around 17:55. 


2.  Attempts to reabsorb water from tissue spaces 

 3.  Albumin accounts for about 60% of the oncotic pressure 
  
 C.  A small amount of albumin is in the interstitial environment.   
   Interstitial Tissue Oncotic Pressure  
     About 3-6 mmHg is normal and pulls water out of capillary

capillary albumin and Pcapillary

D. Interstitial Tissue hydrostatic pressure Pif 1. In most tissues, slightly negative 2. Varies from assisting filtration if negative to assisting reabsorption if positive 3. Excessive fluid causes edema, or free fluid in the interstitium 4. External compression can be used to prevent filtration or enhance reabsorption of water Support stockings Massage interstitial pressure and volume

capillary hydrostatic vs oncotic forces E. The Starling - Landis Equation for filtration - reabsorption of water 

1.  Filtration forces 
  (Pcap + COPif) 
    2.  Reabsorption forces 
             (COPp - Pif) 
3.  Hydraulic Conductivity - a measure of water permeability per unit area 
   and  per mmHg 
         K =  ml/min/area/mmHg


IV. Idealized concept of the balance of filtration and reabsorption forces across the capillary wall 

1.  Capillary pressure is gradually dissipated by friction of flow along the             capillary 
2.  Plasma oncotic pressure gradually increases along capillary as water is      filtered out 
   3.  Reality - most organs filter plasma water such that in a 24 hour period,      the entire plasma volume is lost at least once.  Also, the capillaries  leak a    mass of albumin equal or greater than the blood mass of albumin

CAPFILTR

V. The Lymphatic System: Tidies up the lost water and protein from the vascular system

Problem: Once albumin or any large protein is out of the capillary, it must be physically carried back to the blood by lymph

Solution: Suck interstitial fluid into the terminal lymphatic vessels

1. Contract or compress lymphatic structures to push lymph through valves to next lymphatic tube

2. Recoil of lymphatic structure generates negative pressure to assist filling of lymph vessel

3. Recoil aided by anchoring filaments on edges of lymphatic endothelial cells


LYMPH

Clinical Example Mrs. Clark was washing her windows when she broke a large glass pane. A glass shard cut her arm and leg. She lost a great deal of blood. A neighbor brought her to the emergency department. The first blood sample before infusion of saline solution indicated a hematocrit of 33% and past records indicate her hematocrit is normally 39-40%. A probable cause of the decrease in hematocrit is A. loss of more red blood cell than plasma volume. B. contraction of the spleen and liver veins to add plasma. C. absorption of interstitial water to dilute the blood. D. decreased excretion of water by the kidneys. E. increased absorption of water from the intestinal contents.



NORMAL VOLUME AND RED CELL MASS

INITIAL BLOOD VOLME LOSS


PHYSIOLOGICAL COMPENSATION


ELECTROLYTE FLUID ADDED




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