Lecture 6 Transcapillary Exchange

From Iusmphysiology

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**This provides a force pulling water out.
**This provides a force pulling water out.
**This pressure is generated by a negative pressure in the ECF.
**This pressure is generated by a negative pressure in the ECF.
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**So as these many liters of water rush by in the caps, the ECF wants some of that water action.
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**The tissue feels firm because of the cells, but the interstitial space is negatively pressurized.
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**So taking water from the negative pressure is hard.
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**Adding water also increases the pressure dramatically.
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**So the interstitial space resists the change of pressure.
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**At some point of adding water, however, you suddenly change the volume without having changed the pressure much.
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**Then you have something like jello--it can absorb lots of fluid without changing the pressure much.
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**Think about an injury: it swells slwoly, then rapidly, then turn sinto a hard edema.
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*How can we affect water in the tissue?
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**The easiest way is to apply pressure to the area: support stalkings, massage, etc.
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**This will push the water back into the cardiovascular system.
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====The Starling - Landis Equation for filtration - reabsorption of water====
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*So when we put all these pressures and forces together and look at water, how do we describe the relationship?
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*We have the Starling-Landis equation:
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**Pcap = pressure of the capillaries
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***This is a filtration force
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**COPif = coloidal osmotic pressure (oncotic pressure) of the interstitial fluid
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***This is a filtration force
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**COPp = coloidal osmotic pressure (oncotic pressure)
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***This is a reabsorption force
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**Pif = pressure of interstitial fluid (negative or slightly positive)
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***This is a reabsorption force
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**K = ml/min/area/mmHg
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***This is a measure of water permeability, called hydraulic conductivity
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**Jv = K ((Pc - COPif) - (COPp + Pif))
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***Jv = K ((capillary pressure - interstitial osmotic pressure) - (osmotic pressure of blood? + pressure of the interstitial fluid))
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*Two forces are osmotic and two are hydrostatic.
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*Don't need to know much of this, just know when you'd leak more or less when each factor goes up or down.
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*stopped here at around 17:55.
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====Idealized concept of the balance of filtration and reabsorption forces across the capillary wall====
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*Note that the osmotic pressures can change as you move through caps / organs.
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**So this will change the state: absorption or filtration.
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*All organs filter, there is only a little absorption.
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  2.  Attempts to reabsorb water from tissue spaces
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===The Lymphatic System: Tidies up the lost water and protein from the vascular system===
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*We use lymphatics to take care of all the absorption that the organs do.
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  3.  Albumin accounts for about 60% of the oncotic pressure
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*The brain doesn't have a lymphatic system.
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**The CSF and the meninges act like a lymphatic system, though.
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  C.  A small amount of albumin is in the interstitial environment.  
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    Interstitial Tissue Oncotic Pressure 
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      About 3-6 mmHg is normal and pulls water out of capillary 
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capillary albumin and Pcapillary
 
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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 
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*Albumin is coming out fo the caps
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interstitial pressure and volume
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*Hard to get it back into the blood because concentrations are all wrong between ISF and blood.
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*Lymphatics are made of endothelial cells
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*These open slightly when tissue is at rest.
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*When the tissue moves / contracts, it squishes whatever is in the lymphatic tube to the next valve.
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*The endothelial cells recoil upon relaxation because they are anchored to the ECF.
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*Recoiling causes anegative pressure such that they suck liquid and proteins from the ECF into the lymphatic duct.
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capillary hydrostatic vs oncotic forces
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====Video====
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E. The Starling - Landis Equation for filtration - reabsorption of water
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*There are valves and lymphatic endothelial cells.
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1. Filtration forces
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*The valves can close to keep backflow from occuring.
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  (Pcap + COPif)
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**Closes as the flow attempts to run backward.
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    2. Reabsorption forces
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*Bradykinin makes the endothelial cells relax.
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              (COPp - Pif)
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**Works via produciton of NO and relaxation of smooth muscle cells.
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3. Hydraulic Conductivity - a measure of water permeability per unit area
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**Bradykinin comes from tissue injury causing mast cells to granulate.
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    and per mmHg
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**Mast cells have bradykinin in their granules; this makes sense because it will cause vascular and lymphatic smooth muscle cells to relax, thus increasing tissue fluid flow.
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          K =  ml/min/area/mmHg
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*Norepi causes the endothelial smooth muscle cells to contract and to squeeze lymph along.
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**NE comes from sympathetics
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====Clinical example: Clark====
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*Loss of blood.
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*Saline given.
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*Hematocrit of 33.
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**Assume she is not anemic.
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*
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*A: no, Bleeding loses RBCs and plasma at the same concentrations as they are natively found.
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*B: spleen and liver help with RBC production but don't add much plasma, so no.
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*C: difficult but feasible; pull water out of the interstitial fluid would dilute the blood.  adults can pull out 750 - 1000 ml
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**Correct answer
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*D: this happens, cannot dilute the blood, can only prevent it from getting
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*E: can happen, does happen, but not the reason.
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IV.  Idealized concept of the balance of filtration and reabsorption forces across the capillary wall
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=====Explanation=====
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1.  Capillary pressure is gradually dissipated by friction of flow along the            capillary
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*Red is RBC volume; tan is plasma
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2. Plasma oncotic pressure gradually increases along capillary as water is      filtered out
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*Bleeding decreases both, proportionally.
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    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 
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*Kidneys start reabsorbing, GI absorbs more water but she still can't get her back to normal
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*ER docs would give saline but probably not blood unless loss was very severe.
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**Let body restore itself.
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CAPFILTR
 
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V.  The Lymphatic System:  Tidies up the lost water and protein from the vascular system
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*continued on to [[Lecture 7 Neural Control]] on 01/27/11 at 8:37 ish.
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Problem: Once albumin or any large protein is out of the capillary, it must be physically carried back to the blood by lymph
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Solution: Suck interstitial fluid into the terminal lymphatic vessels
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1.  Contract or compress lymphatic structures to push lymph through valves to next lymphatic tube
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2.  Recoil of lymphatic structure generates negative pressure to assist filling of lymph vessel
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3.  Recoil aided by anchoring filaments on edges of lymphatic endothelial cells
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LYMPH
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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.  
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NORMAL VOLUME
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AND RED CELL MASS
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INITIAL BLOOD VOLME
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LOSS 
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PHYSIOLOGICAL
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COMPENSATION
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ELECTROLYTE
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FLUID ADDED
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Current revision as of 13:15, 28 January 2011


  • test questions will come from objectives and clinical examples.

Contents

[edit] Capillaries

[edit] 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.

[edit] 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

[edit] 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.

[edit] 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.

[edit] 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


[edit] 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.

[edit] 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.


[edit] 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)

[edit] 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)


[edit] 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

[edit] 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

[edit] 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.

[edit] 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.
    • The tissue feels firm because of the cells, but the interstitial space is negatively pressurized.
    • So taking water from the negative pressure is hard.
    • Adding water also increases the pressure dramatically.
    • So the interstitial space resists the change of pressure.
    • At some point of adding water, however, you suddenly change the volume without having changed the pressure much.
    • Then you have something like jello--it can absorb lots of fluid without changing the pressure much.
    • Think about an injury: it swells slwoly, then rapidly, then turn sinto a hard edema.
  • How can we affect water in the tissue?
    • The easiest way is to apply pressure to the area: support stalkings, massage, etc.
    • This will push the water back into the cardiovascular system.

[edit] The Starling - Landis Equation for filtration - reabsorption of water

  • So when we put all these pressures and forces together and look at water, how do we describe the relationship?
  • We have the Starling-Landis equation:
    • Pcap = pressure of the capillaries
      • This is a filtration force
    • COPif = coloidal osmotic pressure (oncotic pressure) of the interstitial fluid
      • This is a filtration force
    • COPp = coloidal osmotic pressure (oncotic pressure)
      • This is a reabsorption force
    • Pif = pressure of interstitial fluid (negative or slightly positive)
      • This is a reabsorption force
    • K = ml/min/area/mmHg
      • This is a measure of water permeability, called hydraulic conductivity
    • Jv = K ((Pc - COPif) - (COPp + Pif))
      • Jv = K ((capillary pressure - interstitial osmotic pressure) - (osmotic pressure of blood? + pressure of the interstitial fluid))
  • Two forces are osmotic and two are hydrostatic.
  • Don't need to know much of this, just know when you'd leak more or less when each factor goes up or down.

[edit] Idealized concept of the balance of filtration and reabsorption forces across the capillary wall

  • Note that the osmotic pressures can change as you move through caps / organs.
    • So this will change the state: absorption or filtration.
  • All organs filter, there is only a little absorption.

[edit] The Lymphatic System: Tidies up the lost water and protein from the vascular system

  • We use lymphatics to take care of all the absorption that the organs do.
  • The brain doesn't have a lymphatic system.
    • The CSF and the meninges act like a lymphatic system, though.


  • Albumin is coming out fo the caps
  • Hard to get it back into the blood because concentrations are all wrong between ISF and blood.
  • Lymphatics are made of endothelial cells
  • These open slightly when tissue is at rest.
  • When the tissue moves / contracts, it squishes whatever is in the lymphatic tube to the next valve.
  • The endothelial cells recoil upon relaxation because they are anchored to the ECF.
  • Recoiling causes anegative pressure such that they suck liquid and proteins from the ECF into the lymphatic duct.

[edit] Video

  • There are valves and lymphatic endothelial cells.
  • The valves can close to keep backflow from occuring.
    • Closes as the flow attempts to run backward.
  • Bradykinin makes the endothelial cells relax.
    • Works via produciton of NO and relaxation of smooth muscle cells.
    • Bradykinin comes from tissue injury causing mast cells to granulate.
    • Mast cells have bradykinin in their granules; this makes sense because it will cause vascular and lymphatic smooth muscle cells to relax, thus increasing tissue fluid flow.
  • Norepi causes the endothelial smooth muscle cells to contract and to squeeze lymph along.
    • NE comes from sympathetics

[edit] Clinical example: Clark

  • Loss of blood.
  • Saline given.
  • Hematocrit of 33.
    • Assume she is not anemic.
  • A: no, Bleeding loses RBCs and plasma at the same concentrations as they are natively found.
  • B: spleen and liver help with RBC production but don't add much plasma, so no.
  • C: difficult but feasible; pull water out of the interstitial fluid would dilute the blood. adults can pull out 750 - 1000 ml
    • Correct answer
  • D: this happens, cannot dilute the blood, can only prevent it from getting
  • E: can happen, does happen, but not the reason.
[edit] Explanation
  • Red is RBC volume; tan is plasma
  • Bleeding decreases both, proportionally.
  • Kidneys start reabsorbing, GI absorbs more water but she still can't get her back to normal
  • ER docs would give saline but probably not blood unless loss was very severe.
    • Let body restore itself.


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