Microcirculation and Lymphatic System Prof.Dr. Ümmühan İşoğlu-Alkaç İ.Ü. İstanbul Tıp Fakültesi Fizyoloji Anabilim Dalı alkac@istanbul.edu.tr YU Medical Faculty, 09.10.2013

Microcirculation and the Lymphatic System 3

Structure of the microcirculation and capillary system The arterioles are highly muscular … Metarterioles (the terminal arterioles) do not have a continuous muscular coat, but smooth muscle fibers encircle the vessel at intermittent points Precapillary sphincter between the metarteriole and capillary The venules are larger than the arterioles and have much weaker muscular coat Local conditions of the tissues and regulation of blood flow 6

Structure of the microcirculation and capillary system 7

Structure of the capillary wall Total thickness of the capillary wall is only about 0.5 µm, 500-900 m2 , 4-9 µm, funct.cell:20-30 µm 9

Special types of pores and certain organs In the brain, junctions between the capillary endothelial cells are mainly “tight” junctions that allow only extremely small molecules such as water, O2, CO2 for passage In the liver, the opposite is true. The pores of the gastrointestinal capillary membranes are midway between those of the muscle and liver In the glomerular structure of the kidney, there are small oval windows on the capillary walls called “fenestrae” (fenestrated capillaries) 10

Liver, Bone Marrow, Spleen

Flow of Blood in the Capillaries- Vasomotion Blood usually does not flow continuously through the capillaries It flows intermittently every few seconds or minutes This phenomenon is called “vasomotion” The most important factor to affect the degree of openning and closing of the metarterioles and precapillary sphincters is the oxygen concentration Average function of the capillary system… 12

Exchange of water, nutrients and other substances between the blood and interstitial fluid Diffusion through the capillary membrane: the most important means for transport of substances between the plasma and interstitial fluid Lipid soluble substances can diffuse directly through the cell membranes of the capillary endothelium (e.g. O2 and CO2) Water-soluble, non-lipid-soluble substances diffuse only through intercellular pores in the capillary membrane (e.g. water molecules, Na ions, Cl ions and glucose) Effect of concentration difference on net rate of diffusion through the capillary membrane 14

Exchange of water, nutrients and other substances between the blood and interstitial fluid 15

Effect of molecular size on passage through the pores Substance Molecular Weight Permeability Water 18 1.00 NaCl 58.5 0.96 Urea 60 0.8 Glucose 180 0.6 Sucrose 342 0.4 Inulin 5,000 0.2 Myoglobin 17,600 0.03 Hemoglobin 68,000 0.01 Albumin 69,000 0.001 16

The Interstitium and Interstitial Fluid Interstitium and interstitial fluid (12 lt, ~1/6¨, -2 --- -3 mmHg) Two major types of structures Collagen fiber bundles Proteoglycan filaments Proteoglycan filaments: 98% hyaluronic acid and 2% protein “Gel” in the interstitium: because of large number of proteoglycan filaments, it is difficult for fluid to flow easily through tissue gel Interstitial fluid is the same as plasma except it contains low concentrations of proteins Formation of edema… (%1 free fluid) 17

The Interstitium and Interstitial Fluid 18

Fluid filtration, hydrostatic and oncotic pressures The hydrostatic pressure in the capillary tends to force fluid and its dissolved substances through the capillary pores into the interstitial spaces Conversely, colloid osmotic pressure (oncotic pressure) of the plasma proteins tends to cause fluid movement by osmosis from the interstitial spaces into the blood This oncotic pressure prevents significant loss of fluid volume from blood Lymphatic system and recovery of proteins from the interstitial space 19

Fluid filtration, hydrostatic and oncotic pressures Starling Powers: The hydrostatic pressure Kolloid osmotic pressure (oncotic pressure) 20

Capillary hydrostatic pressure (Pc) Four primary hydrostatic and colloid osmotic forces determine fluid movement through the capillary membrane Capillary hydrostatic pressure (Pc) Interstitial fluid (hydrostatic) pressure (Pif) The capillary plasma colloid osmotic (oncotic) pressure Interstitial fluid colloid osmotic (oncotic) pressure 21

Net filtration pressure The net filtration pressure is positive, under normal conditions 22

Capillary and Interstitial Hydrostatic Pressures Capillary hydrostatic pressure: Arterial end of capillary: 30 mmHg Venous end of capillary: 10 mmHg Interstitial fluid (hydrostatic) pressure: The true interstitial fluid pressure is negative, averaging about -3 mmHg Pumping by the lymphatic system is the basic cause of negative interstitial pressure 23

Plasma Colloid Osmotic (Oncotic) Pressure Proteins in the plasma cause oncotic pressure Non-permeability of plasma proteins Normal values: plasma oncotic pressure of normal human plasma is about 28 mmHg 19 mmHg of this is caused by molecular effects of dissolved proteins and 9 mmHg by Donnan effect (i.e. Osmotic pressure caused by Na, K and other cations held in the plasma by proteins) About 80% of plasma oncotic pressure results from Albumin, 20% from globulin and almost none from fibrinogen 24

Interstitial Fluid Colloid Osmotic (Oncotic) Pressure Although size of the usual capillary pore is smaller than the molecular sizes of the plasma proteins, this is not true for all pores. Therefore, small amounts of proteins leak into the interstitial space Presence of these proteins cause interstitial fluid oncotic pressure (8 mmHg) 25

Exchange of Fluid Volume Through the Capillary membrane The average capillary pressure at the arterial ends of the capillaries is 15 to 25 mmHg greater than at the venous ends. Because of this difference, fluid filters out of the capillaries at the arterial end, but it is reabsorbed at the venous end. 26

Analysis of the forces causing filtration at the arterial end of the capillary Forces tending to move fluid outward:     Capillary pressure (arterial end of capillary) 30   Negative interstitial free fluid pressure 3   Interstitial fluid colloid osmotic pressure 8     total outward force 41 Forces tending to move fluid inward:   Plasma colloid osmotic pressure 28 Summation of forces:   Outward   Inward     net outward force (at arterial end) 13

Analysis of reabsorption at the venous end of the capillary Forces tending to move fluid inward:     Plasma colloid osmotic pressure 28     total inward force Forces tending to move fluid outward:   Capillary pressure (venous end of capillary) 10   Negative interstitial free fluid pressure 3   Interstitial fluid colloid osmotic pressure 8     total outward force 21 Summation of forces:   Inward   Outward     net inward force 7

Starling Equlibrium for Capillary Exchange Mean forces tending to move fluid outward:     Mean capillary pressure 17.3   Negative interstitial free fluid pressure 3.0   Interstitial fluid colloid osmotic pressure 8.0     total outward force 28.3 Mean force tending to move fluid inward:   Plasma colloid osmotic pressure 28.0     total inward force Summation of mean forces:   Outward   Inward     net outward force 0.3

Net Filtration Outward forces: 28.3 mmHg Inward forces: 28 mmHg This slight excess of filtration is called net filtration: 0.3 mmHg 2 ml / min in the body Abnormal imbalance of forces at the capillary membrane If the mean capillary pressure rises above 17 mmHg, the net force increases. As a result fluid will accumulate in the interstitial space and edema will result. Conversely, if the capillary pressure falls very low, net reabsorption of fluid will occur and blood volume will increase… 30

arterial end

venous end

Vasodilatator theory According to this theory, greater the rate of metabolism or the less the availability of oxygen or some other nutrients to the tissue, the greater the rate of formation of vasodilatator substances Adenosine, CO2, adenosine phosphate compounds, histamine, K ions and H ions Importance of adenosine in local vasodilatation 33

Oxygen lack theory for local blood flow control Vasomotion, metarteriole and precapillary sphincter Smooth muscle requires oxygen to remain contracted 34

Lymphatic System

Lymphatic System: Overview Consists of two semi-independent parts A meandering network of lymphatic vessels Lymphoid tissues and organs scattered throughout the body Returns interstitial fluid and leaked plasma proteins back to the blood Lymph – interstitial fluid once it has entered lymphatic vessels

Lymph vessels from lower parts of the body – Thoracic Duct Lymphatic System Exceptions for the lymphatic system: superficial portions of the skin, central nervous system, endomyosium of muscles and bones. But even these tissues have prelymphatics through which interstitial fluid can flow Lymph vessels from lower parts of the body – Thoracic Duct 37

Lymphatic System Lymph from the left side of the head, left arm, and parts of the chest also goes into thoracic duct Lymph from right side of the head, right arm, and parts of the thorax enters the right lymph duct which empties into the venous blood at the right side (juncture of jugular vein and right subclavian vein) 38

Lymphatic System: Overview

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Lymphatic Capillaries Similar to blood capillaries, with modifications Remarkably permeable Loosely joined endothelial minivalves Withstand interstitial pressure and remain open The minivalves function as one-way gates that: Allow interstitial fluid to enter lymph capillaries Do not allow lymph to escape from the capillaries

Lymphatic Capillaries * Total quantity of lymph is normally only 2-3 liters/day * This lymph is continually absorbed from the tissues by lymphatic capillaries and returned to the blood circulation

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Lymphatic Vessels A one-way system in which lymph flows toward the heart Lymph vessels include: Microscopic, permeable, blind-ended capillaries Lymphatic collecting vessels Trunks and ducts

Lymphatic Capillaries During inflammation, lymph capillaries can absorb: Cell debris Pathogens Cancer cells Cells in the lymph nodes: Cleanse and “examine” this debris Lacteals – specialized lymph capillaries present in intestinal mucosa Absorb digested fat and deliver chyle to the blood

Rate of Lymph Flow Any factor increasing interstitial fluid pressure also increases lymph flow. Such factors include Elevated capillary pressure Decreased plasma colloid osmotic pressure Increased interstitial fluid colloid osmotic pressure Increased permeability of the capillaries Maximum lymph flow rate 47

Lymphatic Pump Intrinsic intermittent contraction of the lymph vessel walls External factors: Contraction of surrounding skeletal muscles Movement of parts of the body Pulsations of arteries adjacent to the lymphatics Compression of the tissues by objects outside the body The lymphatic pump becomes very active during exercise 48

The lymphatic system lacks an organ that acts as a pump Lymph Transport The lymphatic system lacks an organ that acts as a pump Vessels are low-pressure conduits Uses the same methods as veins to propel lymph Pulsations of nearby arteries Contractions of smooth muscle in the walls of the lymphatics www.youtube.com/watch?v=Kh-XdNnTZUo&feature=related

Lymphatic Pump Primary factors that determine the lymph flow: Interstitial fluid pressure Activity of the lymphatic pump 50

Interstitial Protein Concentration, Fluid Volume and Pressure The lymphatic system plays an important role in controlling protein concentrations in the interstitial fluid volume of interstitial fluid interstitial fluid pressure Significance of negative interstitial fluid pressure as a means for holding the body tissues together Different tissues of the body are held together by connective tissue fibers Skin sliding over the back of the hand and face It acts partially as a vacuum pump In its absence, edema develops. 53

Lymph Nodes Their two basic functions are: Filtration – macrophages destroy microorganisms and debris Immune system activation – monitor for antigens and mount an attack against them

Structure of a Lymph Node http://trc.ucdavis.edu/biosci10v/bis10v/media/ch23/human_lymphatic.html