Oxygen Transport and Asphyxia AnS 536 Spring 2016 Goals To transport oxygen from maternal blood across the placenta to fetal blood, and after birth from the lungs to the blood stream To move oxygen from blood to tissues to allow aerobic metabolism (efficient production of ATP) To move carbon dioxide in the reverse direction Erythrocytes After maturation from stem cells in bone marrow, erythrocytes have a circulating life of ~120d Highly specialized cells: Cytoplasm contains ~35% solution of hemoglobin, but is devoid of subcellular organelles Cannot synthesize nucleic acids or proteins, limited lipid metabolism Carbohydrate metabolism devoted to maintaining functional pumps on cell membrane Erythrocytes After cell death, hemoglobin degraded and iron recycled to bone marrow As they pass through capillaries, cells deform into ellipsoidal, hemispheric, or teardrop shapes Cell fragility increased during newborn period Increased risk and incidence of hemolytic diseases Transport of Gases in Blood P O2 not only determines the dissolved oxygen content of blood, but also affects the amount of oxygen in reversible chemical combination with hemoglobin Chemical and physiological actions of gases depend on the partial pressures they exert in the gas phase and in solution in various body fluids Hemoglobin The binding of one molecule of O 2 to Fe2+ increases the affinity of the other sites for oxygen binding (4 total) Carbon dioxide binds to the globulin portions of the molecule rather than to the iron molecules Accounts for about 10% of CO 2 transport The sigmoidal shape of the oxygen dissociation curve is physiologically important Permits blood to deliver much more oxygen to tissues than a hyperbolic curve Hemoglobin Video BreakXxNEoOXYGEN TRANSPORT VIDEO: OXYGEN BINDING VIDEO: O 2 -Hb Dissociation Curve Illustrates a relationship between the partial pressure of oxygen (PO 2 ) and percent saturated hemoglobin (Hb) Hemoglobin Increasing pH in RBC will increase the affinity of Hb for oxygen (in the lungs) When Hb binds to oxygen, it undergoes a conformational change that releases H ions from globin chains, decreasing pH in the cell In capillaries H + generated by carbonic anhydrase activity in RBC decreases pH and facilitates oxygen delivery to tissues as well (high CO 2 concentrations) Oxygen Loading and Unloading Bohr and Haldane Effects Bohr Effect Describes the influence of CO 2 and pH on the release of O 2 in pH ( in acidity) due to CO 2 and hydrogen ions can combine reversibly with Hb at the sites other than the O 2 binding sites (allosteric binding) Results in a structural change of Hb, reducing its affinity for O 2 Haldane Effect Displacement of O 2 from Hb increases affinity for CO 2 and hydrogen ions Bohr and Haldane Effects Work together facilitating O 2 liberation and the uptake of CO 2 and hydrogen ions at the tissue level A Bohr or Haldane shift reduces Hb affinity for O 2 Important in placental O 2 transport pH is highest in veins where O 2 is picked up (umbilical and placental arterioles) pH is lowest at arteries after CO 2 and hydrogen ions have been picked up Changes in pH and CO 2 on both maternal and fetal side of placenta regulate the rate of O 2 transfer to a great extent Bohr and Haldane Effects Fetal pH is lower (more acidic) than maternal pH Fetal acidosis is metabolic and not related to the high PCO 2 Primarily due to placentally produced lactate and pyruvate The effect of low pH on O 2 delivery to tissues is often overlooked, but may be important in maintaining O 2 delivery to tissues at an appropriate rate 2,3-Bisphosphoglycerate (2,3-BPG) Binds with greater affinity to Maternal deoxyhemoglobin Once it binds to first binding site, it allosterically affects other sites in hemoglobin to effectively increase the rate of release of oxygen at tissue level Right-shift of curve Fetal Hemoglobin (HbF) HbF has a higher affinity for O 2 than HbA Two alpha-gamma dimers rather than two alpha-beta dimers Creates a LEFT shift in the dissociation curve much like the effect of pH, temperature, or 2,3 BPG affinity for O 2 by Hb in the fetal blood enhances O 2 transport across the placenta After birth HbF declines as neonates begin to manufacture new erythrocytes and HbA HbF binds 2,3-BPG poorly Hemoglobin Transitions Fetal Hemoglobin Cytochrome P 450 O 2 is MUCH more soluble in lipids (like membranes) than in water (as in plasma or cytoplasm) Cytochrome P 450 enhances transport processes due to its high affinity for O 2 and accumulates along the endoplasmic reticulum (ER) of placental cells Many different varieties Most involve drug metabolism All incorporate oxygen into metabolic processes Tissues can up- or down-regulate the levels of this molecule to enhance O 2 transport into cell Cytochrome P 450 ER forms channels from the cell membrane to the mitochondria allowing O 2 to move more freely throughout or across the cell Alignment of P 450 along the ER channels creates a high affinity, O 2 soluble freeway for O 2 to travel P 450 enhances transplacental O 2 transport Studies have shown blocking P 450 will decrease transplacental O 2 flux by over 75% Fetal Gas Exchange CO 2 diffuses across placenta primarily in molecular form - not as bicarbonate ion Fetal P CO2 is higher than maternal Fetal oxygen consumption is equivalent to adult values Placenta is designed to protect the fetus from inadequate or excessive oxygen availability Fetal Gas Exchange Cont Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birth Increased oxygen in fetal blood may have more adverse effects than beneficial effects Induction of superoxide dismutase is due to increased exposure to oxygen postnatally Questions?