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Physiology of the Metabolic Gases

Physiology of the Metabolic Gases. Claude A. Piantadosi, M.D. Professor of Medicine Director, Center for Hyperbaric Medicine And Environmental Physiology. The metabolic gases. Questions for today What are the physiological gases? What is physiological O 2 sensing?

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Physiology of the Metabolic Gases

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  1. Physiology of the Metabolic Gases Claude A. Piantadosi, M.D. Professor of Medicine Director, Center for Hyperbaric Medicine And Environmental Physiology

  2. The metabolic gases • Questions for today • What are the physiological gases? • What is physiological O2 sensing? • What is hypoxic vasodilation? • What is ROS signaling? • When does ROS production become pathological?

  3. The metabolic gases • Metabolic gases • CO2 • O2 • NO • CO • H2S • ROS • Inert gases • N2 • Ar • He • H2

  4. The metabolic gases • Metabolic Gas • CO2 • O2 • NO • CO • H2S PhysiologyToxicity pH/Vasodilation Narcosis Respiration/ Oxidation Vasoconstriction Vasodilation Nitration Vasodilation Asphyxia Vasodilation Asphyxia Metabolic gas concentrations vary not just with solubility and partial pressure, but with quantity and number of binding targets in cells and tissues— this defines their reactivity

  5. The metabolic gases • Physiological, adaptive, and toxic effects of all metabolic gases depend on dose and time Toxic Concentration Adaptive Physiological Time

  6. Carriage of CO2 in Blood • CO2 is produced by mitochondrial TCA cycle and transported in the blood from tissue to lungs in three ways: • Dissolved in solution • Buffered with water as carbonic acid • Bound to proteins, particularly hemoglobin • About 75% of CO2 is transported in RBCs and 25% in plasma

  7. Carriage of CO2 in Blood* 100% 100% • *Approximate values (CO2 content of blood is influenced by hemoglobin concentration and saturation, 2, 3-DPG, and pH). Estimates include bicarbonate and CO2 inside the RBC 5% Carbamino 30% 60% HCO3- 90% Dissolved 10% 5% 0% 0% Arterial Venous CO2 distribution in arterial & venous blood

  8. C O + H O 2 2 CO2— —CO2 - + H + H C O 3 The metabolic gases • CO2 transport: RBC plays a critical role Tissue CO2 production by tissues favors O2 unloading RBC + H2O CA CO2 H2CO3 SaO2 CA Bohr effect Band 3 PaO2 Plasma Cl- HCO3- Lungs

  9. The metabolic gases: CO2 Deoxyhemoglobin 60 Haldane effect • CO2 dissociation curve of blood Oxyhemoglobin 40 • O2 dissociation curve of blood O2 or CO2 content (mL/100 mL) HbO2 Bohr Effect 20 Dissolved CO2 Dissolved O2 0 0 50 100 150 PO2 or PCO2 (mmHg)

  10. Oxygen transport to tissues • The O2 cascade 150 100 PO2 (mmHg) 50 0 Air Alveolus Artery Capillary Mitochondrion

  11.  Increasing oxygen affinity 100 100 NADH or Cyta,a3 (% Oxidation) NADH Hb or Mb (% Oxygenation) Cyt a,a3 50 50 Mb Hb State 3 State 4 0 0 10-8 10-7 10-6 10-5 10-4 10-3 Oxygen concentration (M) The metabolic gases • Mitochondrial sink for cellular O2 diffusion

  12. The main consumer of O2 Mitochondria ~95% Respiration: 6O2+ C6H12O6+ 30Pi2-+ 30ADP3-+ 30H+ 6CO2+ 30ATP4-+ 36H2O

  13. The metabolic gases • Rate of O2 consumption depends on the Michaelis-Menton constant: • O2is rarely, if ever, rate-limiting under hyperbaric conditions Vmax VO2 50% Diving and hyperbaric range 3-4 ATA [O2] KM

  14. Physical processes of O2 transport • Diffusion— alveolus to blood • Chemical combination— hemoglobin • Convective transport— tissues • Chemical release— hemoglobin • Diffusion— blood plasma to cells • Chemical reduction to water— mitochondria

  15. Dissolved oxygen Normal AVO2 difference The metabolic gases • HBO2 and the HbO2 dissociation curve 2 5 2 0 CaO2 (ml/dl) 1 5 1 0 5 0 0 1 0 0 5 0 0 1 0 0 0 1 5 0 0 PO2 (mmHg)

  16. The metabolic gases • Arterial O2 content— Sea level Air O2 and HBO2 at 2.5 ATA CaO2 = 1.34 ml/g [Hb](SaO2) + 0.003 ml O2/dl/mmHg = 1.34ml/g [15.0g/dl](1.0) + 0.003 ml/dl/mmHg O2x100 mmHg = 1.34ml/g [15.0g/dl](1.0) + 0.3 ml O2 = 20 ml O2/dl + 0. 3 ml O2/dl= 20.3 ml O2/dl (Air) = 20 ml O2/dl + 2. 1 ml O2/dl= 22.1 ml O2/dl (O2) = 20 ml O2/dl + 5.4 ml O2/dl= 25.4 ml O2/dl Dissolved Oxygen

  17. The metabolic gases • Determinants of PO2 in tissue • Capillary hematocrit • Position of hemoglobin O2 dissociation curve • Adequacy and uniformity of perfusion • O2 shunting • Capillary transit time • Rate of cell respiration

  18. HBO2 The metabolic Gases

  19. The metabolic gases • O2 diffusion into tissue—Krogh cylinder model Venous r Arterial r A A PO2 PO2 VO2 max V Dead corner V } } r r

  20. The metabolic gases • O2 diffusion into tissues Venous Air r = 12mm HBO2 r = 60mm r r PaO2 Arterial Air r = 60mm HBO2 r = 300mm HBO2 Air r

  21. Other O2 consumers e- e- e- e- ROS generation:O2 .O2-  H2O2  .OH  2H2O +2H+ +2H+ NADPH Nitric oxide synthase:O2+ L-arginine  NO.. + L-citrulline NADPH ~5% Heme oxygenases:O2+ heme  CO+ Fe + biliverdin NADPH Cytochrome P450:O2 + RH + 2H+ + 2e– ROH + H2O NADPH oxidases::2O2 + NADPH NADP+ + 2.O2- + H+

  22. e- e- e- e- O2 .O2- H2O2  .OH  H2O +2H+ The metabolic gases • High PO2 promotes ROS generation • Protein oxidation • Thiol (SH) oxidation • Lipid peroxidation • DNA oxidation

  23. Redox Signaling BY ROS Physiological States Pathological States Low ROS Levels High ROS Levels De-localized Localized Kills pathogens Interferes with cell function Blocks cell repair Causes apoptosis/necrosis Promotes tissue injury Cell proliferation Adaptation to stress Promote injury repair Change cell phenotype Chronic anti-oxidant therapy ineffective or harmful Chronic anti-oxidant therapy more likely to be effective

  24. The metabolic gases: vascular control BY NO • Many vascular control events require NO production • Examples: • CO2-induced vasodilation • NO plays a permissive role • O2-induced vasoconstriction • Profound vasoconstriction at PO2 >500 mmHg • Arterial and venous vessels • Reduces cerebral, retinal, and renal blood flow • Limits inert gas clearance from tissues

  25. The metabolic gases • O2-induced vasoconstriction • HBO2 decreases vasodilator activity of NO by generating superoxide (.O2-) • .O2-inactivates NO forming the strong oxidant peroxynitrite (ONOO-) • Hyperoxia prevents allosteric unloading of NO from RBCs by SNO-hemoglobin

  26. Vascular NOS: iNOS eNOS nNOS metabolic gases: NO • NOS isoforms • nNOS (type I constitutive) • iNOS (type II inducible) • eNOS (type III constitutive and inducible) • mtNOS (nNOS variant)

  27. metabolic gases: NO • O2-induced vasoconstriction O2 Reactive nitrogen species (RNS) e- NOS NO. + .O2 - (superoxide) ONOO- (peroxynitrite) ONOOH (peroxynitrous acid) H+ (6.7 X 109 M-1 s-1) NO2 + OH. Constriction Dilation Toxicity

  28. L-arginine L-ornithine Arginase (-) Arginosuccinate NG-OH-L-arginine R-SNO + H+ R-SH metabolic gases: NO • The L-arginine-nitric oxide pathway GTP cGMP L-arginine + O2 NO-heme-sGC NOS NO L-citrulline + NO Effector cell (endothelial) Target cell (smooth muscle)

  29. metabolic gases: NO • Multiple levels of eNOS regulation • Transcriptional control • Translational control • Cytokine-driven mRNA degradation • Post-translational modification • Phosphorylation/ Myristoylation/ Palmitoylation • Protein-protein interactions (enzyme localization) • Calmodulin/ Hsp90/ Caveolin • Uncoupling • BH4/ L-arginine deficiency Fleming I. Molecular mechanisms underlying the activation of eNOS. Pflugers Arch. May;459(6):793-806, 2010

  30. H2O2 is a pleiotropic vasodilator • H2O2 mediates endothelium-dependent or independent vasorelaxation • NO-dependent • NO- independent • H2O2 activates eNOS in large vessels, leading to eNOS-dependent relaxation • In small vessels, e.g. coronary arterioles, mitochondrial-derived H2O2 is responsible for flow-mediated vasodilation (NO-independent) • In disease, e.g. atherosclerosis and hypertension, H2O2 produced by large vessels mediates compensatory, endothelial-dependent, but NO.-independent relaxation • H2O2 may cause endothelium-independent relaxation via catalase compound I activation of smooth muscle cGMP

  31. metabolic gases: CO • Carboxyhemoglobin(COHb) derived from endogenous and exogenous sources

  32. metabolic gases: CO • CO decreases blood O2 content and tissue PO2 20 100% HbO2 AVDO2 15 CaO2 or CvO2 (ml/dl) 10 50% COHb AVDO2 5 0 75 100 0 25 50 PaO2 (mm Hg)

  33. Hypoxia metabolic gases • CO and CO body stores • OSHA 8-hour exposure limit is 50 ppm • Endogenous CO production by HO reflects ~ 1-5 ppm Intravascular Extravascular Myoglobin Hemoprotein enzymes CO Alveolar gas COHb Endogenous CO production Metabolism to CO2

  34. metabolic gases: CO • Dual mechanism of CO poisoning • Chemical asphyxia (CO hypoxia) • COHb has increased O2 affinity • COHb does not carry O2 • Haldane’s First Law: [COHb]/[HbO2]= M (PCO/PO2), M=220 • Cellular poisoning—heme protein binding • Warburg constant: K= (n/1-n)(CO/ O2) Where n, the fraction bound to CO, is equal to 0.5 K is the ratio of CO:O2 to half-saturate the binding site Tissue hypoxia

  35. Redox-regulation of mitochondrial biogenesis Sepsis-induced inflammation TLRs -SH oxidation Proteasome MyD88 Keap1 HO-1/CO NFkB PI3K/ PTEN P GSK3b P Hmox1 P NO Akt1 NRF-1 NRF-1 Mitochondrial biogenesis Anti-oxidant enzyme induction Anti-apoptosis (Bcl2) Counter-inflammation (IL-10) Mitophagy (p62) PGC-1a P NRF-1 Ub Nrf2 Nrf2 Nrf2 Nrf2 Nrf2 Nucleus ARE ARE

  36. CO NO RSH .OH ONOO- H2O2 Fe III Fe II O2 e- Anti-oxidant .O2- .O2- Pro-oxidant The metabolic gases • CO binds iron and other transition metals allowing it to interact with ROS and NO

  37. metabolic gases: H2S • Hydrogen sulfide • Sewer gas (rotten eggs) • Poisons mitochondrial ETC at high levels • Generated enzymatically by cells and plays several physiological roles • Relationship to O2 mainly involve sulfide oxidation

  38. Hydrogen sulfide chemosynthesis • Chemosynthesis • Biological conversion of one or more carbons (usually CO2 or CH4) into organic matter by oxidation of inorganic molecules (H2or H2S) or CH4 as a source of energy, rather than by sunlight (photosynthesis) • Some bacteria do this, e.g. purple sulfur bacteria, instead of photosynthetic release of O2 • Yellow sulfur globules produced that are visible in the cell • Proposed that chemosynthesis may support life below the surfaces of Mars, and Jupiter's moon Europa Hydrogen sulfide chemosynthesis: 6CO2 + 6H2O + 3H2S = C6H12O6 + 3H2SO4

  39. metabolic gases: H2S Kabil O, Motl N, Banerjee R. H2S and its role in redox signaling. Biochim Biophys Acta 2014 Jan 11

  40. metabolic gases: H2S • Enzymatic H2S Production • 3-mercaptopyruvate sulfurtransferase (MST) • Cystathione gamma lyase (CSE) • Cystathionine beta-synthase (CBS) • CBS normally condenses serine and homocysteine to cystathionine: L-serine + L-homocysteine = L-cystathionine + H2O • Only pyridoxal phosphate-dependent enzyme that contains a heme co-factor that functions as a redox sensor; modulates activity in response to redox potential. • Resting form of CBS has ferrous heme (Fe II) that is activated under oxidizing conditions by conversion to ferric state • Fe (II) form is inhibited by CO or NO binding; activity doubles when Fe (II) Fe (III)

  41. metabolic gases: H2S • Controversies surround the sometimes conflicting effects of H2S (e.g. both pro- and anti-inflammatory) • Highlights problems associated with interpreting studies • Very wide concentration range of H2S • Technical challenges of handling a redox-active gas • Multiple mechanisms of H2S-based signaling • Protein persulfidation • Sulfhydration of electrophiles • Interaction with S-nitrosothiols • Interaction with metal centers

  42. Sulfide biosynthesis H2S synthesis and degradation • Tissue H2S concentration is low 10–30 nM except in aorta • Sulfur flux into H2S in murine liver is comparable to GSH (6–10 mM at steady-state) • Thus, sulfide clearance rate must be high to account for low steady-state H2S concentrations Sulfide clearance Kabil O, Motl N, Banerjee R. H2S and its role in redox signaling. Biochim Biophys Acta 2014 Jan 11

  43. Cytochrome oxidase Sulfmyoglobin Sulfhemoglobin NMDA receptor KATP channel metabolic gases: H2S O2 Storage Iron sulfide (Fe-S) Sulfane sulfur Polysulfides O2 O2 Biosynthesis CBS CSE MST Interactions Neuromodulation Muscle relaxation Hibernation-like state Cysteine H2S O2 Degradation Oxidation Methylation H2S is degraded mainly in mitochondria through a series of oxidations that convert the gas to sulfite (SO3-2), thiosulfate (S2O3-2), and sulfate (SO4-2 ) Olson KR, Whitfield NL (2010) Hydrogen sulfide and oxygen sensing in the cardiovascular system. Antioxid Redox Signal 12:1219–1234.

  44. The metabolic gases • Summary • O2’s role is not limited to aerobic metabolism, but is involved in the production of and interactions with other metabolic gases • Of the O2 used in the body, ~95% is reduced to H2O by respiration • Non-respiratory processes use ~5% (ROS, NO, and CO) • An increase in tissue PO2 above that needed to support respiration does not increase VO2, but does increase O2 utilization by the other processes (depending on Km) • This may interfere with O2 regulation of these processes • Excessive ROS production leads to delocalization of redox signaling, and macromolecular damage (oxidative stress), disordered repair and cell death

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