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154 Cards in this Set
- Front
- Back
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highly polar molecules
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amino acids, proteins, carbohydrates, nucleotides
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important amphipathic biomolecules
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pulmonary surfactants, bile acids, phospholipids
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components of biological membranes
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sheet-like structure consists of proteins, lipids, with carbohydrates
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function of proteins in the membrane
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transporters, channels, enzymes, signal transducers
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plasma membrane core
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1/3 cholesterol, 2/3 phospholipids, sphingomyelin
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outer face of the membrane bilayer
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sphingomyelin and phosphatidylcholine
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inner face of the membrane bilayer
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phosphotidylethanolamine and phosphatidylserine
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membrane glycolipids
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cerebrosides and gangliosides
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effect of heat on membrane fluidity
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promotes fluid state
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functions of membrane lipids
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1. act as a permeability barrier
2. act as a solvent for membrane proteins to perform other functions |
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permeability barrier
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a. membrane is a selectively permeable barrier between the cell and the external environment. barriers to the flow of charged molecules.
b. its function is to maintain homeostasis. its selective permeability allows the cell to maintain a constant internal environment. c. plasma membranes form compartments within cells |
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solvent for membrane proteins to perform other functions
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a. regulate cell volume
b. maintain intracellular pH c. selectively regulate ionic composition d. concentrate metabolic fuel |
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fluid-mosaic model
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1. amphipathic molecules stabilized by the hydrophobic interaction from the lipid bilayer
2. asymmetric property 3. it is a fluid like structure 4. lateral movement |
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asymmetric property of lipid bilayer
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the components of membranes with lipids and proteins are asymmetrically oriented: the two faces are different
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two faces of the lipid bilayer
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a. glycoproteins acting as hormone receptors on the outside of the cell
b. the Na+-K+ pump transports Na+ out of the cells in exchange for K+ |
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regulation of fluidity of lipid bilayer
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-number of double bonds in the fatty acids
-cholesterol content |
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lateral movement in lipid bilayer
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proteins and the components are free to move laterally, but no or little flip-flopping allowed (flippase or transporter is needed)
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cellular fraction of blood
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1. erythrocytes (40-45%)
2. leukocytes 3. thrombocytes |
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types of WBC
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a. granulocytes (aka polymorphonuclear, or PMN cells) - neutrophils, eosinophils, basophils
b. agranulocytes - lymphocytes and monocytes |
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thrombocytes
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-blood platelets
-fragments of megakaryocytes |
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serum
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overlying extracellular fluid in blood after clot formation
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plasma
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overlying extracellular fluid portion when an appropriate anticoagulant is added to blood
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chemical components present in plasma but not serum
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1. fibrin precursor (fibrinogen)
2. added anticoagulant 3. unused expendable clotting factors |
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major components of plasma
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a. water
b. proteins c. smaller molecular weight molecules |
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water makes up what percentage of plasma?
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93%
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proteins in plasma
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-7%
1. albumin 2. globulins 3.fibrinogen |
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smaller molecular weight molecules in plasma
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-0.1%
1. anabolic constituents 2. catabolic products |
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noncellular fraction of blood
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1. plasma/serum
2.electrolytes 3. hormones, vitamins, etc |
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free radical
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a chemical compound with an odd number of electrons; an unpaired electron in its outermost shell of electrons
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reactivity of free radicals
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-very unstable so highly reactive
-react quickly with other compounds trying to capture the needed electron to gain stability -attack the nearest stable molecule "stealing its electron". the attacked molecule then becomes a free radical itself, beginning a chain reaction -ends up disrupting the living cell |
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types of free radicals
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1. reactive oxygen species
2. reactive nitrogen species |
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reactive oxygen species
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a. non-ion, non-radical molecules such as hydrogen peroxide and hydroperoxide (R-OOH)
b. ions such as hypochlorite anion (OCl-) and peroxynitrite anion (O=N-O-O-) c. ion-radicals such as superoxide anion, peroxyl radicals (ROO.-), hydroxyl radical (OH.-) |
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reactive nitrogen species
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a. NO radical (NO.-)
b. non-radicals such as nitrosonium cation (NO+) or peroxynitrite (ONOO-) |
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formation of free radicals
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1. interaction of ionizing radiation with biological molecules
2. byproduct of cellular respiration 3. synthesized by enzymes in phagocytic cells 4. produced during prostaglandin synthesi 5. cytochrome P450 system in liver for drug and toxin removal 6. cells of the thyroid gland generate hydrogen peroxide 7. hypoxia or hyperoxia 8. drugs, pesticides, anesthetics, industrial solvents have oxidizing effects leading to oxygen radicals 9. cigarette smoke, environmental pollutants, UV light, ozone |
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physiological functions of ROS and RNS
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1. hydrogen peroxide required for synthesis of thyroxine
2. macrophages and neutrophils must generate ROS to kill bacteria 3. ROS function as a sensor for changes in oxygen content of the blood 4. ROS are involved in receptor-mediated signaling pathways 5. NO. exerts vasorelaxant effects 6. oxygen radicals are necessary compounds in the maturational processes of cellular structures |
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adverse effects of ROS and RNS - oxidative stress
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1. highly toxic to cells in general
2. ROS cause damage to cellular membranes by lipid peroxidation which increases membrane rigidity 3. can directly attack membrane proteins and induce lipid-lipid, lipid-protein,and protein-protein cross-linking which effects membrane function |
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effects of cross-linking on membrane function
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a. decreased activity of membrane-bound enzymes
b. altered activity of membrane receptors c. altered permeability |
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ROS/RNS and diseases
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1. mitochondrial oxidative stress
2. inflammatory oxidative conditions 3. DNA mutation and carcinogenesis 4. arthrosclerosis, neurogenerative diseases, and rheumatoid arthritis 5. aging |
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mitochondrial oxidative stress
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elevated ROS production correlates with pathogenesis of diabetes mellitus and its complications
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inflammatory oxidative conditions
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inflammation is associated with an excessive stimulation of NADPH oxidase activity, thus increased ROS levels
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ROS production and exercise
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a. ROS production was reported to increase in skeletal muscle tissue after mobilization
b. however, intensive muscular activity was also reported to enhance ROS production |
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enzymatic antioxidants that protect cells from oxidative stress
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1. superoxide dismutases (SOD)
2. hydrogen peroxide catalase 3. glutothione peroxidase |
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dismutation
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reaction or reactions involving two identical molecules in which one gains what the other loses
O2.- +O2.- + 2H+ = H2O2 + O2 |
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benefit of dismutase
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hydrogen peroxide is substantially less toxic than superoxide. SOD accelerates this detoxifying reaction roughly 10,000X. exposure to higher concentration of O2 results in rapid increases in the concentration of SOD.
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glutathione peroxidase
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degrades hydrogen peroxide
H2O2 -> OH.- -> H2O |
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the most important intracellular defense against damage by ROS
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glutathione
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reaction of radicals with glutathione
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-glutathione is oxidized
-the reduced form is regenerated in a redox cycle involving glutathione reductase and the electron acceptor NADPH -NADPH indirectly provides electrons for the reduction of hydrogen peroxide |
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non-enzymatic antioxidants
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1. vitamin E
2. vitamin C 3. vitamin A, bilirubin, uric acid |
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vitamin E as an antioxidant
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a. most widely distributed/potent tocopherol
b. major lipid-soluble antioxidant c. first line of defense against the peroxidation of poly-unsaturated fatty acids d. protects membranes from oxidative damage - traps peroxy radicals in cell membrane e. vitamin E and selenium act synergistically |
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vitamin E and selenium as an antioxidant
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glutathione peroxidase, of which selenium is a key component, provides a second line of defense against hyperoxides. vitamin E and selenium reinforce each other in their actions against lipid peroxides.
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vitamin C as an antioxidant
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a. ascorbic acid - most abundant water-soluble antioxidant in the body
b. acts primarily in cellular fluid c. combats free-radical formation caused by pollution and cigarette smoke d. helps return vitamin E to its active form |
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vitamin E and cardiovascular disease
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there is an inverse relationship between cardiovascular disease and status of vitamin E. vitamin E may protect against cardiovascular disease by defending against LDL oxidation and artery-clogging plaque formation.
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cancer and vitamin C
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high vitamin C intake has been correlated with low rates of cancer of the mouth, larynx, and esophagus
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DMSO
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-dimetylsulfoxide
-potent scavenger of hydroxyl radicals -therapy for laminitis |
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phagocytosis
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the engulfment of microorganisms, foreign particles, and cellular debris by WBC such as neutrophils and monocytes
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phagocytes mechanisms to destroy bacteria
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a. oxygen dependent system
b. oxygen independent system |
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oxygen independent system
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1. pH changes in the phagocytes
2. lysosomal enzymes |
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oxygen dependent system
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generation of free radicals
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generation of superoxide by macrophages/neutrophils to kill bacteria
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1. phagocytosis - bacteria are engulfed into a phagosome, which fuses with a lysosome
2. respiratory burst - subunits of NADPH oxidase assemble in the lysosome membrane forming the active enzyme. NADPH oxidase catalyzes the synthesis of the superoxide anion. This produces a large increase in oxygen consumption = respiratory burst |
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free radicals in WBC
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1. phagocytosis
2. mechanisms to destroy bacteria 3. macrophages/neutrophils generate superoxide anion 4. neutrophils generate ROS via MPO system 5. infections 6. deficiency in NADPH oxidase |
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MPO system
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-myeloperoxidase system
-O2.- -> H2O2 by SOD -H2O2 -> HOCl- by MPO; HOCl- kills bacteria H2O2 -> OH.- by converting Fe2+ to Fe3+ which kills bacteria |
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deficiency in NADPH peroxidase
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-recurrent infection, chronic granulomatous disease
-caused by a defective gene for one of the subunits of NADPH oxidase -bacteria that produce catalase to protect themselves against the hydrogen peroxide generated by the macrophages and neutrophils that engulf them -often the result is the development of a persisting nest of infected cells - called a granuloma |
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composition of RBC
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-composed of a membrane surrounding a solution of hemoglobin
- don't have intracellular organelles -non-nucleated |
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production of RBC
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stimulated by erythropoietin which is synthesized by the kidney and released in response to hypoxia
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RBC metabolism
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a. highly metabolically active
b. highly dependent upon glucose as energy source c. ATP generated from glycolysis d. ATP helps maintain biconcave shape e. production of 2,3-BPG |
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glucose as RBC energy source
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-membrane contains high affinity glucose transporters
-uptake of glucose is not insulin-dependent -90-95% of intracellular glucose is for generating ATP -5-10% is used for the hexose monophosphate pathway |
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ATP in RBC
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-helps maintain its biconcave shape
-regulation of ion transport and of water in and out of the cell |
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2,3-BPG in RBC
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important in regulating Hb-O2 binding
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how is superoxide formed in RBC?
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by the auto-oxidation of hemoglobin to methemoglobin
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G6P dehydrogenase deficiency
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a. most common of all enzymopathies
b. G6PD deficiency -> insufficient NADPH -> reduced regeneration of GSH from GSSG -> impaired ability to dispose of hydrogen peroxide and O2 radicals -> reactive oxidants damage RBC membrane structure -> hemolytic anemia |
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precipitating factors in G6PD deficiency
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1. oxidant drugs - antibiotics, antimalarial drugs, antipyretics
2. consumption of broad beans |
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glutathione synthase deficiency
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causes hemolysis, acidosis, CNS damage
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number of plasma proteins
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at least 200, but many have not yet been characterized
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normal range of total protein
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5-8 mg/dL
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electrophoresis
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a. proteins have charges as a result of N, C terminal ends and R groups
b. because of this charge, protein molecules will migrate in an electrical field with the speed dependent on the magnitude of the charge and interactions between the protein and the support medium |
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characteristics of albumin
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1. albumin is sufficiently different between common domestic species so that injection of albumin from one species results in antibody formation in another
2. the most abundant plasma protein 3. negative charge and physiologic pH 4. single polypeptide chain shaped as an elongated ellipsoid 5. metabolism of albumin |
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metabolism of albumin
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a. synthesized in the liver
b. half-life is relatively short c. many routes of catabolism |
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routes of catabolism of albumin
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1. blood enzymes
2. renal catabolism 3. organ enzymes 4. loss into gut, degraded |
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functions of albumin
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1. osmotic agent by creating oncotic pressure and as a transport agent
2. other proteins may also act as non-specific transport compounds but albumin is the most important |
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types of globulins
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1. alpha
2. beta 3. gamma |
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alpha globulins
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a. alpha 1
b. alpha 2 (pre beta) |
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alpha 1 globulin
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composed mostly of glycoproteins and high density lipoproteins
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alpha 2 globulin
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1. very low density lipoproteins
2. haptoglobulin- transport free Hb in blood |
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beta globulins
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a. low density lipoproteins
b. many complement factors |
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gamma globulins
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immunoglobulins
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state of hydration on plasma proteins
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state of hydration can change the concentration of any plasma component including protein without an actual change in the plasma content of that protein
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faulty or inadequate synthesis of albumin may occur in association with
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1. starvation or inadequate diet
2. faulty gastrointestinal digestion or absorption 3. hepatic disease 4. genetics |
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plasma albumin content can be decreased because
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a. faulty or inadequate synthesis
b. accelerated loss or destruction |
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accelerated loss or destruction of albumin can occur with
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1. severe proteinuria
2. protein-losing gut diseases 3. generalized burns |
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increased plasma albumin content
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a. no causes exist
b. dehydration can cause plasma albumin concentration to increase |
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hemostasis
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the arrest of bleeding either by the physiological properties of vasoconstriction and coagulation or by surgical means
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thrombostasis
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stasis of blood in a part, attended with the formation of a thrombus
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thrombus
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an aggregation of blood factors frequently causing vascular obstruction at the point of its formation
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thrombosis
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the formation, development, or presence of a thrombus
a. physiological thrombosis for thrombostasis b. pathological thrombosis |
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phases of hemostasis
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1. constriction of injured vessels to decrease blood loss
2. formation of a loose platelet plug 3. formation of a fibrin mesh that binds platelets, traps RBCs 4. partial or complete dissolution of the clot |
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formation of loose platelet plug
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a. exposed collagen from injury is a site for platelet adherence
b. internal structures of platelets are disrupted causing release of thromboxane and ADP, which causes further platelet adherence |
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factor I
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fibrinogen
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function of factor I
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conversion to fibrin
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factor II
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prothrombin
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function of factor II
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conversion to thrombin
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factor III
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tissue thromboplastin
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function of factor III
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co-factor for VIIa for activation of X
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factor IV
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calcium
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function of factor IV
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cofactor for several reactions
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factor V
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proaccelerin
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function of factor V
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cofactor
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factor VII
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proconvertin
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function of factor VII
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activation of X
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factor VIII
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antihemophilic globulin
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function of factor VIII
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activation of X
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factor IX
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plasma thromboplastin component
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function of factor IX
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formation of tenase complex (VIIIa, IXa, Ca2+)
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factor X
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Stuart-Prower factor
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function of factor X
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thrombin formation
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factor XI
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plasma thromboplastin
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function of factor XI
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activation of IX antecedent
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factor XII
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Hageman factor
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function of factor XII
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activation of XI
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factor XIII
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fibrin stabilizing factor
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function of factor XIII
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cross-linking of fibrin factor
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factor HMW-K
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high molecular weight kininogen
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function of HMW-K
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activation of XII, XI
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function Ka
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kallikrein
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function of factor Ka
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activation of XII
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clotting pathways
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clotting may be initiated by intrinsic or extrinsic pathways. these 2 different pathways later converge into a common pathway
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initiation of extrinsic pathway
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injury of tissues surrounding or adjacent to blood vessels where blood has extravasated
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extrinsic pathway
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a. factor VII is synthesized by the liver and released into the blood
b. if blood vessels are injured, factor VII leaks into perivascular tissues c. traumatized tissue releases thromboplastin d. factor IIIa activates VII into VIIa. Factor VIIa combines with IIIa to activate factor X into Xa by cleaving an internal peptide bond of factor X e. then becomes common pathway |
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initiaion of intrinsic pathway
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within the blood vessels themselves due to restricted blood flow or vessel wall injury
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intrinsic pathway
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a. involves factors XII, XI, IV, VIII, X as well as prekallikren, HMW kininogen, calcium and platelet phospholipids
b. contact phase- factor XII is produced by the liver in an inactive form, but can be activated by contact with subendothelial collagen or as a consequence of blood stasis c. factor XIIa initiates a cascade of reactions resulting X being activated to Xa. |
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common pathway
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when Xa is formed which initiates conversion of prothrombin to thrombin
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synthesis of prothrombin
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-in the liver
-requires the presence of vitamin K |
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prothrombin
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-has no activity so it must be activated by conversion to thrombin.
-amino acid terminal has many Gla residues that can bind to calcium |
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conversion of prothrombin to thrombin requires
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the formation of prothrombinase complex consisting of platelet anionic phospholipids, calcium, factors Va, Xa, and prothrombin. platelet anionic phospholipid is located internally and exposed by collagen-induced platelet rupture.
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formation of prothrombin complex
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a. calcium binds to both the Gla region of prothrombin and the anionic phospholipid of platelet membrane bringing these components together
b. factor V is produced by the liver, kidney and spleen. It is present in both platelets and plasma. Factor V is activated by Xa and thrombin. c. Factor Va binds to platelet membrane receptors. d. Factor Va acts as a receptor to Xa. Xa is a protease which cleaves prothrombin in the middle of the molecule. When cleaved the COOH terminal portion (thrombin) acts to convert fibrinogen to fibrin. |
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fibrinogen-fibrin conversion
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1. the liver makes fibrinogen, a glycoprotein with peptide subunits of alpha2-beta2-gamma2 plus sugars as side chains
2. the N terminal end of each fibrinogen chain is highly negatively charged - thus the chains repel each other but are held together by cysteinyl residues. repelling of chains is with keeps fibrinogen from clotting. negative chargekeeps the molecule plasma soluble 3. formation of a clot involves removal of the negatively charged tails of the chain so that the molecules now associate with one another and also become plasma insoluble |
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mechanism or converting fibrinogen to fibrin
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a. tissue damage -> thrombin
b. thrombin cataalyzed hydrolysis of alpha, beta chains at a point 10-20 residues from the N-terminal. this removes the highly negative charges: the bulk of the molecule that remains can associate as a fibrin monomer c. many fibrin monomers aggregate into a clot in which weak, non covalent bonds hold the molecules together d. thrombin also converts XIII to XIIIa e. factor XIII is a transglutaminase. it forms strong, covalent links between fibrin monomers. this contributes to clot retraction which yields more stable fibrin clot and more resistance to proteolysis. |
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role of calcium in clotting
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a. prothrombin contains Gla residues which bind Ca
b. other clotting factors as well have Gla groups that bind Ca (VII, IX, X) c. elimination of Ca from blood prevents clotting by interference with the normal function of these factors |
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deficiency of clotting system
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a. hemophilia A - deficiency of factor VIII
b. hemophilia B - deficiency of factor IX c. antiplatelet drugs modify the behavior of platelets by irreversibly acetylates and thus inhibits the platelet cyclooxygenase system involved in formation of thromboxane A2, a potent platelet aggregator and a vasoconstrictor |
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thrombin activity
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a. plasma levels of thrombin must be carefully controlled to prevent excessive thrombosis
b. main antithrombin activity in the blood is antithrombin III and alpha 2 macroglobulin c. thrombin has a self-limiting function |
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activity of thrombin is modulated by
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1. its presence in an inactive form
2. the presence of antothrombin activity |
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self-limiting function of thrombin
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1. thrombin-thrombinmodulin activates protein C
2. activated protein C + protein S = degrades factor Va and VIIIa |
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calcium chelators
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-anticoagulants
-oxalate, citrate, fluoride, and EDTA -cannot be used in vivo |
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heparin
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-naturally occurring compound found in the lung, lining of blood vessels, and on the surface of mast cells
-major activity is to activate antithrombin III which inactivates thrombin. reacts with thrombin releasing heparin for additional antithrombin III activation - activity is dependent on its anionic character |
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coumarin compounds
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may affect clotting when administered to animals because of their activity as vitamin K antagonists
-vitamin K dependent -inhibit Glu-Gla |
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common blood thinners
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heparin and warfarin
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dynamic state of clotting system
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microscopic-size fibrin clots are constantly being deposited and dissolved
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active factor in fibrin degradation
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plasmin
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plasmin
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protease which degrades fibrin, fibrinogen, factors V, VIII, complement and some polypeptide hormones
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inactive form of plasmin
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plasminogen
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activation of plasminogen
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cleaving Arg-Val bond in plasminogen to give two-chain plasmin molecules. the two chains are held together by a disulfide bond
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plasminogen activators
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a. tissue plasminogen activator
b. urokinase c. bacterial plasminogen activators |
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tissue plasminogen activator
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1. release into blood from endothelium under conditions of injury or stress
2. inactive unless bound to fibrin 3. t-PA on fibrin = plasminogen into plasmin 4. neither plasmin nor tPA can remain bound to the degredation products |
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urokinase
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synthesized by monocytes/macrophages, fibroblasts and epithelial cells
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tests for the adequacy of the blood clotting process
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1. platelet count
2. clotting time 3. prothrombin time 4. partial thromboplastin time 5. thromboplastin generation time 6. fibrin degredation products 7. fibrinogen |
