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377 Cards in this Set
- Front
- Back
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example of cellular adaptations to stress?
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in cells that don't replicate (cardiac/skeletal muscle cells) in response to a chronic increased blood flow-->cells will undergo hypertrophy
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define hypertrophy
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increase in cell and organ size
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how can hypertrophy lead to heart failure?
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there is a limit to muscle mass-->enlargement can no longer compensate for increased burden
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classes of hypertrophy?
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phsyiologic-->weightlifting. Hormonal stimulation-->uterus during pregnancy. Pathologic-->LV hypertrophy in hypertension
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in cardiac hypertrophy, what are the triggers?
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mechanical (has to pump more) and trophic (alpha adrenergic stimulation)
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what is hyperplasia and what types of cells does it occur in?
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increase in the # of cells-->occurs in tissues capable of replicating (can occur with hypertrophy)
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classes of hyperplasia?
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physiologic (hormonal, breast enlargement at puberty or compensatory when remove parts of liver). Pathologic-->excessive hormonal or growth factor stimulation-->imbalance in estrogen production, wound healing, viral infections
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is hyperplastic process reversible?
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yes, if stimulus is removed. If cell can’t control-->unregulated cell growth-->cancer
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what can lead to cancer?
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pathologic hyperplasia
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what is atrophy?
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reduced function of size of cells or organs-cells get smaller cytoplasmically
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reduction of organ size may reflect what?
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reversible cellular atrophy or irreversible loss of cells. Reversible if stressor is removed
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list a few examples of atrophy
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disuse atrophy of muscle (paralyzed). Starvation. Aging. Chronic inflammatory disease-->persistant cellular injury
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how does atrophy affect the cellular machinery?
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it's an active, specific cellular adaptive response-->specific proteins decrease synthesis others increase. Anabolic shuts down, catabolic pathway activated. Ubq pathways activated. Longer term protein levels governed by selective expression of genes
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define metaplasia
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one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type
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give example of metaplasia
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in smokers, normal columnar epithelium can't resist heat and carcinogens so it changes to squamous which can resist smoke but they aren't specialized with cilia/mucus to protect. You see squamous metaplasia in bronchus. * can also induce malignant transformation-->squamous cell carcinoma in airways
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define ischemia
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loss of blood supply to tissues
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what are the causes of cell injury and cell death?
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oxygen deprivation due to hypoxia-->interferes with oxidative respiration: ISCHEMIA, inadequate oxygenation of blood (pneumonia, anemia, CO). Chemical agents-->poisons that interfere with cellular metabolism, membrane permeability, osmotic regulation. infectious agents-->bacteria, parasites. immunologic reactions-->allergies, autoimmunity. genetic defects-->single AA substitution leading to protein malfunciton. nutritional imbalances, phsyical agents-->trauma, heat, cold. Aging-->diminished replicative, repair ability.
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what is the first manifestation of injury to a cell?
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cellular swelling-->failure of energy dependent ion pumps to maintain fluid homeostasis-->cells letting too much water in, Na and Ca go in too.
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morphology of reversible injury?
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small clear vacuoles in cytoplasm, organ appears pale, turgid. Chromatin clumps. Mitochondria and ER swell. Membrane blebs.
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example of reversible injury?
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in liver, see lipid vacuoles in cytoplasm of hepatocytes. In liver, FA's taken in from diet are digested into lipoproteins, cholesterole, phospholipids, ketone bodies, CO2. If you metabolically screw up the breakdown of free FA's then FA's will accumulate in the liver and it will become large, yellow, slippery. but if you fix the problem-->it's reversible
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what 2 phenomena characterize the point which is no longer reversible and are typical of necrosis?
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inability to reverse mitochondrial dysfunction-->can't make ATP so can't maintain Na/K ATPase. Disturb membrane function too much (lysosomes membrane breaks inside cell and enzymes release inside cell. Plasma membrane, mitochondrial membrane)-->enzymatic action, flooding, leaking out components
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morphology of irreversible injury?
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swelling of ER and loss of ribosomes. Lysosome rupture. Nuclear condensation. Swollen mitochond with amorphous densities. Myelin figures----->fragmentation of cell membrane and nucleus-->contents leak out-->starts immune response
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nuclear changes include?
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karyolysis (disintegration of nucleus). Pyknosis (nucleus condenses). Karyorrhexis (chromatin is distributed irregulary throughout cell-->destructive fragmentation of nucleus)
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how can you clinically detect tissue specific necrosis?
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by assaying blood or serum samples of tissue specific cellular proteins
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examples of tissue specific proteins involved in necrotic tissues
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cardiac muscle-->creatine kinase, troponin which are unique isoforms. Hepatic bile duct epithelium has temperature resistant isoform of alkaline phosphatase. Hepatocytes contain transaminases
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define autophagy
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lysosomal digestion of cells own components-->is a subcellular response to injury
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what events can lead to autophagy?
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if proteins sense nutrient deprivation. Undigested debris can persist as residual bodies or can be extruded. Organelles/cytosol sequestered in autophagic vacuoles formed from ribosome-free areas in RER-->fuse with lysosomes
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what is lipofuscin?
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pigment granules derived from free-radical mediated lipid peroxidation
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steps of autophagy?
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organelle is taken up by vacuole-->digested-->forms residual body-->is released by exocytosis
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what is induction (hypertrophy) of smooth ER?
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an adaptive response. SER is involved in metabolism of a number of chemicals. Long term use of barbiturates leads to increase in P-450 mixed function oxidase system that metabolizes the drugs so you get more P-450 and thus need more drugs to feel the same affect since they are being oxidized so quickly-->also is injurious because forms reactive oxygen species (ROS)
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what are some cytoskeletal abnormalities that can result in subcellular response to injury?
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detective cell locomotion, aberrant movements of intracellular organelles, abnormal buildup of fibrillar material inside cell in alcoholic liver disease. Defects in microtubules result in lack of sperm motility and ciliary action in respiratory epithelium with chronic infections. defects in microtubles or drugs preventing normal function inhibit leukocyte phagocytosis, migration and prevent mitotic spindle formation (antiproliferative)-->without microtubules, can't bring lysosome over to get rid of phagosome
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what are the 5 mechanisms of cell injury?
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1. Depletion of ATP. 2. Damage to mitochondria. 3. Influx of Ca. 4. Accumulation of Free Radicals 5. Defects in membrane permeability.
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what are the major causes of depletion of ATP?
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ischemia-->reduced oxygen and nutrient supply, mitochondrial damage-->action of toxins (cyanide)
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what happens to the cell when ATP is depleted
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Na pump doesn't work-->cellular swelling. Increased anaerobic glycolysis-->decreases intracellular pH. Ca pump fails with Ca inlfux-->metabolic poison. Ribosomal detachment from ER and loss of protein synthesis. Ultimately leads to irreversible damage to mitochondrial and lysosomal membranes and necrosis
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what damages mitochondria?
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increased cytosolic Ca ions, ROS, oxygen deprivation
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what are the 2 major consequences of damage to the mitochondria?
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leakage of proteins (cytochrome c) into cytosol-->initiates cell death by apoptosis. Formation of high conductance channel in mito membrane leads to loss of membrane potential, pH changes,failure of oxidative phosphorylation and drop in ATP production-->necrosis
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explain normal Ca levels
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cytosolic free Ca levels are kept at very low level by Ca transporter.
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what can lead to Ca influx?
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ischemia and toxins can damage membranes and transporters
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what happens if Ca transporter is damaged?
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intracellular stores release Ca and later get influx of extracellular Ca-->that increased cytoplasmic Ca activates ATPases that decrease ATP, Endonuclease-->nucleus chromatin damage, Phospholipase and protease results in membrane damage.
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explain the accumulation of free radicals
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ROS are normally produced during mitochondrial respiration and energy generation. But if you have increased production and decreased degradation-->leads to oxidative stress on cells and resultant injury-->oxygen toxicity, chemicals, radiation injury, microbial killing by phagocytic cells, tissue injury caused by inflammatory cells.
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what happens when Free Radicals accumulate?
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lipid peroxidation of membranes disrupts plasma membranes and organelles, cross-linking of proteins via S-S bonds leads to abnormal folding, DNA fragmentation at thymine leads to mutations, breaks
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how are free radicals normally removed?
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degraded by superoxide dismutase, GSH (glutathione) peroxidae soaks up free radicals, catalase in peroxisomes, antioxidants, increased binding of Fe and Cu ions to transport proteins
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what can lead to defects in membrane permeability?
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decreased phospholipid synthesis, increased phospholipid breakdown, ROS, cytoskel abnormalitites, lipid breakdown products that act as detergents or re-insert themselves into membrane altering its properties
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what are the most important membranes to be affected?
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plasma membrane, mitochondrial membrane, lysosomal membrane
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does the membrane stay intact during apoptosis?
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yes, but it has opsonic molecules on it and is target for phagocytic cells-->no inflammatory response
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examples of physiologic apoptosis?
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to reduce cell numbers-->embryogenesis, elimination of self-reactive lymphocytes, involution of hormone-dependent tissues, cell loss in proliferating populations
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examples of pathologic apoptosis?
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when DNA is damaged beyond repair-->p53 mediated. When accumulate misfolded proteins in the ER (mutation, exogenous chemical). Cells infected by virus or immune response. Pathologic atrophy in parenchymal organs with duct obstruction
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what are the 2 major pathways to activate caspases? Explain
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mitochondrial (intrinsic) pathway-->growth factor withdrawal, DNA damage, protein misfolding-->bcl-2 family sensors-->Bcl-2 family effectors (Bax, Bak)-->mitochondria produces cyto. C or pro-apototic proteins which initiate caspases. Death receptor (extrinsic) pathway-->receptor ligand interactions (Fas, TNF Receptor)-->adaptor proteins-->iniator caspases-->executioner casp
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both caspase pathways lead to what?
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endonuclease activation and breakdown of cytoskeleton-->cytoplasmic bleb-->apoptotic body-->engulfed by phagocyte
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the CNS includes?
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brain & spinal cord
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what connects the CNS to all other parts of the body?
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PNS
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Explain inputs of CNS
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all through sensory-->process and integrate information, store info, determine emotions
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explain outputs of CNS
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all through motor--> initiate commands for muscle contraction, glandular secretion, hormone release (regulate and maintain homeostasis)
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location of gray matter? White matter?
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gray matter outside. White inside, deep in cortex
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what is in gray matter?
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neuronal cell bodies, dendrites, glia and blood vessels.
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what is in white matter?
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myelinated axon tracts (pathways for communication) where axon travels
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what are association fibers?
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connect gyri in same hemisphere
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what are commissural fibers?
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connect gyri in opposite hemispheres (crossing fibers) connect 1 side to other side
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projection fibers?
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connect cerebrum with other parts of the brain and spinal cord-go the longest distance, very long axons
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describe the cerebellum
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the little brain-has 2 hemispheres, highly folded. Functions include control of skeletal muscles for balance, coordination and posture (unconscious). Stores patterns of movement. Links to brainstem
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describe contralateral motor control
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motor nerves cross sides in spinal cord, many pathways are crossed
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what are the 3 types of neurons that connect the CNS to the body?
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sensory, motor, interneurons
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sensory neurons connect what?
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sensory receptors outside in the periphery go to the CNS
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motor neurons connect what?
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within spinal cord, connects CNS out to the muscles and organs
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interneurons connect what?
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connect all sensory and motor connections within the CNS
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main function of neurons?
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conduct electrical impulses (action potentials) along the plasma membrane
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do neurons divide?
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no, but they can live and function for a lifetime
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neurons require what to survive?
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abundant oxygen and glucose
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describe the structure of the neuron? How do they vary?
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has only 1 axon and many dendrites. Vary based on length of axon and branching of dendrites
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main function of dendritic spine?
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receivces info and makes synpases-->produce electric potential- postsynaptic transmission
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main function of axon?
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undergo action potential to transmit info to other places in NS via neurotransmitters from the axon terminal -->synpases on spine of next neuron
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what are nuclei?
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clusters of neuron cell bodies in CNS
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what are ganglia?
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clusters of neuron cell bodies in the PNS
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fibers transmit electrochemical signals towards where?
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toward the nerve cell body- so basal dendrites have higher probability to produce action potential then the apical dendrites
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complexity of neurons?
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the more complex the branching, the greater the synaptic input
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where does action potential begin?
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at the axon hillock in the neuron cell body
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bundles of axons (fibers) in the CNS?
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tracts or columns
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bundles of axons in the PNS?
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nerves
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difference between electrical synpase and chemical synapse?
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chemical synapses take longer
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what makes graded potentials and why?
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when dendrites receive info, they undergo graded potentials which then accumulate and axon will produce action potential
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what accounts for the resting membrane potential of -70mV?
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the electrical difference between the fluid inside the cell and the fluid outside the cell. Na high outside cell and K high inside the cell. At rest, neurons have a higher permeability to K so equili potential will be closer to that of K+. K is -89 equili potential and Na is +60mV
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how does the cell membrane affect the membrane potential?
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non permeable membrane-provides high resistance and the charge difference is needed to establish membrane potential. (-) inside cell and (+) outside cell
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what is the potassium equilibrium potential?
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build up of positive charge in compartment 1 produces an electrical potential that exactly offsets the K chemical concentration gradient-->voltage potential generated neutralizes the chemical concentration gradient
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sodium equilibrium potential?
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buildup of positive charge in comp2 produces electrical potential that exactly offsets the Na chemical concentration gradient
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what is the nernst equation?
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describes the equilibrium potential for an ion- it gives the voltage of the equili. Potential 60log[outside]/[inside]
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what is the main reason neurons require so much energy?
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to operate the Na/K ATPase pump- 1 ATP is hydrolyzed to operate pump-->resulting in 3 Na exit cell and 2 K enter cell-->which creates a slight charge
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characterisitics of graded potential?
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decremental, magnitude of potential change can vary-all depends on intensity of stimulus, confined to small region, can be depolarizing or hyperpolarizing
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action potentials are propagated by what?
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local current flow
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characteristics of action potentials? What governs speed of action potential propagation?
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active, regenerative-in front of the propagating action potential the membrane is below threshold and the mechanisms of passive conduction prevail-->these passive mechanisms govern the speed of action potentials
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how does the length of the axon affect conduction velocity
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the larger the axon-->the faster/higher the conduction velocity
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in neurons, what generates action potentials?
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graded potentials
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once graded potential reaches threshold what happens to voltage gated ion channels?
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all Na channels open up at the same time and Na rushes in and membrane becomes depolarized and becomes + inside axon. Na channels inactivate and K channels open so K rushes out of the cell (at this point cannot reactivate AP) then all channels close. but there is an undershoot when K channels slowly start to close near the resting potential
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difference between voltage gated Na channels and K channels?
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Na- fast opening, fast closing, inactivate spontaneously. K slow opening and closing, only inactivate when membrane repolarizes
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how do Aps propagate down axons?
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as waves
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activation of Na channels induces
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depolarization
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Na channels inactivating and K activating induces what?
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repolarization
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what is saltatory conduction?
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action potentials move rapidly along myelinated axons because the only parts of the neuronal membrane that undergo ion movements are the sections at the nodes of ranvier- the AP jumps across nodes and increases conduction velocities
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inflammation is a protective response of what type of tissue?
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living, vascularized tissue
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inflammation is what type of response and what are the components?
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connective tissue response. Blood vessels, blood cells, plasma, mast cells, macs, fibroblasts
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how does inflammation eliminate harmful agents?
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destroying, diluting with edema, sequestering the harmful agent/injured tissue to permit healing/repair
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how does inflammation eliminate itself?
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injurious agents-->cell/tissue damage-->inflammation can cause cell/tissue damage or can repair tissue
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acute inflammation is designed to deliver what to where?
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intravascular pre-formed defensive elements of blood to the extravascular site of injury
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what does acute inflammation deliver?
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plasma fluid and plasma proteins, neutrophils
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what are the vascular changes in an acute response?
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dilation, increased permeability
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what are the cellular events in an acute response?
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emigration, activation, chemotaxis
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how do arterioles change during inflammation?
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constrict then dilate
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result of vasodilation?
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results in increased blow flow in capillary beds (hyperemia) and increased hydrostatic pressure
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increased intravascular hydrostatic pressure leads to what?
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an increased filtration of fluid through the vessel wall (transudate)-->pushes water out of blood stream
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difference between transudate and exudate?
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transudate-there is no change in protein levels so the proteins suck the water back into the vessel. Exudate-->fluid and proteins leak out so proteins like Abs and fibrin help eliminate infection-->don't have proteins to suck water back in, get increased interendothelial spaces
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mechanisms of increased permeability?
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endothelial cell contraction. Endothelial retraction. Direct endothelial injury. Leukocyte mediated endothelial injury
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what elicits endothelial cell contraction?
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histamine, bradykinin, leukotrienes, etc bind to specific receptors on endothelium that lines post-capilarry venules-->immediate transient response
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result of contraction?
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widened intercellular gaps
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what induces endothelial retraction?
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IL-1, TNF, hypoxia, sublethal injury-->onset within 4-6 hours after stimulus
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result of retraction?
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widened intercellular gaps in post-capillary venules
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how does retraction occur?
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reorganization of cytoskeleton, lasts more than 24 hours
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how does direct endothelial injury increase permeability?
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endothelial necrosis and detachment (severe mechanical injuries, burns, bacterial lytic infections). Platelets bind to damaged endothelium and thrombi form but leakage is immediate and sustained until completely thromboses or repaired with new endothelium
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how do leukocyte-mediated endothelial injury increase permeability?
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leukocytes accumulate at sites of injury and release toxic substances that can damage adjacent endothelial cells.
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where can damage occur due to leukocyte releasing toxins?
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Largely restricted to sites where leukocytes adhere to the endothelium (venules at sites of inflammation, pulmonary capillaries)
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leukocyte-mediated endothelial injury is associated with what?
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late stages of inflammation, long-lived (hours)
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describe the events leading up to neutrophils and leukocytes migrating to the site of inflammation and the process of rolling
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increase in vascular permeability of the microvasculature causes an outpouring of protein rich fluid into the extravascular tissues. Less fluid in venous return results in a higher downstream [RBC] which forms sort of a plug and makes the blood more viscous, which slows upstream circulation (stasis) because the blood stream is slowly flowing (stasis), neutrophils can bind to the endothelium along the vessel periphery and roll-->there are mediators near the dead tissue that make endothelium sprout receptors (selectins) wanting to catch neutrophils. when intergrin binds selectin on endothelium, integrin changes to high affinity and binds ICAM-1 (integrin) goes through basement membrane and enters connective tissue--> migrate into the extracellular matrix
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where does transmigration mostly occur?
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intercellular junctions of PCVenules
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timing of inflammatory cells during acute inflammation
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neutrophils enter first because they are most numerous in blood and the initial slectins select for neutrophils, macrophages become more numerous around 23-48 hours later. It's a graded response, if you have bad bug, will have more neutrophils and macs for longer
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how are leukocytes activated?
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by chemical factors bind TLRs and induce metabolic changes-->increase synthetic activity, increase secretion of lysosomal enzymes, mediators, become more phagocytic
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explain leukocyte chemotaxis
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unidirectional migration up a chemical gradient. Receptor-chemotaxin binding triggers actin assembly, movement.
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exogenous chemotaxins?
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soluble bacterial products, LPS, various lipids
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endogenous chemotaxins?
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C5a, IL-8, other chemokines
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what triggers leukocyte phagocytosis?
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binding opsonin to cell. IgG on antigen, Fc fragment bind FcR on cell. C3b coats bacteria-->c3bR on cell
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what kills bacteria in phagolysosome? Process?
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reactive oxygen species. Burst in oxygen consumption, as NADPH oxidase converts oxygen to superoxide free radical. MPO uses Cl- and H202 to create HOCl free radical---->most efficient form of killing!! Radicals kill. Enzymes Digest!
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what results from MPO deficiency? NADPH deficiency?
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without MPO, person can still kill microbes via superoxide. Without NADPH results in chronic granulomatous disease.
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what are the non-oxygen dependent mechanisms to kill bacteria?
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bacterial permeability-increasing protein, lysozyme, arginine-rich cationic peptides (definsins)
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how can phagocytosing leukocytes cause injury?
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may release lysosomal products into ECM through regurgitation, frustrated phagocytosis, secretion-->releases lysosomal enzymes, ROS
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what are some defects in leukocyte function?
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increased susceptibility to infection, defect in leukocyte adhesion molecules so can't get to site of infection. Defects in fusion of intracellular vacuoles, defects in phagocytosis, chronic granulomatous disease, acquired diseases that disrupt stages of response-->diabetes, leukemia-blood is full of leukemia cells so they interfere with selectin and leukocytes interacting with endothelium.
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what cells produce histamine?
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perivascular mast cells, basophils, platelets
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what stimuli makes cells release histamine?
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cold/heat, IgE, C3a or C5a, IL-1, IL-8, neuropeptides
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how does histamine affect the cell?
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causes arteriolar vasodilation-->increases vascular permeability in venules via endothelial contraction because they have receptors for histamine
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what do arachidonic acid metabolites do?
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substrate for enzymes results in leukotriene 4 series and prostaglandin 2 series (both proinflammatory)
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what do lipoxins do?
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inhibit inflammation, inhibit PMN chemotaxis and adhesion to endothelium
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what are glucocorticoids?
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potent inhibitors of inflammation- it upregulates gene that inhibits phospholipase A2 release
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what do omega-3 FA's do?
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compete with omega 6 FA's and result in structurally different FA's in plasma membrane that are less affective molecules for immune reactions
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what are the 2 most important cytokines in acute inflammation?
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IL-1 and TNF-->they modulate the function/differentiation of other cells
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how do cytokines help inflammation?
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activate endothelial cells, increase adhesion molecules for leukocytes, procoagulant. IL-1 activates fibroblasts with increased production and turnover of the ECM (REPAIR), systemic effects--> fever, lethargy-->acute phase responses via endocrine action
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role of ROS?
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aid in killing ingested microbes-->they are released in low levels, are proinflammatory and increase expression of other mediators.
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what does NO do? How is it produced? What produces it?
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causes smooth muscle relaxation/vasodilation-can also kill microbes. Produced enzymatically by NO synthetase (NOS). Endothelial cells produce it constantly at low levels. Also inducible in macrophages, endothelium, and other cells
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why is NO turned on during inflammation?
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prevents hypertension, relaxes smooth muscle
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how do lysosomal constituents effect tissue?
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potential mediators of inflammation and tissue destruction. Neutral proteases (elastase, collagenase) break down the ECM, cleave precursors to form C3a and C5a, bradykinin.
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when can lysosomal constituents cause tissue damage?
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when enzymes overwhelm the anti-proteases that are in the tissue and serum
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what is complement?
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a series of plasma proteins that serve to activate C3
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what do C3a and C5a do? (anaphylatoxins)
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vasodilation and increase vascular permeability via histamine. CAUSE INFLAMMATION
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what are the effector functions of complement activation?
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recruitment and activation of leukocytes-->destruction of microbes. Recognition of bound C3b by phagocyte C3b receptor-->phagocytosis of microbe. MAC complex lyses microbe
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what does C3b do?
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opsonin which enhances phagocytosis
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what is the main example of plasma proteases?
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kinin cascade
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what activates the kinin system?
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rough surfaces, collagen. Activated by XII
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ultimately what does kinin system make and what does that do?
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bradykinin-->causes early vasodilation, increased vascular permeability of venules and pain. Similar to histamine. Also causes extravascular smooth muscle (bronchial) contraction like histamine. Is inactivated by kinases
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what is the plasma protease system involved with clotting? What does it do?
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fibrinolytic system-->is activated as part of clotting mechanism-->generates plasmin
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How do C3a, C5a and bradykinin affect the vessel?
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increase vascular permeability
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what are abscesses?
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localized foci of suppurative (purulent) inflammation-->neutrophils, edema and necrotic debris (pus) typically do to bacterial infection
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what does factor XII (Hageman factor) initiate?
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kinin cascade, clotting cascade, fibrinolytic system, complement cascade. Once you start 1 pathway, all other pathways will join in due to the enzymes released
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summary. What mediators causes vasodilation?
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prostaglandins, NO, histamine
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summary. What mediators causes increased vascular permeability?
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histamine, bradykinin, C3a & C5a-->(because they release histamine), PAF, substrance P. Leukotrienes C4-E4
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summary. What mediators are involved with chemotaxis and leukocyte activation?
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C5a, LTB4, IL-1/TNF, chemokines. Bacterial products (N-formly methyl peptides)
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what chemical mediators cause fever?
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prostaglandins, IL-1, TNF
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what chemical mediators cause pain?
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bradykinin, prostaglandins, neuropeptides
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what chemical mediators cause tissue damage?
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neutrophil and macrophage lysosomal enzymes. ROS, NO
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what is serous inflammation?
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when exudate is protein-poor resulting in watery fluid that accumulates in area of injury (skin blister)
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what kinds of injury causes acute inflammation?
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infarction, bacterial infections, toxins, trauma
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what kind of injury causes chronic inflammation?
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viral infections, chronic infections, persistent injury, autoimmune diseases
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what happens to the vessel during acute inflammation
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vascular changes, neutrophil recruitment, limited tissue injury
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what happens to vessel during chronic inflammation?
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angiogenesis, MNC infiltrate, fibrosis, progressive tissue injury
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what occurs with fibrosis?
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collagen deposition, loss of function
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what is chronic inflammation?
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prolonged duration (weeks/months) that is active-->tissue destruction and healing happen at the same time
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dominant cell in chronic inflamm?
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macrophage, B & T cells
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how does macrophage change when it becomes activated?
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larger, increased metabolism, increased ability for phagocytosis and killing
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what is secreted by activated T cells and activates macrophages to be pro-inflammatory?
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IFNg
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when do macrophages hang around tissue?
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only if irritant is not eliminated-->macs will accumulate and can cause lots of tissue damage
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when are eosinophils present?
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during parasitic infections, allergies. They secrete MBP which are toxic to parasites and human cells
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when are mast cells important? What do they do?
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both chronic and acute. Secrete cytokines, chemokines, and growth factors, PG/LT
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what are granulomas?
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histological pattern of chronic inflammation. Macrophages-->surrounded by collar of lymphocytes, plasma cells and outer rim of fibroblasts, fibrosis
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when is granulomatous inflammation seen? Examples?
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TB, leprosy, syphilis, crohn's disease
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what happens with severe bacterial infections (sepsis)?
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results in large amounts of TNF, IL-1, IL-12 in the bloodstream-->lead to disseminated intravascular coagulation, hypoglycemia, hypotensive shock
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what is an increase in WBC in blood? And what produces it?
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leukocytosis. IL-1/TNF stimulate WBC production and release from bone marrow
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what triggers activation of genes involved in cell replication?
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both injurious agents and certain inflammatory mediators
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what are the 2 repair processes?
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regeneration-replacement of cells by cells of the same type to try to restore function. Or replacement by connective tissue (scarring)-serves as a patch to hold things together
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what are labile tissues?
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composed of continuously dividing stem cell populations to replace lost cells. Surface epithelia in ducts, skin, GIT, GUT, airways. Hematopoietic cells
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what are stable (quiescent) tissues?
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cells are in G0 with a normal, low level of replication, but can be activated to proliferate rapidly by re-entering G1. parenchymal cells of most solid organs, liver. Mesenchymal cells (fibroblasts, smooth muscle-->will make new blood vessel). endothelium. except for liver, these tissues have limited capacity to regenerate.
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what determines if function is destroyed or not?
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if the connective tissue matrix stays together..good! If it is destroyed, not good.
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permanent tissues?
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most nerve cells, skeletal and cardiac muscle-->nondividing cells-->have left cell cycle--> with no or very little ability to regenerate. Repair is dominated by scarring
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what is granulation tissue?
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proliferation of endothelial cells and fibroblasts
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components of scarring? 4
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formation of new blood vessels (angiogenesis). Migration and proliferation of fibroblast. Deposition of new ECM by fibroblasts..collagen. Maturation and organization (remodeling) of the ECM to form a scar
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what is angiogenesis?
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pre-existing vessels send proliferative sprouts into the repair zone
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sprouts are stimulated by?
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VEGF, FGF
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remodeling of new vascular tube with enveloping ECM is stimulated by? And stimulate fibroblasts to proliferate? And migrate into the repair zone? Synthesize increasing amounts of ECM to support vasculature
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TGFb, PDGF
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how does the ECM change after it undergoes remodeling?
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use to be loose to permit cells to migrate thru, but after remodeling, it become dense fibrous tissue as collagen increases. Vascularity also decreases so that the reparative connective tissue is minimally scarred
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what does collagen look like in tissue?
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lines up horizontally
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what is healing by first intention? Time frame of cells involved?
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perfect sterile wound closed by sutures. Within 24hrs neutrophils have migrated into clot and epidermis is mitotically active after 48 hours epithelium has covered the wound with a basal layer. Day 3, neutophils are replaced by macs, epidermis is thickening and granulation tissue is invading the fibrin clot meshwork. day 5, epithelium is normal thickness, agiogenesis is maximal. during 2nd week, fibroblasts and collagen become much more evident as edema, WBC and vascularity decrease. end of month-->noticeable scar..fibroblasts have dec. and blood vessels are sparse
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what is healing by 2nd intention?
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wounds with separated edges. Infarcts, uclers, abscesses, surface wounds. Larger amounts of granulation tissue produced. More necrotic debris that has to be removed. A LOT more vascularity, neutrophils Myofibroblasts lay down collagen and contract and keep contracting until scar is small
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final strength of wound?
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70-80% because collagen arranged only in 1 direction so not complete meshwork
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pathologic aspects of wound repair?
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infection, nutrition, glucocorticoids, mechanical factors, foregin bodies, circulatory status
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what are osme excessive amounts of healing during wound repair?
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can form keloid, aggressive fibromatoses. Excessive contracture of wounds give rise to deformity-->loss of function (burns). Prolonged chronic inflammation-->continued stimulation of reparative mechanisms with abundant fibrous tissue produced-->RA, lung fibrosis (organ replaced with fibrosis)
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what happens during chronic inflammation? Activation of macrophages and lymphocytes leads to activation of growth factors, cytokines and what?
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growth factors (PDGF, TGFb) lead to proliferation of fibroblasts, endothelial cells and specialized fibrogeneic cells-->increased collagen synthesis-->fibrosis. Cytokines (TNF/IL-1) lead to increased collagen synthesis-->fibrosis. Also, decreased collagen degradation-->fibrosis
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what is infarction?
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necrosis caused by an obstruction of the tissues blood supply-->leads to local lack of oxygen
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different btwn pharmacokinetics and pharmacodynamics?
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kinetics is the movement of drug around the body, what the body does to the drug, metabolized or excreted, drug in tissue distribution. Dynamics is what effect the drug can produce.
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examples of pharmkinetics stats?
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oral avail, renal excretion, plasma protein bind, Cl, Vd, T1/2
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examples of pharmdynamics?
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effective concentration, toxic concentration
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where do you look to find the therapeutic range?
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plama concentration
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enteral?
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oral
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enteral-related?
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sublingual, rectal
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parenteral
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anything but enteral/enteral related. So respiratory (inhalation), Injectable (IV), Skin (topical, transdermal, inunction)
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when is it better to use sublingual or rectal route?
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if you want it in circulation faster and want to increase amount that gets in the blood stream, bypasses liver
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what is high 1st pass metabolism?
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starts getting metabolized in the liver
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what to do if pill has high 1st pass metabolism?
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choose different route, not oral.
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why do you give insulin shots subcutaneously?
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to big of protein and ionized to cross the membrane
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route for enteral administration of drug?
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oral-->stomach-->small intestine-->liver-->general circulation
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what is elixirs?
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liquid form that contains alcohol
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what are the different ways drugs are absorbed into systemic circulation?
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passive diffusion (vs. filtration) active transport
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explain absorption of water-soluble drug
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passive diffusion through an aqueous channel or pore
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explain absorption of lipid-soluble drug?
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passive diffusion, dissolves in a membrane
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what is carrier-mediated active transport of drug?
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goes against its concentration gradient. Uses carriers and requires ATP. Only certain drugs bind to carriers, shape of drug must be similar to structure in body that binds carrier
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difference btwn passive and active transport on rate-absorption?
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passive-->if you increase concentration of drug, you will increase absorption rate. With active, at some point the carrier becomes saturated and can no longer increase absorption rate by increasing concentration of drug
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how can you increase the rate of passive absorption?
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increase [] of drug, make more lipid soluble, lower the molecular weight, larger surface area, increase the regional blood flow
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example of how increasing regional blood flow affects passive absorption rate?
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blood picks up drug which allows more drug to enter through the membrane-->the faster the blood is going by the faster the drug can enter. At dentist, with local anesthetic they give a vasoconstricter to decrease blood flow of that area
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why are acids/bases important for drugs?
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can be ionized or nonionized form. Nonionized part of drug can cross the membrane
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how can you remember if drug should be weak acid or weak base?
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like in like is not ionized. So weak acid in acetic stom is not ionized
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equation for weak acid?
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pKa-pH=log non-ionized/ionized
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aspirin is a weak acid with pka 3.5 and stomach ph=1.5. what do we know?
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3.5-1.5=2 10^2=100 so for every 100 molecules non-ionized there is 1 molecule ionized
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weak acids get absorbed where?
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stomach and small intestine
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weak bases get absorbed where?
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small intestine only
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charged molecules get absorbed where?
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not absorbed, no nonionized form
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neutral molecules get absorbed where? (ethanol)
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highly absorbed in stomach and small intestine
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what is distribution of drug?
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get drug out of circulation and to the site of action
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things to consider in regards to distribution>?
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physicochemical characteristics-->lipid soluble if want it to go to brain. Cardiac output, heart pump drug to tissues-->if you have heart failure, drug distributes more slowly. Regional blood flow. Degree of plasma protein binding. Degree of tissue protein binding. CNS and placenta
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how do blood perfusion rates affect distribution?
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some organs get blood flow rapidly (lungs, kidney, liver, heart, brain so they will be able to interact with drug faster. Takes longer for drug to get to muscle, skin or adipose
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what happens if you give warfarin in too lose a dose?
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it will bind plasma protein and have very low concentration of free protein-->risk getting clot
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what if give warfarin in dose greater than available binding sites?
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most albumin (plasma protein) contains bound drug so the concentration of free drug is significant-->a lot free circulating
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what happens if patient is on warfarin and gets infection and is prescribed another drug that binds plasma protein?
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the new drug will knock off warfarin so there is more free warfarin floating around-->greater risk of bleeding. Should have lower warfarin dose first
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what happens after binding gets saturated?
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free drug goes up a lot
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what do you do if you want a peripheral affect but not a CNS affect?
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make drug less lipid soluble so it has a harder time crossing the blood brain barrier. Try a charged drug?
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what are the 3 processes to terminate the action of drugs?
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redistribution, biotransformation (metabolism) and excretion
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elimination from body =?
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metabolism + excretion
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what is redistribution of a drug
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movement of drug away from active site and to other tissues in body
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describe the process of redistribution
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gets out of blood quickly and goes to brain and viscera (heart, kidney) then goes to lean tissue and then to adipose tissue where it can be screted again
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when can you say a drug is metabolized?
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if when the drug interacts with the biological system, it causes a chemical change in the drug (adds an OH) ex.
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are all drugs inactivated?
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NO! Some drugs aren't metabolized at all
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what is interesting about valume?>
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a couple of its metabolic products are active too
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what is a prodrug?
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it starts as inactive, then its product becomes active and is the drug
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what is special about tylenoyl?
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it is more toxic after it is broken down-->toxic to liver
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how do most drugs work after metabolized?
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most are inactivated.
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what is the purpose of drug metabolism?
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to increase water solubility, decrease lipid solubility, and increase excretion to get drug out of body
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what are the 2 categories of metabolic reactions?
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phase 1 (non synthetic rxns) phase 2 (synthetic rxns)
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what are phase 1 rxns?
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oxidation, reduction, hydrolysis
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what are phase 2 rxns?
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conjugation/synthetic-you are adding something onto drug making it more readily excited. Glucuronidation, acetylation, methylation
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where does drug metabolism occur?
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LIVER. Oral-->small intestine-->liver-->circulation
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what system accounts for how most drugs are metabolized?
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p450 enzyme system. Includes P450, NADPH, Flavoprotein. Happens in the smooth ER. DMMS drug metabolism microsomal system.
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what accounts for almost 1/2 of all drug metabolism?
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CYP3A4/5
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what factors influence drug metabolism?
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rate of blood flow to liver (if cardiac output is normal, if vasoconstricted, not dilated). Rate of entry into liver (is it highly bound to plasma proteins). Enzyme induction/inhibition. Drug-drug interactions. Genetic factors (polymorphisms). Diet, exercise, environmental factors. tissue pathology (impaired liver function-->won't metabolize well). age & gender
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give example of how one drug (the inducer) can alter another drug my enhancing its metabolism
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rifampin increases p450 synthesis, thus increasing drug metabolism. Therefore, warfarin is less effective because it is being metabolized so quickly. Thus, the person would be more succeptible to stroke. It also would affect oral contraceptives-->leading to pregnancy because birth control pills metabolize too fast.
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give example of how one drug (the inhibitor) can alter another drug my reducing its metabolism
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if you take cimetidine for heart burn-->it inhibits p450 so thus slows down metabolism. So when you take warfarin, it will metabolize more slowly and you will get excessive bleeding. Or if you take disulfiram-->it inhibits metabolism of acid aldehyde to co2 and h20 and so you get really sick if you drink ethanol
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give examples of how some drugs don't follow normal distribution
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due to genetic polymorphisms. Ethanol-->facial flushing, CV symptoms. Different people can hold different amounts of alcohol. Or succinylcholin which paralyzes patients for surgery-->in some groups of people-->they will experience prolonged apnea.
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what is unique about isoniazid?
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TB drug that has 2 normal distributions. people that are fast acetylators and people that are slow acetylators. The slow ones are more likely to get toxicity from the drug.
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what are the various ways drugs can be excreted?
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lungs, tears, sweat, saliva, breast milk, renal excretion, biliary excretion
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explain lung excretion
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small % of ethanol is exhaled. Laughing gas is inhaled and then exhaled.
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breast milk excretion?
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women nursing can't drink alcohol because it will make the baby sleepy as some of the ethanol is excreted through the milk. Weak bases are more likely to stay in brest milk.
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what is the most important route for drug excretion?
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renal-goes out through the urine.
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what are the different types of renal excretion?
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glomerular filtration, active tubular secretion, active tubular reabsorption, passive reabsorption, ion trapping
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explain glomerular filtration
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clearance rate of 125mL/min. Passive process. Free drug can be filtered, if bound to plasma protein cannot be-->must go through active secretion
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active tubular secretion secretes what?
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free and bound drug, it is both active and passive-->excretes 650mL/min.
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what is active tubular reabsorption?
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some drug can bind to carriers and be reabsorbed
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what is ion trapping?
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you can trap drugs in the nephron and change pH of urine-->allowing you to control how much drug is secreted in body.
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example of when ion trapping is a good idea?
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if someone overdoses and there is no specific antidote-->change pH of urine and trap drug in nephron
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in the kidney what can be passively reabsorbed back in the blood stream?
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non ionized and lipid soluble drugs
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drugs that can be secreted by proximal tubules?
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acidic and basic. Penicillin goes to kidney and has active tubular secretion
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how is the rate of urinary clearance dependent of urinary pH?
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if you have a weak base drug in acidic urine, it will increase excretion. If you have a weak acid, it will be more ionized in basic urine and will be secreted better at higher pH
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what is probably excreted by biliary excretion?
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large MW proteins
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what is enterohepatic recirculation?
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when a drug gets recirculated from circulation back to liver, and back to small intestine where it is excreted to bile
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factors altering rate of elimination?
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age-immature kidney/liver function, environmental factors (charchol grilled food, grapefruit juice), disease, gender, individual variation, drug-drug interactions-->1 can inhibit tubular secretion of another drug
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difference bw 1st and 0 order kinetics
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in 1st order kinetics, rate of elimination is proportional to plasma [], the more drug you have the faster it will be eliminated. 0 order is the rate that is eliminated is constant per unit time. Not proportional to plasma []. 1 drink per hour-->will not change with increasing [] of drug
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a patient enters the emergency room overdosed on weak acid with ph 7.2. ph of his urine is 5.2. how much of the drug is excreted vs reabsorbed? How would you enhance excretion?
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7.2-5.2=2 10^2 is 100 so 100 molecules are non-ionized and will get reabsorbed. To enhance excretion, increase pH of urine so more is ionized and less is reabsorbed and more is excreted.
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what are the general functions of astrocytes?
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supportive cells, involved with neuronal metabolism and signaling and help regulate the synpase. They have developmental and structural functions, vascular functions, and help main CNS homeostasis.
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how do astrocytes provide a host of essential support functions?
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structural and metabolic support to neurons. Regulate pH of the CNS. Regulate cerebral blood flow. Buffer the extracellular space against excess K+ ions. Respond to injury-->effector function ? And glial scar development.
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how are astrocytes like neurons?
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they are organized into networks. Interconnected through gap junction channels that allow the exchange of information. Tile with other astrocytes to occupy unique spatial domains in the CNS.
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describe the critical interactions bw neurons and astrocytes
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bidirectional communication is essential for neuronal survival and normal CNS function. Uptake, synthesis and release of neurotransmitters/gliotransmitters. Form synaptic connections with neurons that modify signal neurons send/receive.
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what are the various types of astrocytes?
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the true stellate astrocytes are protoplasmic and fibrous. Radial glia-->muller cells or bergmann glia. Minor subsets are velate, interlaminar, perivascular astrocytes and marginal glia
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what are the various types of oligodendrocytes (4 classifications)
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the 4 classifications are based on morphology. # and orientation of their cellular processes, shape and size of their somata, size of the axon they were associated with and their distribution within the CNS. Type I & II are similar-->both have small cell bodies with 4-6 processes that branch to myelinate. type II found only in white matter. III & IV are similar they have larger somas. III has several thick primary processes that myelinate no more than 5 thick axons. IV doesn't have processes and instead forms a single long myelin sheath over a large diameter axon, usually these are near the entrance of nerve roots into the CNS
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what is the tripartite synpase?
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how neurons communicate. Neurotransmitters released from presynpatic terminal generate postsynatpic potential in the neuron and leads to a rise in Ca in the astrocyte-->Ca signaling may trigger release of gliotransmitters from astrocytes which can signal onto pre and postynpatic neuronal membrane--can inhibit or enhance neuronal activity. this allows astrocytes to control synpase formation, regulate presynaptic function and modulate the response of the postsynaptic neuron to neurotransmitters. Ca waves propagate neuronal signaling
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how do astrocytes help maintain a healthy [K+] in the CNS?
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glial Na/K pumps are specifically designed for the removal of K from the extracellular space when [K]outside is increased, glial cells accumulate K. uptake of K occurs primarily through Kir channel, which is highly expressed at the synpases and the endfoot processes surrounding capillaries. astrocytes take up the K through the Kir channel and then redistribute it rhough astroglial syncytium via gap junctions by transferring K from higher to lower [] gradient. release of K occurs through Kir4.1 at the endfoot process-->clearance of K+. because Kir4.1 is rectifying (allows K influx and efflux) Also Na/K/Cl- co transporters assist in local K uptake-->so you get increase in [K]inside and water enters the cells with K causing swelling. spatial K buffering is more powerful mechanism for removing [K]outside
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why/how do astrocytes maintain intracellular Ca levels ([Ca2+]i)
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prolonged elevation of ca levels can be detrimental (Ca excitotoxicity). Also, Ca signaling in glia is a form of glial excitability-->Ca traverses gap junctions without lessening and is substrate for glial activity. By controlling gap junction conductance, Ca waves may define limits of functional glial networks. Astrocytes propagate intercellular Ca waves via gap junctions over long distances in response to stimulation-->determined by the Ca sensitivity of RyR and InsP3 receptors. Maintained by diffusion of InsP3 through gap junctions and secondary initiation of InsP3-induced Ca release. maintained by regenerative Ca dependent release of gliotransmitters acting on neighboring cells through extracellular diffusion. diffusion of an extracellular messenger after release from a single cell
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what is a glial scar and what is its purpose?
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when there is neuronal injury, astrocytes start expressing GFAP and they enlarge, proliferate, and modify the ECM by secreting major ECM molecules. They form dense web of plasma membrane extenstions that fills the empty space resulting from dead/dying neurons. the mature glial scars act as a barrier to inflammatory cells, infectious agents and non CNS cells to protect healthy tissue from nearby areas of intense inflammation
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what is neurovascular coupling?
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astrocytes maintain the exchange bw the blood and its own territory. Reciprocal interaction bw the astrocytes and pre and post synaptic elements meadiate endotheliala cell action. For normal brain function, there must be a tight spatial and temporal coupling bw synaptic activity, neuronal metabolism and CBF )neurovascular coupling). some thing synaptic activity is the trigger for activity dependent vasodilation or constriction.
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location and function of the 2 types of radial glia-like cells present in the adult CNS?
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bergmann cells are in the cerebellum, found in the purkinje cell layer and extend with endfeet at the pial surface-->regulate synpatic plasticity-->many elaborate side branches form very close contact with synpases on pukinje dendrites. they express high densities of glutamate transporters that limit diffusion of glutamate during its release from synpatic terminals. Muller cells are the principal glial cell in retina, oriented in the direction along which light travels through the eye-->participates in bi-directional communication with neurons, forming extensive contacts with retinl neurons. each muller cell is coupled to one cone photoreceptor cell plus a certain # of rod photoreceptor cells.
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what is the funciton of the myelin sheath and the cell type that provides it?
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oligodendrocytes. Icreases impulse speed of action potentials. Reduces ion leakage and decreases the capacitance of the cell membrane. Growth of axon is linked to the myelin sheath. Has role in Na/K channel clustering.
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what are microglia?
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resident macrophages of the CNS that reside in the parenchyma.
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what is believed to be the primary function of microglia in the CNS?
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1st defense against pathologic changes. Disturbances in the CNS activate microglia. They communicate with neurons (role is monitoring and maintaining synpases), other glia, and cells of the peripheral immune system. If injury, migrate to site of injury, proliferate, and phagocytose. 2 main functions: provoke and amplify CNS inflammation through production of pro-inflam factors and antigen presentation. produce factors needed for CNS tissue repair
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what are neuronal on and off signals?
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neuron mediated on/off molecules contribute to the maintenance of microglial quiescence or activation
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how do neuronal on/off signals participate in microglial activation?
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off signals are constituitely expressed in healthy brain and when they disappear, microglia are activated which contributes to pathology. On signals are found in damaged neurons-->microglia are activated by appearance
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why do glia violate the neuron doctrine?
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because they don't have synpases or electricity
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what do glia do?
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can sense and control neural activity-->they express every known neurotransmitter receptor and numerous ion channels, they secrete neurotransmitters. And create their own communication network. Regulate the flow of information bw neurons with Ca waves
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what do astrocytes touch?
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the extenstions touch the synpase and other side touches the blood vessel
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how do astrocytes help with developmental and structural function?
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form the scaffold of the CNS and define architecture. Regulate neuro/gliogenesis. Form a continuous syncytium and integrate other neural cells into it. Assist in injury to the CNS
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how do astrocytes affect vasculature?
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formation of glial-vascular interface. Regulate cerebral blood flow.
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how do astrocytes help maintain CNS homeostasis?
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regulate extracellular ions. Regulate brain pH
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compare protoplasmic and fibrous astrocytes?
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protoplasmic found in grey matter, fibrous found in white matter. Both have perivascular and subpial endfeet. Fibrous are arranged in rows parallel to axons, longer but less branched than protoplasmic. Protoplasmic contact much of the available neuronal surfaces. fibrous has finger like outgrowths inside the site of action potential propagation
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where is the pia mater?
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inner most layer of meinges
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what astrocyte is most involved in the developing brain? Characterisitics of it?
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radial glia. Forms endfeet on ventricular wall and the other at the pial surface. First cell to develop from neuronal progenitors. Scaffold to assist neuronal migration
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as local neurogenesis begins in the neural tube, neuroepithelium differentiate into what?
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radial glia
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describe what happens to radial glia in the mature brain?
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most transform into stellate astrocytes. Radial glia like cells remain in the cerebellum and retina
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where are velate astrocytes found?
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granular layer or the cerebellum-->they are a protoplasmic astrocyte
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where are interlaminar astrocytes found?
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in the supragranular layer cerebral cortex of higher primates
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what are the specialized astrocytes that are in vary close proximity to the pia matter? Chacterisitics?
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perivascular and marginal astrocytes-->don't have direct neuronal contact-->form numerous endfeet with vasculature. Form a glial limiting zone- a physical/immunological barrier against unwanted cells or molecules
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how are physiological effects of Ca produced?
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intracellular Ca sensors are activated by temporary increases in [Ca]I through the opening of Ca channels in the plasma membrane or or release from the ER
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what is the major source of Ca in glia Ca signaling?
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ER which serves as an intracelluar store of Ca
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what is the leading mechanism of Ca signaling in glia?
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InsP3 receptors
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how is low intracellular Ca maintained?
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To maintain low intracellular Ca, Ca is actively transported from the cytosol into the EC space, ER and mitochondria with the use of transmembrane Ca permeable channels and ATP driven Ca pumps and electrochemically driven Ca exchangers.
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why is maintaing steady K+ ion concentrations important?
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any shift in extracellular ion [] can profoundly affect the neurons and their excitability
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what is the most abundant ion channel in the majority of glia?
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K voltage gated channels (Kir) Kir4.1
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characterisitics of Kir4.1?
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contributes to the very negative resting potential of glia. It is closed when membrane is depolarized and open when it is hyperpolarized. Favors K+ diffusion INTO the cell
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difference bw pharmacologic receptors and physiologic receptors?
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pharmacologic receptors are any biological macromolecule that binds a drug-->binds to DNA, enzymes, cell membrane proteins. Physiologic are true receptors-->cellular proteins that bind endogenous ligands (glucose, uric acids, histamine) and transmit a signal leading to a change in the target cell
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what is intrinsic activity?
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the ability of a drug to produce an effect. Some drugs bind to receptors but have no intrinsic activity
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what is efficacy?
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the maximum effect
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difference bw agonist and antagonist?
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both have affinity, but agonists also have intrinsic activity and mimic effects of endogenous compounds. (full agonists and partial agonist). Antagonist has no intrinsic activity and will inhibit the action of the agonist.
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what does a graded dose response curve tell you?
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compare efficacy and potency
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what does potency tell you?
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how much of drug is necessary to produce effect-->potency doesn't have affect on efficacy
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difference bw partial and full agonist?
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partial cannot reach maximum that full can
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what happens if you have a full agonist, but then give it with an antagonist?
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it will change potency of drug, no efficacy
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what does a quantal dose-response curve tell you?
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safety of drug. Shows therapeutic index. Compares dose vs percent of people responding. With mice will have both ED50 which is efficacy dose and LD50-->lethal dose. The more farther apart the 2 the safer.
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plasma membrane receptors?
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G protein, tyrosine kinase linked, cytokine (JAK/STAT), ligand gated ion channels
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what are the steroid hormone receptors?
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they get into cell and affect protein synthesis. They are highly lipophilic molecules carried by transport protein through plasma membrane and once cross membrane they bind to their receptor inside the cell.
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types of steroid hormone receptors?
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glucocorticoids, estrogens, thyroid hormones, calcitriol, vitamin A
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how are steroid receptors activated? Mechanism of action?
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hormone +transport protein (like plasma protein) lets it go through membrane. It binds and knocks off the heat shock proteins so it gets into the nucleus where it dimerizes and binds to DNA increasing trxp and tsl. Slowly leading to a response
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types of ion channels
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voltage-operated, ligand operated, remote sensor channels
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characterisitics of ion channels?
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fastest action! Mostly neurotransmitters
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how do ligand operated channels work?
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ligand binds to receptor on membrane and activates the channel opening it and letting the neurotransmitter inside the cell.
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what type of signaling does nicotinic cholinergic receptor follow?
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Ach binds and changes the formation-->Na gets into cell and cell depolarizes-->affecting skeletal muscle contraction at the neuromuscular junction
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ion gated Ca channels usually have what affect on the cell?
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excitatory
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Cl- channel usually has what affect on the cell?
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inhibitory
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what does GABA do when it binds to its receptor?
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makes inside the cell more negative so it doesn't reach threshold and depresses the cell, relaxing it.
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how do G protein coupled receptors work?
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hormone receptor complex activates a transducer protein and these proteins are activators of several cell proteins. Agonist binds receptor and activates G protein (guanine nucleotide binding proteins)
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explain the dual receptor regulation of adenylyl cyclase
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if stimulus binds the receptor that stimulates Gs then it will increase AC and thus increase cAMP which will increase the force of contraction of the heart. If it binds to Ri, which activates Gi, it will inhibit AC and decrease cAMP levels because Gi is an inihbitor
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what does GPCR activate? That leads to intracellular Ca so it has a stimulatory affect?
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phospholipase C which increases IP3 and DAG.
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G proteins regulate what types of channels?
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ion channels-->when increase heart rate, more Ca is stored so more is released?
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examples of some GPCRs?
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beta adrenergic receptor which are usually stimulatory. Except alpha2 which is inhibitory. Dopamine, Ach, mucarinic (some of these are essential neurotransmitters), histamine, GABA, serotonin
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what is guanylyl cyclase regulated by?
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integral part of receptor and directly activated by ligand binding (NO G proteins involed). Or cytoplasmic form which is activated by Nitric oxide (NO)
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atrial natriuretic peptide binds where and does what?
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binds to receptor which increase guanylyl cyclase-->increases cGMP leading to vasodilation
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how does NO affect guanylyl cyclase
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it binds intracellularly to G cyclase and increases cGMP, increasing blood flow
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what is typical of receptors associated with tyrosine kinase?
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insulin binds-->autophosphorylation of kinase receptors-->which phosphorylates various proteins and decreases glucose production
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what does cAMP and cGMP ultimately do?
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phosphorylates proteins
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what is different about the JAK/STAT pathways? Example?
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the kinase is a separate subunit and is not part of the receptor itself. Growth hormone binds to growth hormone receptor and JAK phosph other proteins which phosphorylates other proteins
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2nd messanger removal systems?
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cAMP and cGMP phosphodiesterases which will inhibit and increase cAMP which will increase force of contraction of heart. Calcium pumps-->to storage sites and to extracellular medium. Diacyglycerol which is converted back to phosphatidyl inositol. IP3 degraded by phosphatases
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what is receptor desensitization?
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mechanism to prevent excessive response to a prolonged or overwhelming stimulus.
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exampple of receptor desensitization?
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smell-->it wanes over time of exposure. Smell receptors are desensitized
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difference bw homologous and heterlogous desensitization?
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homologous is when drug desensitizes receptor to itself only but doesn't affect other part of the receptor that might have same outcome if it works by a different mechanism. Heterologous causes change to cell so it can't produce same effect. desensitizes to itself and other things.
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mechanisms for desensitization?
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receptor internalization (sequestration), receptor phosphorylation and thus inactivation, down regulation-->so reduced synthesis or increased breakdown and receptor is degraded-->if give agonist, will have less total # of receptor. If give antagonist-->will get more receptors and upregulation
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what does betaAR do to protein kinase A?
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phosphorylates receptor so it can't activate GCPR. Increased cAMP activates protein kinase A. This phosphorylates BAR and interferes with coupling to G protein. Most important at low agoinst levels. Provides only partial desensitization. Can be heterologous. as heart fails-->increase BAR which phos receptors so can't bind to g protein
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example of receptor down/up regulation?
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overuse drugs, so when you don't have drug, it will make you feel the opposite. Sometimes after receptor is internalized, its degraded. Body pumps out more receptors. Give drug which stimulates heart-->tolerance develop to drug b/c it down regulates B1 receptors and so you don't see people on drug for long
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how does agonist affect receptors?
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down regulates receptors
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how does antagonist affect receptors?
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up regulates receptors
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what organisms require a circulatory system?
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only large ones. Small multicellular (worms and parasites) and single cell ones do not. Because single celled organisms are in direct contact with their environment and can easily diffuse short distances. Simple multicellular organisms have some organization-->digestive sac and that is how they deliver nutrients and get rid of toxins
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what are the main units of the cardiovascular system?
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the cardiac chambers (atria & ventricle), the pulmonary circulation, and the systemic circulation.
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how are they main units organized?
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in series and parallel arrangement.
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how does blood flow through the heart chambers and large vessels?
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specific closed loop pathway
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what controls the allocation of blood flow to individual organs based on their metabolic needs?
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CNS
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what are the 4 major tissue types?
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muscle (specialized for contracting and generating tension), nervous (specialized in impulse production and transmission), connective (specialized for connecting and supporting), epithelial (specialized for surface lining and exchange)
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human body has how many ogran system levels?
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11-digestive, respiratory, cardiovascular, etc.
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the internal envrionment is made up of what?
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ECF-extra cellular fluid
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difference bw local (intrinsic) and systemic (extrinsic) homeostatic control systems?
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local controls are built into an organ. Systemic is outside of organ, involves neural and endocrine regulation (coordinates various organs and systems)
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4 components of a negativee feedback loop?
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controlled variable, sensor, control center, effector
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how do you determine if feedback loop is positive or negative?
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look at direction of initiating force, if its in same direction-->positive like uterine contractions. Controlled variable moves in one direction
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living cells are metabolically active and rely on the cardiovascular system to do what?
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bring nutrients to tissue in order to sustain metabolic activity and then remove noxious by products of metabolism through excretory system
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blood goes through artery and viens and then where?
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to microvasculature and microcirulation, comes back as venous blood looking to get oxygenated
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what are the 2 systems in series and what does that mean?
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systemic circulation and pulmonary circulation-if you affect one, it will affect the other-->they must be working all the time. They are highly synchronized
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what if they are in parallel like the kidney and legs?
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you can shut down one without affecting the other that is downstream
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why does the cardiovascular system need to pump blood?
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the heart raises the pressure of the blood contained within it so that the blood will flow from the heart to the periphery since bulk flow occurs from high to a lower pressure. SA node is excitable and depolarizes spontaneously. Left ventricle is connected to the aorta and must build enough pressure up to open the aortic valvue
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when organ is resting, if doesn't need a lot of blood so what happens?
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in the capillary bed (microcirculation) the blood is shunted to go only where it is needed. So at all times they are closed to peripheral area.
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what do metabolites do? And who controls it?
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they instruct microcirculation. CNS is the government that controls it
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what is the #1 goal of the cardiovascular system?
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to maintain enough pressure to perfuse all of the organs during different physiologic conditions. And to control allocation of blood to organs according to their metabolic needs
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what organs must receive oxygen and blood flow at all times?
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brain and heart
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what regulates blood flow to organs? What else must they do?
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arterioles. Arterioles of the systemic circulation must also maintain adequate levels of vascular resistance-->the resistance to flow that must be overcome to push blood through the circulatory system
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difference bw artery and vein?
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artery has thick wall and brings blood from the heart to the body. Veins are thin walled and bring blood to the heart-->which permits more blood flow by changing diameter of vessel to constrict or dilate
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why is vascular resistance necessary?
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without it, pressure wouldn't be high enough to distribute blood to all tissues-->if all microvessels in the systemic microcirculation were open at the same time, not enough blood volume available to generate the pressure required to sustain blood flow.
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