PHRD5015 Lecture 9 - Intro to Inflammation

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daynuhmay
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PHRD5015 Lecture 9 - Intro to Inflammation
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2013-10-29 22:03:55
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inflammation
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  1. physical findings at 4 levels in which inflammation encompasses
    • 1) clinical
    • 2) physiological
    • 3) cellular
    • 4) molecular
  2. clinical level of inflammation
    • redness and swelling with heat and pain
    • +loss of function
  3. consists of T & B cells which recognize antigen and produce killer cells & antibodies
    adaptive immune system
  4. consists of everything other than T/B cells and includes cells that mediate inflammation
    innate immune system
  5. type of information inflammatory cells provide to T cells
    antigenic information
  6. function of immune cells
    provide essential signals to inflammatory cells
  7. what is inflammation mediated by
    by cells of the innate immune system
  8. Janeway's definition of the immune system
    ancient pathogenic molecules that are conserved are the driving force behind inflammation
  9. PAMPs
    • pathogen associated molecular patters
    • associated with Janeway's definition
  10. Matzinger's definition of the immune system
    • Danger Model
    • the immune system (and cells that mediate inflammation) is concerned primarily with danger signals rather than issues of self and non-self
  11. in which model would it be as likely that a damaged tissue would elicit inflammation as an infection?
    Matzinger's
  12. discovery of the inflammasome and its ability to illicit pro-inflammatory cytokine secretion supports which model?
    Matzinger's
  13. central to autoimmune disease such as type 1 diabetes
    self antigens
  14. useful for explaining how infection is handled
    PAMP danger signals
  15. useful for explaining how inflammation underlies non-immunological diseases such as atherosclerosis and type 2 diabetes
    danger signals
  16. 3 issues sufficient to elicit an inflammatory response
    • 1) infection
    • 2) trauma
    • 3) toxicity
  17. detected via pattern recognition receptors that recognize Janeway's PAMPs and by antigens recognized by T cells
    infection
  18. sentinel cells
    dendritic cells, macrophages
  19. results in overt tissue damage including the rupture of blood vessels that exposes basement membrane
    trauma
  20. binds to components of the basement membrane and begin to form a clot and secrete inflammatory mediators
    platelets
  21. intracellular components released during necrosis that act as inflammatory signals (2)
    • 1) fibrin
    • 2) bradykinin
  22. buildup of ROS intermediates in the cell leads to activation of an intracellular receptor called the ___.
    inflammasome
  23. initiates a signal transduction process that results in the secretion of inflammatory mediators
    inflammasome
  24. cytokine inflammatory mediators (4)
    • IL-1
    • IL-6
    • IL-8
    • TNF
  25. 4 types of inflammatory mediators
    • 1) cytokines
    • 2) chemokines
    • 3) growth factors
    • 4) autacoids
  26. signaling molecules that recruit inflammatory cells and provide a "bread crumb" trail back to the site of injury
    inflammatory mediators
  27. how inflammatory mediators prepare for incoming inflammatory cells (3)
    • 1) slow blood flow in the area (relax vascular smooth muscle)
    • 2) decrease integrity of vessel walls to allow fluid/cells to move in (edema)
    • 3) degrade ECM to allow access
  28. means "local hormone"
    autacoid
  29. family of molecules that provide inflammatory signals in a local area
    autacoids
  30. 8 types of autacoids
    • 1) prostaglandins
    • 2) thromboxanes
    • 3) leukotrienes
    • 4) histamine
    • 5) serotonin
    • 6) bradykinin
    • 7) platelet activating factor (PAF)
    • 8) NO
  31. expressed on the surface of the vessel wall to which circulating inflammatory cells bind during the vascular response
    CAMs - cell adhesion molecules
  32. secreted to break down collagen during the vascular response
    matrix metalloproteinases
  33. takes place later in the vascular response if there is damaged tissue that needs to be repaired
    angiogenesis
  34. produce the sensation of pain associated with inflammation when released during the neurogenic response (2)
    • 1) substance P
    • 2) CGRP (calcitonin gene related peptide)
  35. can induce vascular leakage in the absence of infection or trauma
    neurogenic inflammation
  36. circulating cells that adhere to regions expressing CAMs
    neutrophils and monocytes
  37. differentiate into macrophages during extravasation
    monocytes
  38. extravasation/diapedesis
    neuts/monos squeeze through holes between vascular endothelial cells and follow the chemokine gradient leading to the site of damage
  39. process during which phagocytic cells become 10x better at engulfing
    activation
  40. process during which the MHC is upregulated
    activation
  41. holds onto peptides to present to T cells as antigens
    MHC
  42. process during which complement proteins are expressed and secreted
    activation
  43. process during which enzymes which generate reactive molecules (peroxides) are expressed and release said reactive molecules
    activation
  44. activated by a cascade of protein cleavage events where the cleaved protein fragments assemble to form the MAC
    complement system
  45. 4 purposes of the complement system
    • 1) drill holes in the cell walls of pathogens/transformed cells
    • 2) coat pathogens to increase adhesiveness for phagocytosis
    • 3) serve as chemokines
    • 4) assist in the removal of dead blood cells
  46. 3 systemic responses of inflammatory mediators to inflammation
    • 1) travel to liver to promote expression of acute phase proteins
    • 2) travel to bone marrow to increase rate of production of inflam. cells
    • 3) travel to brain to induce fever, activate hypothalamus to induce cortisol secretion
  47. negative regulator of inflammation
    cortisol
  48. 4 types of granulocytes
    • 1) neutrophils
    • 2) eosinophils
    • 3) mast cells
    • 4) basophils
  49. granulocytes with multilobed nucleus
    neutrophils
  50. granulocytes with bilobed nucleus
    eosinophils
  51. granulocytes (2 types) with lobed nucleus and heavily granulated cytoplasm
    mast cells and basophils
  52. most common granulocytes & percentage of WBCs
    • neutrophils
    • 50-70%
  53. phagocytic granulocytes
    neutrophils, eosinophils
  54. secondary function of granulocytes
    release of pyrogens to raise body T/cause fever
  55. first of granulocytes to respond/arrive at the site of infection
    neutrophils
  56. leukocytosis
    presence of an increased number of neutrophils
  57. length of time neutrophils reside in a tissue
    ~1 day
  58. major role of eosinophils
    fight against parasitic organisms - granules damage parasite membrane
  59. major roles of basophils
    • fight helminth infections
    • certain allergic reactions
  60. what do basophil granules contain?
    • heparin
    • histamine
    • serotonin
  61. type of granulocyte that does not circulate in the blood
    mast cells
  62. major roles of mast cells
    • important mediators of allergy
    • fighting pathogens (viruses, bacteria, parasites)
    • tissue remodeling, wound healing, angiogenesis
  63. characteristics that distinguish tissue macrophages from monocytes
    • -10x larger
    • -increased phagocytic capacity
    • -increased number/complexity of intracellular organelles
    • -produce higher levels of hydrolytic enzymes
    • -secrete soluble factors
  64. histiocyte
    connective tissue specific macrophage
  65. Kupffer cell
    liver specific macrophage
  66. mesangial cell
    kidney specific macrophage
  67. microglial cell
    brain specific macrophage
  68. macrophages express _____ which bind to _____.
    • TLR
    • PAMPs
  69. M1
    classically activated macrophages
  70. M2
    alternatively activated macrophages
  71. implications of the presence of M2-like macrophages in cancer
    poor prognosis prediction
  72. factors in platelets that promote clotting/wound healing (4)
    • 1) serotonin
    • 2) epinephrine
    • 3) fibrinogen
    • 4) PDGF (platelet derived GF)
  73. how platelets are activated
    by contact with tissue collagen, air, or foreign surfaces
  74. 4 major types of dendritic cells (DC)
    • 1) Langerhans 
    • 2) interstitial
    • 3) monocyte-derived
    • 4) plasmacytoid-derived
  75. general role of DCs
    gather info and transport it where it is needed (encoded as an antigen)
  76. DC that resides in epidermal layers of the skin, shuttles to lymph nodes
    Langerhans DC
  77. DC found in the interstitial spaces of almost all internal organs (except brain)
    interstitial DC
  78. highly mobile DC
    monocyte-derived DC
  79. DC that plays roles in innate response and as APCs
    plasmacytoid-derived DC
  80. virtually all genes related to the inflammatory response are targets for this TF
    NF-B
  81. NF-B mechanism of action
    bound inhibitor IB phosphorylated by IKK & becomes ubiquitinated -> degraded by proteasome to expose nuclear localization signal -> translocated to nucleus & activates genes involved in inflammation/immune response
  82. how glucocorticoids inhibit inflammation
    transcriptional repression
  83. process in which glucocorticoid receptor binds to other proteins that had themselves bound to DNA, in order to repress NF-B
    transrepression

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