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PHRD5015 Lecture 10 - Process of Inflammation

  1. major precursor of eicosanoids
    arachidonic acid
  2. 3 types of eicosanoids
    • 1) prostaglandins
    • 2) thromboxanes
    • 3) leukotrienes
  3. eicosanoid that plays an important role in asthma
    leukotrienes
  4. eicosanoid targeted by NSAIDs
    prostenoids (prostaglandins)

    -> COX
  5. -highly proinflammatory molecule (NOT eicosanoid) 
    -growth/survival factor for fertilized eggs
    -used for in-vitro fertilization
    platelet activating factor (PAF)
  6. type of hormone prostenoids are
    local -> rapidly inactivated
  7. beginning of synthesis of prostaglandins/thromboxanes
    arachidonic acid -> COX -> PGH2-> -> ->
  8. type of COX constitutively expressed and found in many cells
    COX1
  9. type of COX that is inducible and thought of as the inflammatory COX
    COX2
  10. functions of PGE2
    • induce: GI mucus secretion, fever, pain
    • inhibit: gastric acid secretion
  11. functions of PGI2
    • dilate: blood vessels
    • inhibit: plt aggregation, immune system
  12. functions of TXA2
    • constrict: blood vessels
    • induce: plt aggregation, immune system

    **OPPOSITE OF PGI2**
  13. functions of PGF2Image Upload 2
    constrict: smooth muscle
  14. how leukotrienes are formed
    action of lipoxygenase on arachidonic acid
  15. 3 types of lipoxygenase
    • 1) 5LO
    • 2) 12 LO
    • 3) 15LO
  16. type of LO found in eosinophils
    15LO
  17. type of LO found in platelets
    12LO
  18. type of LO that converts arachidonic acid to 5HPETE
    5LO
  19. principle metabolite of neutrophils
    LTB4
  20. principle metabolites of mast cells
    LTC4, LTD4, LTE4
  21. physiological actions of LTB4
    • chemotaxis/kinesis
    • vascular permeability
    • afferent nerve sensitization
  22. physiological actions of LTC/D/E4
    • hypotension
    • airway smooth muscle constriction
    • vascular permeability
  23. what histamine is formed from
    L-histidine
  24. functions of H1 receptors
    • in epidermis - induce itching
    • in dermis - cause pain
    • in epithelial cells of post capillary veinules - induce contraction
  25. H1 mediated dilation
    • occurs via endothelium
    • release of NO & PGE2
    • rapid, short-lasting
  26. H2 mediated dilation
    • occurs via smooth muscle
    • generation of cAMP
    • slow in onset, more sustained
  27. mechanism for PGE and NO mediated relaxation of smooth muscle
    increase SR Ca2+ pump -> plasma membrane ion channel (hyperpolarization) -> reduce MLCK activity -> reduce actin-myosin complex efficiency
  28. effect of histamine on vascular smooth muscle
    relaxation/dilation
  29. effect of histamine on nonvascular smooth muscle
    constriction
  30. triple response
    • flush
    • flare
    • wheal
  31. loss of outgoing fluid
    wheal
  32. what serotonin is derived from
    L-tryptophan
  33. what serotonin is metabolized by
    monoamine oxidase
  34. functions of serotonin (5HT) in inflammation
    • increase capillary permeability/edema
    • constriction of non-vasc SM 
    • itching/pain
    • stop bleeding
  35. primary inflammatory signaling molecule
    IL-1Image Upload 4
  36. 3 types of IL-1
    IL-1Image Upload 6, IL-1Image Upload 8, IL-1RA
  37. Kineret/Anakinra
    IL-1RA as a drug
  38. cleaves TNFImage Upload 10 to turn it into a soluble mediator
    TACE
  39. 2 types of signals TNFR1 contains
    • 1) survival/proliferation/activation
    • 2) death
  40. where TNF is derived from
    Th1 T cells
  41. Acute Phase Response
    systemic response that accompanies the local inflammatory response
  42. Acute Phase proteins
    • 1) Mannose binding lectins (binds to carb targets on pathogens; activates complement via Lectin pathway)
    • 2) C-reactive protein (activates complement via alternative pathway)
  43. major family of pattern recognition receptors
    TLR
  44. diseases associated with TNF
    • RA
    • Crohn's
    • age-related macular degeneration
  45. what do TLRs recognize?
    • 1) PAMPs
    • 2) danger signals
  46. where TLRs are located
    phagocytic cells
  47. TLR signaling pathway ultimately activates ___
    NF-Image Upload 12B
  48. endogenous ligands recognized by TLR (3 examples)
    • heat shock proteins
    • beta-amyloid
    • oxidized LDL
  49. innate recognition uses ___.
    TLR ligands
  50. adaptive recognition uses ____.
    fragments of proteins present by MHCII to CD4+ TCR
  51. danger signal cell surface proteins
    B7
  52. NLR proteins
    • family of proteins that are nucleotide binding and leucine rich
    • NLRP3 capable of sensing cellular stress
  53. protein complex in which NLRP3 resides
    inflammasome
  54. caspase-1
    • promotes cleavage of procytokines (IL-1, IL-8)
    • aggregated by NLRP3
    • does NOT induce apoptosis
  55. Muckle-Wells disease
    • caused by mutation in NRLP3
    • over-activation of the inflammasome with IL-1 secretion
    • responds well to IL-1RA
  56. components of NLRP1 inflammasome
    NLRP3, Asc adapter protein, Caspase-1
  57. 2 common requirements for all activators of NLRP3
    • 1) induce ROS generation
    • 2) promote decrease in intracellular K+
  58. diseases associated with mitochondrial dysfunction (4)
    • 1) T2DM
    • 2) cardiovascular disease
    • 3) cancer
    • 4) neurodegenerative diseases
  59. binding element of CAMs on the WBC
    sialyl Lewisx (ganglioside)
  60. activates transcription of CAMs (ex: ICAM, E-selectin)
    NF-Image Upload 14B
  61. vasculature changes associated with leaky vessels
    • decreased blood flow
    • decrease in intracellular Ca2+
    • relaxation of vasc. SM
  62. change in VEC to become leaky
    • intracellular Ca2+ INCREASES
    • VEC contract
  63. how is a signal transmitted from the VEC to neutrophil?
    ICAM interacts with LFA-1 -> combines with LTB4 signal -> heparin binding protein (HBP) released -> permeability
  64. 4 steps of extravasation
    • 1) rolling
    • 2) activation
    • 3) adhesion
    • 4) chemotaxis
  65. main goal of complement
    deposit large quantities of C3b on surface of infecting pathogen
  66. classical complement pathway
    C1 binds @ least 2 Abs bound to Ag -> C1 activated -> C1 cleaves C2, C4 -> C2/4 (convertase) cleave C3
  67. common to all 3 complement pathways
    C3b associates w/ convertase and cleaves C5
  68. formation of MAC
    C5b binds C6, then C7-9
  69. function of MAC
    create hole in bacterial wall to dysregulate osmolarity
  70. complement alternative pathway
    C3 spontaneously hydrolyzes in serum -> binds factor B -> bound factor B cleaved by factor D to form fluid phase C3 convertase -> cleaves C3
  71. stabilizes C3 convertase
    properdin
  72. factors inhibiting complement activation
    • Factor H (C3 competitive inhibitor)
    • Factor I (cleaves C3b)
  73. complement lectin pathway
    mannose binding lectins (MBL) bind to mannose on glycoproteins on bacterial cell surface -> recruits MASP-1 & MASP-2 -> C2 & C4 converted into C3 convertase
  74. 3 organisms/cells MAC can induce lysis in
    • 1) Gram negative bacteria
    • 2) parasites
    • 3) viruses
    • 4) erythrocytes/nucleated cells
  75. strategies of MAC evasion
    • 1) thick walls
    • 2) capsule
    • 3) enzymes that inactivate complement
    • 4) rapid endocytosis of MACs
  76. regulation of complement system
    • complement components are labile
    • inhibitors present at all levels of cascade
  77. major opsonin of complement system
    C3b
  78. major source of CR1
    erythrocytes
  79. mechanism of immune complex clearance
    complex C3b-bound -> C3b binds CR1 (bound to RBC) -> RBC travels to liver/spleen -> macrophages phagocytize complex
Author
daynuhmay
ID
237834
Card Set
PHRD5015 Lecture 10 - Process of Inflammation
Description
inflammation
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