CHAPTER 13- INFLAMMATION AND CYTOKINES.txt

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CHAPTER 13- INFLAMMATION AND CYTOKINES.txt
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  1. Inflammation phases:
    • Injury-
    • leads to exposed collagen, platelet-activating factor release, tissue factor release from endothelium.

    • Platelets bind-
    • release important growth factors (platelet-derived growth factor PDGF) and cytokines (IL-1 and TNF-alpha)

    • Macrophages-
    • dominant role in wound healing, release important growth factors (PDGF) and cytokines (IL-1 and TNF-alpha)
  2. See image on pg 60 (and commentary below)
    Establishment of a provisional wound matrix:

    • 1) platelets bind to the exposed wound matrix through interaction of beta-1 and beta-3 integrins and collagen, laminin, and fibronectin receptors
    • 2) after wounding, the coagulation cascade is activated, generating thrombin, which activates platelet glycoprotein gpIIb/IIIa and increases platelet aggregation.
    • 3) A provisional wound matrix is formed, made up of platelets, fibrin, fibrinogen, and fibronectin. The activated platelets in the wound generate transforming growth factor beta (TGF-beta), PDGF, and thrombin.
    • 4) TGF-beta is strongly chemotactic for neutrophils, macrophages, and fibrobrasts, recruiting these cells into the provisional wound matrix, where they are also subsequently activated by TGF-beta.
    • 5) Increasting concentrations of TGF-beta results in macrophage activation, producing increased amounts of tumor necrosis factor-alpha (TGF-alpha) and interleukin-1 (IL-1). TGF-beta also stimulates fibroblast production of extracellular matrix proteins. These reactions further enhance migration of macrophages and fibroblasts into the wound, facilitating repair.
  3. Growth and Activating Factors (on following slides)
  4. PDGF
    • 1) similar effects as TGF-beta
    • 2) chemotactic and activates inflammatory cells (PMN and macrophages)
    • 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
    • 4) angiogenesis
    • 5) epithelialization
    • 6) chemotactic for smooth muscle cells
    • 7) has been shown to accelerate wound healing
  5. EGF (epidermal growth factor)
    • 1) acts on similar receptors as TGF-beta
    • 2) less potent
    • 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
    • 4) angiogenesis- V-EGF stimulates angiogenesis and is involved in tumor metastasis
    • 5) epithelialization
  6. FGF (fibroblast growth factor)
    • 1) chemotactic and activates fibroblasts --> collagen and ECM proteins
    • 2) angiogenesis
    • 3) epithelialization
  7. PAF (platelet-activating factor)
    • 1) not stored
    • 2) generated by phospholipase in endothelium and other cells
    • 3) stimulates many types of inflammatory cells chemotactic; increases adhesion molecules
  8. Chemotactic factors:
    For inflammatory cells:
    For fibroblasts:
    • For inflammatory cells:
    • 1- TGF-beta
    • 2- PDGF
    • 3- PAF
    • 4- IL-8
    • 5- LTB-4
    • 6- C5a and C3a

    • For Fibroblasts:
    • 1- TGF-beta
    • 2- PDGF
    • 3- EGF
    • 4- FGF
  9. Angiogenesis factors:
    • 1) TGF-alpha
    • 2) TGF-beta
    • 3) EGF
    • 4) FGF
    • 5) IL-8
    • 6) hypoxia
  10. Epithelialization factors:
    • 1) TGF-alpha
    • 2) TGF-beta
    • 3) EGF
    • 4) FGF
    • 5) PDGF
  11. How long do PMNs stay in tissues? How long in blood?
    last 1-2 days in tissues (7 days in blood)
  12. How long do platelets last?
    platelets last 7-10 days
  13. Lymphocytes
    1) involved in chronic inflammation (T cells) and antibody production (B-cells)
  14. Cell Types in Type I hypersensitivity reactions: (following slides)
  15. Eosinophils
    • 1) have IgE receptors that bind to allergen
    • 2) release major basic protein, which stimulates basophils and mast cells to release histamine
    • 3) eosinophils increased in parasitic infections
  16. Basophils
    • 1) have IgE receptor
    • 2) main source of histamine in blood
    • 3) not found in tissues
  17. Mast cells
    • 1) primary cell type in type I hypersensitivity reactions
    • 2) main source of histamine in tissues other than stomach
  18. Histamine
    • 1) vasodilation
    • 2) tissue edema
    • 3) postcapillary leakage
    • 4) primary effectors in type I hypersensitivity reactions (allergic reactions)
  19. Bradykinin
    • 1) vasodilation
    • 2) increased permeability
    • 3) pain
    • 4) contraction of pulmonary arterioles
  20. Angiotensin-converting enzyme (ACE)
    inactivates bradykinin
  21. Nitric Oxide
    • 1) has arginine precursor
    • 2) Activates guanylate cyclase and increases cGMP, resulting in vascular smooth muscle dilation
    • 3) is also called endothelium-derived relaxing factor (EDRF)
  22. Endothelin
    vascular smooth muscle constriction
  23. Important Cytokines (to follow)
  24. What are the main initial cyokines involved in injury/infection:
    TNF-alpha and IL-1
  25. TNF-alpha (tumor necrosis factor-alpha)
    • 1) macrophages- largest producers of TNF
    • 2) increases adhesion molecules
    • 3) overall, a procoagulant
    • 4) causes cachexia in patients with cancer
    • 5) activates neutrophils and macrophages--> more cytokine production, cell recruitment
    • 6) can cause myocardial depression
    • 7) fever, hypothermia, tachycardia, increased cardiac output, decreased SVRI --> high concentration can cause circulatory collapse and multisystem organ failure
  26. IL-1
    • 1) main source also macrophages
    • 2) effects similar to TNF and synergizes TNF
    • 3) Responsible for fever (PGE2 mediated in hypothalamus)
    • 1- raises thermal set point, causing fever
    • 2- NSAIDs- decrease fever, reducing PGE2 synthesis
    • 4) alveolar macrophages- cause fever with atelectasis by releasing IL-1
    • 5) IL-1 also increases IL-6 production
  27. IL-6
    • 1) increased hepatic acute phase proteins (C-reactive protein, amyloid A)
    • 2) lymphocyte activation
  28. Interferons
    • 1) released by lymphocytes in response to viral infection or other stimulants
    • 2) activate macrophages, natural killer cells, and cytotoxic T cells
    • 3) inhibit viral replication
  29. Hepatic acute phase response proteins
    • 1) IL-6 is most postent stimulus
    • 2) Increased:
    • 1- C-reactive protein (an opsonin, activates complement)
    • 2- amyloid A and P
    • 3- fibrinogen
    • 4- haptoglobin
    • 5- ceruloplasmin
    • 6- alpha-1 antitrypsin
    • 7- alpha-1 antichymotrypsin
    • 8- C3 (complement)
    • 3) Decreased:
    • 1- albumin
    • 2- transferrin
  30. Cell Adhesion Molecules (upcomming slides)
  31. Selectins
    L-selectins, located on leukocytes, bind to E- (endothelial) and P-(platelets) selectins; rolling adhesion
  32. Beta-2 integrins -
    Beta-2 integrins (CD11/18 molecules)- on leukocytes, bind ICAMS etc. anchoring adhesion
  33. ICAM, VCAM, PECAM, ELCAM
    on endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets. These are also involved in transendothelial migration
  34. Image at bottom of pg 62: Leukocyte recruitement
    • 1) circulating leukocytes express integrins in a low-affinity conformation
    • 2) exposure to activated endothelium leads to rolling, which is mediated by L-selectin and P-selectin on the neutrophil and E-selectin on the endothelium
    • 3) leukocye exposure to cytokines released by macrophages phagocytosing pathogens induces a high affinity integrin conformation. Tight leukocyte-endothelial adhesion involves integrin engagement with counter-ligand expressed on endothelium
    • 4) subsequent exposure to chemokines leads to diapedesis, which is further mediated by the family of beta-1 and beta-2 integrins
  35. Complement:
    • Classic pathway (IgG or IgM)- antigen-antibody complex activates
    • 1- factors C1, C2, and C4- foudn only in the classic pathway

    • Alternative pathway- endotoxin, bacteria, other stimuli activate
    • 1- factors B, D, and P (properdine) found only in the alternate pathway

    C3- common to and is the convergence point for both pathways

    Mg- required for both pathways

    • Anaphylatoxins- C3a, C4a, C5a;
    • 1- increases vascular permeability
    • 2- smooth muscle contraction (bronchi)
    • 3- activate mast cells and basophils
  36. Image on pg 63: Complement pathways:
    • Alternative pathway:
    • 1) C3 is cleaved to C3b
    • 2) C3b binds and cleaves B to Bb to form C3 convertase (C3bBb)
    • 3) another C3b binds C3 convertase to form C5 convertase (C3bBbC3b)

    • Classical pathway:
    • 1) C1 binds immunoglobulin
    • 2) C1 binds and cleaves C4 and C2 to C4b and C2a to form C3 convertase (C4b2a)
    • 3) C4b2a binds another C3b to generate C5 convertase (C4b2aC3b)

    • Late pathway:
    • 1) C5 convertase cleaves C5 to form C5b, which integrates into the plasmalemma
    • 2) C6-8 are recruited forming the C5b-8 complex
    • 3) C5b-8 recruits numerous C9 subunits, which form a pore in the pathogen cell wall
  37. Prostaglandins (following slides)
  38. PGI2 and PGE2
    • 1) vasodilation
    • 2) bronchodilation
    • 3) increased permeability
    • 4) inhibit platelets
  39. PGD2
    • 1) vasocilation
    • 2) bronchoconstriction
    • 3) increased permeability
  40. NSAIDS:
    1) inhibit cyclooxygenase (reversible)
  41. Aspirin
    • 1) inhibits cyclooxygenase (irreversible)
    • 2) inhibits platelet adhesion by decreasing TXA2
  42. Steroids:
    inhibit phospholipase, which converts phospholipids to arachidonic acid--> inhibits inflammation
  43. Leukotrienes:
    LTC4, LTD4, LTE4-
    LTB4-
    LTC4, LTD4, LTE4- slow reacting substances of anaphylaxis; bronchocontriction, vasoconstriction followed by increased permeability (wheal and flare)

    LTB4- chemotactic
  44. Picture on Pg 64: Eicosanoid production
  45. Catecholamines (following slides)
  46. When do catecholamines peak after injury?
    24-48 hours
  47. Where are norepinephrine and epinephrine released from?
    1) norepinephrine released from sympathetic postganglionic neurons

    2) epinephrine and norepinephrine released from adrenal medulla (neural response to injury)
  48. Neuroendocrine responses to injury:
    • Afferent nerves from site of injury stimulate:
    • 1- CRF
    • 2- ACTH
    • 3- ADH
    • 4- growth hormone
    • 5- epinephrine
    • 6- norepinephrine release
  49. What role does thyroid hormone play in injury:
    thyroid hormone does not play a major role in injury
  50. CXC chemokines:
    • 1) Chemotaxis, angiogenesis, wound healing
    • 2) IL-8 and platelet factor 4 are CXC chemokines
    • 3) C=cysteine X--> another amino acid
  51. Pg 65 (see two figures): oxidants generated in inflammation and Cellular Defenses against antioxidants
  52. What are the RBC antioxidant properties:
    RBCs have some antioxidant properties (superoxide dismutase and catalase)
  53. Reperfusion injury: whats the primary mediator?
    PMNs are the primary mediator
  54. Chronic granulomatous disease:
    • 1) NADPH-oxidase system enzyme defect in PMNs
    • 2) results in decreased superoxide radical (O2-) formation

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