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Inflammation 2.0

Khadija Abdalla English

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Inflammation 2.0

Acute Inflammation
- Stimuli
  - Tissue injury
    - Activation of Hageman Factor
      - Thrombin activation
        Protease-activated receptor
        Platelet activation
        TGFb and PDGF
        Fibrinogen
        Fibrin
        Fibrin clot + fibrinopeptides
        Fibrin degradation products
        Chemotaxis
      - tPA
        Plasminogen activator inhibitor (PAI)
        Plasminogen
        Plasmin
      - Prekallikrein
        Kallikrein
        Kininogen -- HK1 --> Bradykinin
        iNOS/NO
        Inc. vascular permeability
        Vasodilation
        Reversible opening of endothelial cell junctions
        Smooth muscle contraction
    - Hemorrhage
    - Damage associated molecular patterns (DAMPs)
      - Pattern recognition receptors (PRRs)
        Toll-like receptors (TLRs)
        NF-kB translocation into nucelus
        Inflammatory cytokines
        IFNy
        Growth maturation, differentiation of natural killers and B cells
        Leukocyte attraction
        Macrophage activation
        Acute phase response ft. inc. CRP, complement components, fibrinogen, and dec. albumin and IGF-1
        Diagnosis
        IL-1 and TNFa
        Activate endothelial cells
        Upregulation of IL-1 and TNFa
        Exravasation
        TNFa
        Cell survival (default)
        Adhesion molecules
        Adhesive interactions
        Upregulation of E-selectin, ICAM-1, VCAM-1
        Neutrophil adhesion, arrest, diapedesis
        Neutrophil rolling
        Chemokine production
        Leukocyte activation
        Cell apoptosis
        IL-1
        IL-1R and IL-1RAcp
        NF-kB
        Inflammatory cytokine expression
        MAPK
        Synthesis of matrix metalloproteinase (MMPs)
        Tollip
        Cytoskeletal regulation and cell contraction
        Cellular phospholipases
        Arachidonic Acid
        Cyclo-oxygenase pathway
        Lipo-oxygenase pathway
        Lipo-oxygenase pathway
        Leukotrines
        Inc. vascular permeability
        Swelling
        Pain
        Cyclo-oxygenase pathway
        Prostaglandins
        Vasodilation
        Inc. blood flow
        Heat
        Swelling
        Redness
        Pain
        IL-6
    - Chemotaxis of macrophages and neutrophils
      - Phagocytosis
  - Microbial componencts/ Infection
    - Complement activation
      - C--Reactive Protein
        Binds Fc receptor
        Cytokine secretion (IL-1, TNF, IL-1RA)
        Binds Fc receptor
        Cytokine secretion (IL-1, TNF, IIL-1RA)
      - Classical via antigen-antibody complexes
        Activation of C3
        Amplifying proteolytic cascade
        Membrane Attack Complex
        Loss of cellular homeostasis/ cell death
        Anaphylatoxins
        Vasoconstriction
        Bronchoconstirction
        Edema
      - Alternative via microorganisms
      - Lectin via microorganisms
    - Pathogen associated molecular patterns (PAMPs)
Chronic Inflammation
- Autoinflammatory Conditions
  - IL-1b activation disorders
    - Caspase-1
    - Inflammasome
      - NLRP3 mutation
        Cryopsin-associated periodic syndrome (CAPS)
  - NF-kB activation disorders
- Delayed-Type Hypersensitivity Reaction
  - TH1 cell meidated
    - TNFa
      - Tissue destruction
      - Vascular expression of adhesion molecules
    - IL-3/GMCSF
      - Monocyte production
    - Chemokines and IFNy recruit macrophages to the antigen site
  - Host defence against intracellular parasitess
- Autoimmune Conditions
  - Effect women > men
  - Phases
    - Subclinical
      - Initiation
        Genetic predisposition
        HLA
        Cytokine pathways
        AIRE
        Environmental triggers
        Infection
        Traumatic insult
        UV radiation
        Microbiome
    - Clinical
      - Propagation
        Cytokine production
        Epitope spreading
        Molecular mimicry
        APC, T helper cells, macrophages
        Cross-reactive T cells and B cells
        Protein changes, cryptic antigens
        APC, T helper cells
        Tissue damage
        Oxidative stress, cell death
        Activation of self-reactive T cells
        Autoantibodies
        Disrupted Teff/Treg balance
      - Resolution
        Cell extrinsic
        Cell intrinsic
  - Criteria
    - Identification of a target antigen
    - Presence of antibodies and/or T cells in target organ
    - Transfer of disease to animals by cells or antibodies
- Mononuclear infiltrate
  - Macrophages
    - PDGF, EGF, TGFb
      - Fibroblast proliferation and collagen synthesis
        Tissue destruction
    - FGF and VEGF
      - Angiogenesis
  - CD4+ Helper T cells
    - TH1
      - TNFa, IL-2, IFNy
        Activate macrophages
        Bacterial endotoxin
        Fibronectin
    - TH2
      - IL-4, -5, -10, -13
        Activate B cells
  - Plasma cells
    - Auto-antibodies
      - Complement activation
      - Bind self-tissues
- Causes
  - Irritant fails to be eliminated (e.g., persisting infection)
    - Non-granulomatous tissue
  - Self-antigens cause an autoimmune reaction (e.g., rheumatoid arthritis)
  - Irritants of low intensity, but long duration (e.g., tuberculosis)
    - Granulomatous tissue
Wound Healing
- Types of Wound Healing
  - Healing by first intention
    - High inflammation
    - Scar tissue
    - Relatively long healing period
    - High risk of infection
  - Healing by Second Intention
    - Little inflammation
    - Relatively fast healing period
    - Low risk of infection
- Outcomes of Wound Healing
  - Resolution
    - Lipoxins, resolvins, protectins
      - Stop and reduce neutrophil infiltration to inflamed tissues
      - Promote uptake and clearance of apoptotic cells and microorganisms by macrophages
      - Stimulate anti-microbial activities of mucosal epithelial cells
  - Regeneration
  - Replacement
- Proliferation
  - Angiogenesis
    - VEGF, PDGF, FGF, TGFB
      - Granulation tissue formation
  - Epithelialization
    - Keratinocytes
      - Phenotypic changes
      - Integrin receptors and extracellular matrix
      - TGFa, TGFb, EGF, PDGF
        Proliferative burst
        Wound contractions
        Myofibroblast differentiation
        Apoptosis of cells within the wound
        Myofibroblast contraction (alpha smooth muscle actin)
        TGFb signaling pathway
  - Fibroplasia
    - PDGF, GFG, TGFb
      - Activation of fibroblasts and deposition of connective tissue
    - Collagen synthesis
      - Extracellular matrix
        Sequesters water
        Regulates proliferation, differentiation, and migration of cells
        Reservoir for growth factors
        Collagen and elastin
        Proteoglycans and hyaluronans
        Adhesive glycoproteins
      - Tissue remodeling
        Fibrosis
        Possible complications
        Loss of function
        Contracture
        Stenosis
        Adhesions
        Keloids
        Ulcerations
        Collagenases
    - VEGF, HGF, KGF
Cardinal Signs of Inflammation
- Swelling (Tumor)
- Pain (Dolor)
- Loss of Function (Function Laesa)
- Redness (Rubor)
- Heat (Color)

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Description: Mind Map on Inflammation 2.0, created by Khadija Abdalla on 11/02/2021.
Created by: Khadija Abdalla
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Inflammation 2.0

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