Inflammation

Inflammation

1. Associated Cells

   • Present at Site of Inflammation
     • Endothelial Cells
     • Dendritic Cells
   • Recruited to Site of Inflammation
     • Polymorphic Neutrophils
     • Lymphocytes
     • Plasma cells
     • Monocytes/ Macrophages

2. Acute Inflammation

   • Stimuli
     • Tissue injury
       • Damage associated molecular patterns (DAMPs)
     • Infection
       • Pathogen associated molecular patterns (PAMPs)
   • Phases
     • Destruction and Repair
       • Phagocytosis
       • Enzymatic removal of pathogen
     • Termination
     • Amplification
   • Innate Immunity
     • 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 changes
                   • Diagnosis
             • TNFa
               • Cell survival (default)
                 • Adhesion molecules
                 • Chemokines
                 • 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
   • • Reversible opening of endothelial cell junctions
       • Exravasation
     • Adhesive interactions
       • • E-selectin binds Sialyl Leis X
           • Neutrophil rolling
         • ICAM-1 binds LFA-1
           • Neutrophil adhesion, arrest, diapedesis
         • VCAM
           • Neutrophil rolling
     • Cellular phospholipases
       • Arachidonic Acid
         • Leukotrines
           • Inc. vascular permeability
             • Pain
             • Swelling
         • Prostaglandins
           • Pain
           • Vasodilation
             • Inc. blood flow
               • Redness
               • Swelling
               • Heat
     • Upregulation of IL-1 and TNFa
     • Upregulation of E-selectin, ICAM-1, VCAM-1
     • Chemokine production
   • • Activation of Hageman Factor
       • Plasminogen --tPA--> plasmin
         • Complement activation
           • C--Reactive Protein
           • Classical
             • Activation of C3
               • Amplifying proteolytic cascade
                 • Membrane Attack Complex
                   • Loss of cellular homeostasis/ cell death
                 • Anaphylatoxins
                   • Local inflammatory response
                   • Bronchoconstirction
                   • Edema
           • Alternative
           • Leptin
         • Plasminogen activator inhibitor (PAI)
       • Thrombin
         • Fibrin clot + fibrinopeptides
           • Fibrin degradation products
             • Chemotaxis
         • Protease-activated receptor
           • Platelet activation
       • Kininogen --HK1--> kinin
         • iNOS/NO
           • Inc. vascular permeability
           • Vasodilation
           • Smooth muscle contraction
     • Hemorrhage

3. 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
     • Host defence against intracellular parasitess
     • TH1 cell meidated
       • Chemokines and IFNy recruit macrophages to the antigen site
       • TNFa
         • Tissue destruction
         • Vascular expression of adhesion molecules
       • IL-3/GMCSF
         • Monocyte production
   • Autoimmune Conditions
     • Effect women > men
     • Phases
       • Subclinical
         • Initiation
           • Genetic predisposition
             • HLA
             • Cytokine pathways
             • AIRE
           • Environment
             • Infection
             • Traumatic insult
             • UV radiation
             • Microbiome
           • Unchecked non-specific inflammation
       • Clinical
         • Propagation
           • Cytokine production
           • Epitope spreading
             • Molecular mimicry
               • APC, T helper cells, macrophages
                 • Tissue damage
               • 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
           • Disrupted Teff/Treg balance
         • Resolution
           • Cell extrinsic
           • Cell intrinsic
   • Mononuclear infiltrate
     • • Formation of granulomatous tissue
       • PDGF, EGF, TGFb
         • Fibroblast proliferation and collagen synthesis
           • Tissue destruction
       • FGF and VEGF
         • Angiogenesis
     • • TH1
         • TNFa, IL-2, IFNy
           • Cell mediated immunity and protection against intracellular infection
       • TH2
         • IL-4, -5, -10, -13
           • Antibody mediated immunity, hypersensitivity, and protection against extracellular pathogens
     • • 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)
       • Non-granulomatous tissue
     • Irritants of low intensity, but long duration (e.g., tuberculosis)
       • Granulomatous tissue

4. 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
   • Phases of Wound Healing
     • Inflammation
     • Proliferation
       • Granulation tissue formation
       • VEGF
         • Angiogenesis
       • Keratinocytes
         • Phenotypic changes
         • Integrin receptors and extracellular matrix
         • TGFa
           • Proliferative burst
       • Epidermal cells
         • Collagenase
           • Migrate, close wound edges
       • Collagen synthesis
         • Collagens and elastins
         • Proteoglycans
         • Glycoproteins
       • Fibroblasts
         • Fibroplasia
           • PDGF, GFG, TGFb
             • Activation of fibroblasts and deposition of connective tissue
           • Extracellular matrix
             • Sequesters water
             • Regulates proliferation, differentiation, and migration of cells
             • Reservoir for growth factors
         • Myofibroblasts
           • Contraction
             • alpha smooth muscle actin
     • Tissue Remodeling and Wound Contraction
       • Wound contraction
         • Myofibroblast differentiation
         • Apoptosis of cells within the wound
       • Tissue remodeling
         • Myofibroblast
         • Collagenase
         • Apoptosis of cells within the wound
   • Complications
     • Loss of function
     • Contracture
     • Stenosis
     • Adhesions
     • Keloids
     • Ulcerations

5. Cardinal Signs of Inflammation

   • Swelling (Tumor)
   • Pain (Dolor)
   • Loss of Function (Function Laesa)
   • Redness (Rubor)
   • Heat (Color)

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