INFLAMMATION

1. Infection

   Anmerkungen:

   • Toll-like receptors (TLRs)
2. Tissue necrosis

   Anmerkungen:

   • Uric acid, ATP, HMGB-1 -->inflammation Hypoxia --> HIF-1a --> VEGF
3. Hypersensitivity Reaction

   Anmerkungen:

   • Cytokines

1. Blood vessels
   1. Vasodilation

      Anmerkungen:

      • histamine NO stasis of blood (moving slowly as increased calibre, decreased volume --> margination of leucocytes.
   2. ⇑Permeability

      Anmerkungen:

      • IMMEDIATE TRANSIENT RESPONSE (15-30mins) VEGF/histamine/leukotrienes/substance P: endothelium retracts, increased transcytosis DELAYED PROLONGED RESPONSE Toxins/UV/XR - endothelial damage
2. Leukocytes

   Anmerkungen:

   • Neutrophil 6-24h Monocytes 24-48h Varies Pseudomonas - neutrophils for several days Viral - lymphocyte first
   1. Functions
      1. Classical activated
         1. Adhesion
            1. Margination
            2. Rolling

               Anmerkungen:

               • Selectins: P (platelets) E (endothelium) -bond with Sialyl Lewis X-modified glycoprotein L (leukocytes) -Glycam1, CD34Enhanced by increased expression of adhesion molecules by cytokines.
            3. Firm Adhesion

               Anmerkungen:

               • INTEGRINS _leukocyte surface proteins) ICAM-1, various integrins
         2. MIgration

            Anmerkungen:

            • -transmigration/diapedesis -mainly in post-capillary venules -towards chemokines chemical [gradient] -PECAM-1 (CD31) -may adhere at site needed via INTEGRINS and CD44
         3. Chemotaxis

            Anmerkungen:

            • 'locomotion along chemical gradient' ENDOgenous -IL-8, complement, EXOgenous -bacterial products (N-formylmethanyl peptides, lipids) These all react at GPCR -polymerisation of actin leading edge and myosin at back -filopodia that pull back of cell in direction of extension --> migration 
         4. Recognition

            Anmerkungen:

            • See written notes. Various receptors -GPCR (bacterial peptides, chemokines) -TLR (microbial products) -Phagocyte receptors  -Cytokine receptors (IFN 7)
         5. Phagocytosis
            1. Recognition & Attachment

               Anmerkungen:

               • macrophage mannose-R (glycoproteins/glycolipids) opsinons-R  scavenger-R (LDL)
            2. Engulfment

               Anmerkungen:

               • lysosomal enzymes
            3. Killing & Degradation

               Anmerkungen:

               • ROS & NO  phagocyte oxidase RESPIRATORY BURST protected within lysosome H2O2 + Cl- + MPO = hypochlorite (kills by halogenation)
      2. Alternatively activated
         1. Anti-inflammatory

            Anmerkungen:

            • TGFB IL-10
         2. Repair/fibrosis

            Anmerkungen:

            • IL-3, IL-4 Arginate proline polyamnoses
   2. Injury
      1. Collateral damage
      2. Autoimmune
      3. Allergy
   3. Defects
      1. Genetic
         1. Leucocyte adhesion deficiency
            1. 1

               Anmerkungen:

               • mutation in B chain CDH/8
            2. 2

               Anmerkungen:

               • mutation in fucosyl transferase
         2. Chronic granulomatous disease

            Anmerkungen:

            • phagocyte oxidase mutation
            1. X-linked

               Anmerkungen:

               • membrane
            2. Recessive

               Anmerkungen:

               • cytoplasmic
         3. MPO deficiency
         4. Chediak-Higashi syndrome

            Anmerkungen:

            • defect in lysosomal membrane traffic
      2. Acquired
         1. BM suppression

            Anmerkungen:

            • tumours/chemo/radio
         2. adhesion/chemotaxis

            Anmerkungen:

            • DM/cancer/sepsis/dialysis
         3. phagocytosis/microbicidal

            Anmerkungen:

            • leukaemia/anaemia/sepsis/DM/malnutrition
3. Lymphatics

   Anmerkungen:

   • Increase flow to cope with oedema (may proliferate) Can be infected - lymphangitis.  Nodes - lynmphadenitis

1. Cell derived
   1. Vasoactive amines
      1. Histamine

         Anmerkungen:

         • • Physical injury - trauma, cold, heat  • Binding of antibodies to mast cells - alergic reactions  • Fragments of complement - anaphylatoxins  • Histamine releasing prots from leuks  • neuropeps - subs P  • Cytokine - IL-1. Il-8   =vasodilation +^permeability
      2. Serotonin

         Anmerkungen:

         • platelets (aggr) neuroendocrine cells =similar effects
   2. AA metabolites (Eicosanoids)

      Anmerkungen:

      • synthesised by 2 major classes of enzyme COX → Prostglandins Lipo-oxygenases → leukotrienes and lipoxins    
      1. Prostaglandins
      2. Leukotrienes
      3. Lipoxins
2. Plasma derived
   1. Enter text here

1. Persistent Infection

   Anmerkungen:

   • delayed-type hypersensitivity
2. Immune mediated

   Anmerkungen:

   • RA, MS
3. Toxins

1. Tissue destruction

   Anmerkungen:

   • IFNa, cytokines, microbes: ROS, NOS Proteases Cytokines Coag. factors AA metabolites
2. Attempted healing

   Anmerkungen:

   • IL-4 GFs Fibrogenic cytokines Angiogenic factors Remodelling collegenases
   1. Fibrosis
   2. Angiogenesis
3. Cells
   1. MACROPHAGES

      Anmerkungen:

      • MonoCYTE - Circulating MonoBLAST - Bone marrow (Hours) MonoPHAGES - TIssue (months/years)
   2. Lymphocytes

      Anmerkungen:

      • Activate and recruit macrophages via:  TNF  IL-17 chemokines T cells 
   3. Plasma cells

      Anmerkungen:

      • develop fromactivated B lymphocytes produce antibodies
   4. Eosinophils

      Anmerkungen:

      • IgE mediated parasites
   5. Mast cells

      Anmerkungen:

      • display receptor that binds Fc portion of IgE in immediate hypersensitivity IgE bound to Fc recognize antigen → degranulation → ediators released e.g. Histamine and PGs mediators limit/promote infamm reactions in different circumstances
   6. Neutrophils

      Anmerkungen:

      • can also be present in chronic inflammation

Anmerkungen:

• focus of chronic inflammation microscopic aggregation of macrphages epithelial-like cells surrounded by mononuclear leukocytes 'giant-cells'

1. Foreign bodies
2. Immune

   Anmerkungen:

   • T cells → Il 2 → other T cells → IFN-Ɣ → activation of Macros and transformation into epitheloid and multinucleate giant cells    
   1. Caseating
      1. TB

         Anmerkungen:

         • • focus of activated macros - epitheloid cells • rim of fibros, l’cytes, histiocytes, langerhans, giant cells • central necrosis with amorphous cellular debris, acid fast bacilli    
   2. Non-caseating
      1. Leprosy

         Anmerkungen:

         • acid fast bacilli in macros    
      2. Cat scratch

         Anmerkungen:

         • Rounded granuloma with central debris and neuts giant cells uncommon    
      3. Sarcoidosis

         Anmerkungen:

         • abundant macrophages    
      4. Syphillis

         Anmerkungen:

         • Treponema Pallidum    Gumma: microscopic to grossly visible lesion • wall of histiocytes, plasma cell infiltrate • central cells necrotic without loss of cellular outline    
      5. Crohn's

         Anmerkungen:

         • occasional non-caseating granuloma in wall of intestine, with dense chronic inflamm infiltrate