INFLAMMATION

INFLAMMATION

1. Acute

   • Stimuli
     • Infection
       • Toll-like receptors (TLRs)
     • Tissue necrosis
       • Uric acid, ATP, HMGB-1 -->inflammation Hypoxia --> HIF-1a --> VEGF
     • Hypersensitivity Reaction
       • Cytokines
   • Morphology
     • Blood vessels
       • Vasodilation
         • histamine NO stasis of blood (moving slowly as increased calibre, decreased volume --> margination of leucocytes.
       • ⇑Permeability
         • IMMEDIATE TRANSIENT RESPONSE (15-30mins) VEGF/histamine/leukotrienes/substance P: endothelium retracts, increased transcytosis DELAYED PROLONGED RESPONSE Toxins/UV/XR - endothelial damage
     • Leukocytes
       • Neutrophil 6-24h Monocytes 24-48h Varies Pseudomonas - neutrophils for several days Viral - lymphocyte first
       • Functions
         • Classical activated
           • Adhesion
             • Margination
             • Rolling
               • Selectins: P (platelets) E (endothelium) -bond with Sialyl Lewis X-modified glycoprotein L (leukocytes) -Glycam1, CD34Enhanced by increased expression of adhesion molecules by cytokines.
             • Firm Adhesion
               • INTEGRINS _leukocyte surface proteins) ICAM-1, various integrins
           • MIgration
             • -transmigration/diapedesis -mainly in post-capillary venules -towards chemokines chemical [gradient] -PECAM-1 (CD31) -may adhere at site needed via INTEGRINS and CD44
           • Chemotaxis
             • '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 
           • Recognition
             • See written notes. Various receptors -GPCR (bacterial peptides, chemokines) -TLR (microbial products) -Phagocyte receptors  -Cytokine receptors (IFN 7)
           • Phagocytosis
             • Recognition & Attachment
               • macrophage mannose-R (glycoproteins/glycolipids) opsinons-R  scavenger-R (LDL)
             • Engulfment
               • lysosomal enzymes
             • Killing & Degradation
               • ROS & NO  phagocyte oxidase RESPIRATORY BURST protected within lysosome H2O2 + Cl- + MPO = hypochlorite (kills by halogenation)
         • Alternatively activated
           • Anti-inflammatory
             • TGFB IL-10
           • Repair/fibrosis
             • IL-3, IL-4 Arginate proline polyamnoses
       • Injury
         • Collateral damage
         • Autoimmune
         • Allergy
       • Defects
         • Genetic
           • Leucocyte adhesion deficiency
             • 1
               • mutation in B chain CDH/8
             • 2
               • mutation in fucosyl transferase
           • Chronic granulomatous disease
             • phagocyte oxidase mutation
             • X-linked
               • membrane
             • Recessive
               • cytoplasmic
           • MPO deficiency
           • Chediak-Higashi syndrome
             • defect in lysosomal membrane traffic
         • Acquired
           • BM suppression
             • tumours/chemo/radio
           • adhesion/chemotaxis
             • DM/cancer/sepsis/dialysis
           • phagocytosis/microbicidal
             • leukaemia/anaemia/sepsis/DM/malnutrition
     • Lymphatics
       • Increase flow to cope with oedema (may proliferate) Can be infected - lymphangitis.  Nodes - lynmphadenitis
   • Mediators
     • Cell derived
       • Vasoactive amines
         • Histamine
           • • 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
         • Serotonin
           • platelets (aggr) neuroendocrine cells =similar effects
       • AA metabolites (Eicosanoids)
         • synthesised by 2 major classes of enzyme COX → Prostglandins Lipo-oxygenases → leukotrienes and lipoxins    
         • Prostaglandins
         • Leukotrienes
         • Lipoxins
     • Plasma derived
       • Enter text here

2. Chronic

   • Causes
     • Persistent Infection
       • delayed-type hypersensitivity
     • Immune mediated
       • RA, MS
     • Toxins
   • Morphology
     • Tissue destruction
       • IFNa, cytokines, microbes: ROS, NOS Proteases Cytokines Coag. factors AA metabolites
     • Attempted healing
       • IL-4 GFs Fibrogenic cytokines Angiogenic factors Remodelling collegenases
       • Fibrosis
       • Angiogenesis
     • Cells
       • MACROPHAGES
         • MonoCYTE - Circulating MonoBLAST - Bone marrow (Hours) MonoPHAGES - TIssue (months/years)
       • Lymphocytes
         • Activate and recruit macrophages via:  TNF  IL-17 chemokines T cells 
       • Plasma cells
         • develop fromactivated B lymphocytes produce antibodies
       • Eosinophils
         • IgE mediated parasites
       • Mast cells
         • 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
       • Neutrophils
         • can also be present in chronic inflammation
   • Granulomatous
     • focus of chronic inflammation microscopic aggregation of macrphages epithelial-like cells surrounded by mononuclear leukocytes 'giant-cells'
     • Foreign bodies
     • Immune
       • T cells → Il 2 → other T cells → IFN-Ɣ → activation of Macros and transformation into epitheloid and multinucleate giant cells    
       • Caseating
         • TB
           • • focus of activated macros - epitheloid cells • rim of fibros, l’cytes, histiocytes, langerhans, giant cells • central necrosis with amorphous cellular debris, acid fast bacilli    
       • Non-caseating
         • Leprosy
           • acid fast bacilli in macros    
         • Cat scratch
           • Rounded granuloma with central debris and neuts giant cells uncommon    
         • Sarcoidosis
           • abundant macrophages    
         • Syphillis
           • Treponema Pallidum    Gumma: microscopic to grossly visible lesion • wall of histiocytes, plasma cell infiltrate • central cells necrotic without loss of cellular outline    
         • Crohn's
           • occasional non-caseating granuloma in wall of intestine, with dense chronic inflamm infiltrate