Inflammation.

Inflammation

1. General aspects of all inflammation

   • 5 cardinal signs
     • Heat
     • Redness
     • Swelling
     • Pain
     • Loss of function
   • Components of all Inflammatory responses
     • Changes in vascular permeability
     • Induction of homeostasis and fibrinolysis
     • Platelet activation and secretion
     • Monocyte recruitment & Phagocytosis
     • Tissue Repair
   • Beneficial Aspects of Inflammation
     • 1. Dilute/ Inactivate biologic and chemical toxins
     • 2. Kill or sequester microbess, foreign matter, necrotic tissue and neoplastic cells
     • 3. Degrade foreign material
     • 4. Provide wound healing factors to damaged tissues
     • 5. Restrict movement of joints etc to allow time for healing and repair
     • 6. Increase temperature to locally inhibit repro of some microbial agents
   • Outcomes of Inflammation
     • Return to normal
     • Abscess formation
     • Healing by connective tissue replacement
     • Progression to chronic Inflammation

2. Acute Inflammation

   • Classification
     • Minutes - 48 hours
     • Neutrophils are main cells present
     • Increase permeability & vasodilation
     • EC material is oedema & fibrin
   • 3 major components
     • Vascular Phase
       • 1. Alterations in vascular caliber that lead to an increase in blood flow
         • I. Vasoconstriction
         • II. Vasodilation
         • III. Increased Vascular Permeability
           • Retraction of endothelial cells
             • elicited by histamine and bradykini etc.
             • Called the immediate transient response because it occurs rapidly and is short lived (15-30 mins)
           • Endothelial Injury
             • Direct damage to endothelium
             • Rapid reaction which may be long lived
             • Results in endothelial cell necrosis and detachment
           • Leukocyte mediated endothelial injury
             • Neutrophils adhere to endothelium and injure endothelial cells
             • Leakage starts rapidly after injury
           • Transcytosis
             • Increased transport of fluids and proteins through endothelial walls
             • Vascular Endothelial Growth Factor(VEGF) promotes vascular leakage
               • Increases the number and size of transport channels
       • 2. Changes in microvasculature that permit plasma proteins and leukocytes to leave the circulation
     • Cellular Phase
       • 3. Emigration of leukocytes from microcirculation
         • I. Margination: leukocytes accumulate along the periphery of the endothelium
           • II. Rolling: leukocytes roll along the endothelium
             • III. Adhesion: mediated by Selectin & Integrin
               • Produced in response to infection & injury
               • L-selectin: expressed on leucocytes E-selectin: expressed on endothelium P-selectin: expressed on platelets & endothelium
               • IV. Emigration: Chemokines stimulate the cells to migrate through the endothelium towards the site of injury
                 • V. Chemotaxis: Movement of leukocytes along a chemical gradient towards the inflammatory stimulus in the direction of the locally produced chemoattractants
                   • VI. Phagocytosis: Particles are opsonised and then bound to phagocyte receptors and the plasma membrane forms a vescicle that encloses the particle
   • Blood stasis
     • Loss of fluids and increased vessel diameter slows down the blood flow
       • Concentrates RBCs in small vessels and increases the viscosity of blood
   • Termination of the Acute Inflammatory Response
     • Mediators of inflammation have short half lives and are degraded immediately after their release
     • Also a variety of stop signals are triggered that actively terminate the reaction
       • Switch in the type of arachidonic acid metabolite produced
       • Production of anti-inflammatory cytokines (TGF-B)
       • Inhibition of the production of TNF in macrophages
         • Tumour necrosis factor
   • Suppurative, Fibrinous & Serous are all patterns of acute inflammation

3. Cells of Inflammation

   • 1. Neutrophils
     • Acute phase
     • 24-48 hr lifespan in tissues
   • 2. Monocyte / Macrophages/ Histiocytes
     • Sub-Acute to Chronic Phase
     • Days- Years lifespan
     • Mono's become Macro's after they have left the blood
   • 3. Eosinophils
     • Acute to Chronic Phase
     • 5-24 hr lifespan in the blood stream
     • 4-12 day lifespan in tissue
     • Abundant in immune reactions mediated by IgE & in parasitic infections
   • 4. Mast cells
     • Acute to Chronic Phase
     • Long-lived lifespan
   • 5. Lymphocytes/ Plasma Cells
     • Chronic Phase
     • Short to long lived

4. Chemical Mediators of Inflammation

   • Any messengers that act to contribute to an inflammatory response
     • Produced in response to various stimuli
     • One mediator can stimulate the release of others
     • Vary in their range of cellular targets
     • Once activated and released from cells, most are short-lived
   • Plasma Derived Mediators
     • Produced in Liver but enter circulation unactivated
       • require proteolytic cleavage to become functional messengers
     • Can be grouped into 4 main systems
       • 1. Complement 2. Fibrinolytic 3. Coagulation 4. Kinin
         • All 4 are activated by Hageman Factor 12
   • Cell-derived Mediators
     • Present in Intracellular granules and rapidly released by exocytosis
     • Two Major Types
       • 1. Vasoactive Amines
         • Histamine
         • Serotonin
       • 2. AA Metabolites
         • Synthesised by cycloexygenases
           • Prostaglandins
         • Synthesised by Lipooxygenases
           • Leukotrienes
           • Lipoxins
         • Released from membrane phospholipids through the action of cellular lipases
       • Others
         • Platelet-activating factor
         • Reactive Oxygen Species
         • Nitric Oxide
         • Cytokines
           • TNF & IL-2
             • Local Effects
               • On vascular endothelium
               • On leukocytes
               • On fibroblasts
             • Systemic Effects
               • Fever etc.
         • Chemokines
           • Small proteins that act as chemoattractants for leukocytes

5. Chronic Inflammation

   • 7 days - years
   • Macrophages Lymphocytes Plasma Cells Neutrophils
   • Angiogenesis & Neovascularisation
   • Collagen is the extra material Collagen

6. Sub Acute

   • 3-4 days
   • Neutrophils Macrophages Lymphocytes
   • Odema & Fibrin are extracellular material
   • Increased Permeability, endothelial injury, hyperplasia