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• First mediators


  • Histamine
  • Vasoactive amines
  • Serotonin (5-hydroxytryptamine)
  • Lysosomal Enzymes
  • Arachidonic Acid
• Metabolites


  • Prostaglandins
  • Leukotrienes
• Source


  Many cell types, particularly Mast Cells, MCG, as well as circulating Basophils and Platelets
• Histamine is released during platelet aggregation
• Cells that release histamine and other first mediators

  • Neutrophils
  • Monocytes
  • Platelets
• Arachidonic Acid


  Derived from the metabolism of arachidonic acid
• Cells that release arachidonic acid metabolites

  • Neutrophils
  • Macrophages
• Functions of first mediators

  • Arteriolar dilation
  • Rapidly increases vascular permeability
  • Vasoconstriction During Clotting
  • Destroy phagocytosed substances and cause tissue damage
  • Potentiate the effect of histamine
  • Contribute to Pain and Fever that accompany inflammation
  • Potent chemotactic agent for neutrophils and monocytes
  • Increases vascular permeability
• Histaminase


  Inactivates histamine soon after its release
• Antiproteases


  Present in the plasma and tissue fluids, limit the potentially damaging effects of lysosomal enzymes
• Leukocyte product change


  1. Once leukocytes enter tissues, they gradually change their products from leukotrienes to anti-inflammatory mediators called lipoxins

  2. Lipoxins inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes
• Lipoxins


  Anti-inflammatory mediators produced by activated and adherent platelets
• Newly synthesized mediators


  • Cytokines
  • Reactive Oxygen Species (ROS)
  • Nitric Oxide
• Cytokines


  Principally produced by activated lymphocytes and macrophages, modulate the function of other cell types
• Chemokines


  Cytokines that stimulate leukocyte movement (Chemotaxis)
• Important cytokines mediating inflammation produced by macrophages

  • Tumor Necrosis Factor
  • Interleukin-1
• Functions of cytokines


  • Enhance the expression of adhesion molecules on endothelium and inflammatory cells
  • Activate fibroblasts for later healing
  • Induce systemic response such as fever, lethargy, neutrophilia
• Reactive Oxygen Species (ROS)

  • When produced within lysosomes, they function to destroy phagocytosed microbes and necrotic cells
  • When secreted at low levels, they can increase chemokine, cytokine, and adhesion molecule expression
  • At higher levels, they are responsible for tissue injury through endothelial damage, protease activation, and direct injury to other cell types
• Nitric Oxide (NO)


  Short-lived, soluble, free radical gas produced by many cell types, plays roles in inflammation including vasodilation and reduction of leukocyte recruitment at inflammatory sites
• Various antioxidant protective mechanisms (e.g. superoxide dismutase, and glutathione) present in tissues and blood minimize the toxicity of the oxygen metabolites
• INFLAMMATION


  The response of living vascularized tissue to injury. It is a protective mechanism intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair.
• Acute inflammation


  • Onset is fast (minutes or hours)
  • Duration is short (days or weeks)
  • Tissue injury is often severe and progressive
  • Local and systemic signs are prominent
• Subacute inflammation


  • Onset is slow (days)
  • Duration is between acute and chronic
• Chronic inflammation


  • Onset is slow (days)
  • Duration is long (months or years)
  • Tissue injury is usually mild and self-limited
  • Local and systemic signs may be subtle
• Causes of acute inflammation

  • Infections (bacterial, viral, fungal, parasitic)
  • Trauma and various physical and chemical agents
  • Tissue necrosis (from any cause)
  • Foreign bodies
  • Immune reactions
• The acute inflammatory response

  1. Vascular changes

  2. Cellular events
• Vascular changes


  1. Changes in vascular caliber and flow

  2. Increased vascular permeability
• Hyperemia


  Active increase of blood flow in capillaries
• Exudate


  Protein-rich fluid that accumulates in the extravascular tissues due to increased vascular permeability
• Beneficial effects of fluid exudate

  • Dilution of toxins produced by bacteria
  • Entry of antibodies
  • Transport of antibiotics
  • Fibrin formation to impede movement of microorganisms
  • Delivery of oxygen and nutrients for active cells
• Leukocyte recruitment and activation

  1. Margination and rolling of leukocytes

  2. Pavementing of leukocytes

  3. Emigration of leukocytes

  4. Chemotaxis
• Chemotaxis


  The movement of leukocytes toward sites of infection or injury along a chemical gradient
• Chemotactic factors


  • Bacterial products
  • Cytokines, especially chemokines
  • Components of the complement system
  • Products of arachidonic acid metabolism
• Leukocyte activation


  1. Phagocytosis

  2. Liberation of substances that destroy extracellular microbes and dead tissues

  3. Production of mediators that amplify the inflammatory reaction

  4. Role of macrophages
• Phagocytosis


  The process of recognition, attachment, engulfment, killing and degradation of particles by leukocytes
• Opsonins


  Host proteins that coat microbes and target them for phagocytosis, the most important being immunoglobulin G (IgG)
• In most acute inflammations, macrophages play a lesser role in phagocytosis compared with neutrophils. They do not predominate until the later stages when the neutrophils have diminished in number and the macrophages have increased in number by local proliferation.
• Macrophages secrete various growth factors which are important in the process of repair.
• Local signs & symptoms of acute inflammation

  • Redness
  • Swelling
  • Heat
  • Pain
• Macrophages


  • They are responsible for clearing away tissue damaged debris and damaged cells
  • They release lysosomal enzymes to assist in the digestion of inflammatory exudate