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• Inflammation


  The body's natural response to injury and infection. It is an unpleasant transient, coordinated emergency response. The central basis of many diseases.
• Surgeon John Hunter (1728-1793): 'Inflammation is not a disease but a response to tissue injury.'
• Inflammation

  • It delivers nutrients and oxygen to injured sites
  • It generates exudate (tissue fluid) that carries antibodies and protective substances into the affected area to neutralize harmful agents
  • It carries toxins away from the affected area via lymphatic drainage, to local lymph nodes to stimulate the adaptive immune responses
  • It mobilises immune cells to remove debris and defend against harmful agents (neutrophils and macrophages)
  • It limits the spread of harmful agents by encapsulating the injury - abscess walls, fibrin mesh - clot, barrier
  • It resolves inflammation - hydrolases digest inflammatory exudates following the crisis
  • It initiates repair and healing once the emergency is over
• Four Cardinal signs (Roman, Celsus)

  Redness (rubor), Heat (calor), Swelling (tumor), Pain (dolor)
• Fifth sign (Virchow)


  Functio laesa (Loss of function)
• Inflammation

  1. Tissue Injury

  2. Acute Inflammation

  3. Complete Resolution or Successful Healing or Failed Healing and Chronic Inflammation
• Initiation: Cell-derived factors

  Damaged Cells, Bioactive Peptides, Damage Associated Molecular Patterns (DAMPS)
• Initiation: Response to factors

  Tissue Resident mast cells (matured from basophils) and macrophages ('MO' matured from circulating monocytes) respond to damage signals
• Mediators

  Histamine, Proteases (e.g. tryptases), Lipid signals, Cytokines (e.g. tumour necrosis factor TNF)
• Vasodilation

  1. Smooth muscle cells relax in response to mediators

  2. Arteriole lumen (vessel) increases in diameter

  3. Increase blood flow into capillary network

  4. Leads to redness (rubor) and heat (calor) in tissues
• Vasopermeability

  1. Endothelial Cells

  2. Smooth Muscle Cells

  3. Fluid and protein leakage

  4. Increased interendothelial spaces
• Oedema


  Swelling (tumor) is caused by fluid (exudate) build up within tissues in areas between cells called the interstitium. Swelling and stretching of tissues can trigger nerve endings (receptors) and cause pain (dolor).
• Cell-derived Mediators


  Control blood vessel function. Can induce vasodilation, vasopermeability, neutrophil adhesion to endothelial cells, bronchoconstriction, pain or itching.
• Vasoactive Amines

  Degranulation of mast cells/basophils releases vasoactive amines e.g. Histamine. This leads to vasodilation, vasopermeability, neutrophil recruitment, bronchoconstriction.
• Tryptases

  Mast cell derived tryptases cleave protease-activated receptors (PARs) on the surface of other mast, endothelial cells and neutrophils. This leads to vasopermeability, vasodilation, Platelet Activating Factor (PAF) release -> leukocyte adhesion.
• Lipids

  Membrane Phospholipids (Phosphatidylcholine), Cytokines and Chemokines, PLA2 (Phospholipase A2), Arachidonic Acid, 5'-lipoxygenase (LOX), Cyclooxygenases (COX1, COX2). This leads to Leukotrienes, Prostaglandins, Thromboxane, Prostacyclin, Platelet Activating Factor (PAF).
• Circulating Mediators

  Present in precursor forms in the circulation. These are often proteins that require 'activation' via proteolytic cleavage. There are multiple inflammatory signaling cascades including Coagulation, Fibrinolytic, Kinin, and Complement. These cascades have potent vasoactive effects (affect blood flow).
• Coagulation

  Tissue Factor (TF) activates the coagulation cascade leading to Fibrin formation. This traps platelets and cells to form clots for hemostasis (stop bleeding). Abnormal thrombi formation can lead to vessel occlusion and ischemia.
• Fibrinolytic

  The Fibrinolytic system counteracts the coagulation system. Plasmin degrades fibrin, allowing blood flow to occur again. It also cleaves extracellular matrix proteins and activates matrix metalloproteases (MMP) to restore blood flow allowing wound healing and remodelling of damaged tissue.
• Kinin

  The Kinin system is also activated by FXII. Bradykinin induces vascular dilation to increase blood flow, vasopermeability and leakiness into tissues (swelling/oedema), neutrophil chemotaxis, and pain.
• Complement

  The complement system consists of 9 liver derived proteins (C1-9). It is activated by FXII, proteases, antibodies bound to antigen and bacterial products. Proteolytic cleavage produces C3a, C5a (mast cell degranulation, +vascular permeability, neutrophil chemotaxis), C3b (opsonization of particles promoting phagocytosis), and C5b (part of the membrane attack complex for bacterial cell lysis).
• Cytokines

  Small proteins (5-20KDa) released from inflammatory cells that control inflammation
• Types of cytokines

  • Tumour Necrosis Factor (TNF)
  • Interleukins (IL)
  • Interferons (IFN)
• Chemokines


  Chemotactic cytokines that act as a signal to recruit cells to sites of injury and infection ('find me')
• Coley's Toxin

  An injectable bacterial treatment derived from dead S. pyogenes and Serratia marcescens, used to activate the immune system
• Coley's Toxin was a forerunner of today's immunotherapies, through induction of systemic factors
• Tumour Necrosis Factor (TNF)


  A key active agent induced by Coley's Toxin, confirmed by experimental studies in mice in the 1970s
• Acute inflammation

  • Local TNF causes vasodilation, vasopermeability, expression of endothelial cell adhesion molecules, and activation of inflammatory cells
• Chronic inflammation


  • Systemic TNF causes fever, activated coagulation cascade, production of fibrotic (scar) tissue, and cachexia
• Neutrophils


  Major leukocyte population in the blood and in acute inflammation, attracted to sites of injury and infection
• Macrophages


  Tissue resident Macrophages (MO) detect danger signals, and are also recruited to sites of injury (recruited as monocytes from the circulation)
• Mobilisation of inflammatory cells

  1. Attraction to sites of injury or infection

  2. Neutrophil recruitment towards edges of blood vessels (Margination)

  3. Adhesion to sides of vessels

  4. Transmigration into tissues

  5. Chemotaxis to sites of injury
• Damage associated molecular patterns (DAMPS)

  Molecules released by injured cells that bind to receptors on macrophages and other local tissue resident cells, triggering the release of cytokines like IL-1a and IL-1b
• Cell adhesion molecules (CAMs)


  Molecules expressed on endothelial cells that interact with leukocytes, causing them to slow, roll, and then firmly adhere
• Neutrophil function


  1. Opsonisation

  2. Adhesion

  3. Phagocytosis

  4. Degranulation

  5. Respiratory burst
• Neutrophils and macrophages are activated in a coordinated way to eliminate damaged tissues and microbes
• Opsonisation


  Tagging of damaged cell debris/bacteria with immunoglobulins and C3b, allowing recognition by phagocytes
• Phagocytosis


  Internalization of opsonized particles into membrane-bound phagosomes
• Degranulation

  Fusion of phagosomes with acidic lysosomes containing proteases, creating phagolysosomes and removing visible lysosomes from the cytoplasm
• Respiratory burst


  Assembly of the NADPH oxidase complex on phagolysosome membranes, reducing oxygen to superoxide and activating proteases