203b

• Acute Inflammation


  • Visible Necrosis (Abscess, Cyst, Pus)
  • Acute Phase Response
  • Circulating DAMPS
  • SIRS/Sepsis
  • Complement Coagulation
• Immunity


  • Chronic Inflammation
  • Multi-Organ Dysfunction
• Regeneration


  • Replacement of injured cells by cells of exactly the same kind
  • Some cell types do not readily regenerate
  • Restoration of tissue function
  • Only usually possible for minor injuries (e.g. scratches)
• Repair


  • Replacement of injured cells but not fully space filled with fibrosis and scar tissue
  • Can cause loss or reduction of normal tissue function/structure
  • Occurs when large scale damage is sustained or in tissues that do not have the capacity for regeneration
• Cell types in the body

  • Constant regeneration (labile - mitotically active e.g. skin, gut epithelia)
  • Can regenerate if damaged (stable and normally quiescent e.g. liver hepatocytes)
  • No Limited regeneration (permanent - terminally differentiated e.g. neurons, cardiomyocytes)
• Stem Cells


  • They are undifferentiated but can differentiate into other cells
  • Divide infrequently (quiescent) but can divide forever (immortal)
  • Generate transit amplifying cells (TAC) with short, quick proliferation
  • Divide asymmetrically into two daughters to replace themselves and form a TAC
  • Too few stem cells - tissue atrophy (reduce organ size): too many stem cells - tumours
  • Stem cells can be induced for use in regenerative medicine through reprogramming of cells with transcription factors - iPSCs.
• Regeneration of intestinal epithelial cells

  1. Passage of bacterial endotoxin (LPS) through the barrier to activate macrophages via binding to toll-like receptor 4 (TLR4)

  2. Macrophages (MO) activate COX2 to metabolise arachidonic acid cleaved from membrane phospholipids into prostaglandin PGE2

  3. Leads to proliferation of the stem cells into TAC which terminally differentiate into various intestinal epithelial cells to fill the damage.
• Regeneration of hepatocytes


  1. Damage to cells releases DAMPs, detected by liver macrophages, Kupffer cells, via Toll-like receptors (TLRs)

  2. Activated Kupffer cells release cytokines and growth factors that induce hepatocyte mitosis

  3. Mesenchymal and Hepatocyte Stem cells also contribute to regeneration by division and differentiation

  4. Up to 70% of the liver can be lost and regenerated successfully
• Repair


  1. Haemostasis

  2. Inflammation

  3. Proliferation

  4. Remodelling
• Repair


  • When tissue is lost, or both parenchymal (functional) and stromal (supportive) tissues are damaged, repair occurs via formation of a temporary connective tissue (granulation tissue) that resolves as a scar
  • Normal function of a tissue or organ can be reduced
  • Repair can work alongside regeneration in certain tissues
• Macrophages


  • Key to regulate each step in the repair process
  • M1 (IL-6, IL-1, ROS)
  • M2 (PDGF, TGFB, VEGF, TNFa/EGF)
  • pro-resolution (TGFB, IL-10)
• Clotting


  Arrests bleeding (hemostasis)
• Clotting process


  1. Activation of the coagulation cascade by platelets aggregating and degranulating generates fibrin

  2. Transglutaminases cross-link Fibrin to fibronectin and other ECM proteins
• Clotting


  • Provides temporary mechanical stability
  • Provides a barrier to microorganisms
  • Provides a barrier to prevent desiccation
  • Provides a matrix into which cells involved in repair migrate
  • Provides a matrix rich in cytokines and growth factors such as PDGF, TGFB and VEGF secreted from platelets
• Fibrin


  Protein that forms a mesh to arrest bleeding
• Fibronectin (FN)


  Protein that cross-links with fibrin
• Transglutaminase


  Enzyme that cross-links fibrin and fibronectin
• Chemokines


  Signalling molecules that attract cells to the site of injury
• IL-1


  Inflammatory cytokine
• IL-6


  Inflammatory cytokine
• M1 macrophages


  Pro-inflammatory macrophages that secrete IL-1 and IL-6
• M2 macrophages


  Wound repair macrophages that secrete PDGF, TGFB, VEGF
• PDGF


  Growth factor that stimulates fibroblasts
• TGFB


  Growth factor that stimulates fibroblasts
• VEGF


  Growth factor that stimulates endothelial cells
• EGF


  Growth factor that stimulates epithelial cells
• TGFa


  Growth factor that stimulates epithelial cells
• Debridement


  1. Phagocytosis of necrotic tissue and bacteria by neutrophils and macrophages

  2. Secretion of proteases by macrophages to liquefy tissue

  3. Generation of ROS by macrophages that are chemotactic, mitogenic and anti-microbial

  4. Secretion of mitogenic growth factors for fibroblasts, endothelial cells and epithelial cells
• Phagocytosis


  Process where cells engulf and digest debris and pathogens
• Proteases


  Enzymes that break down proteins
• ROS


  Reactive oxygen species that are chemotactic, mitogenic and anti-microbial
• Adaptive immunity


  Immune response involving T cells that is activated by antigen presentation
• Granulation tissue formation


  1. Fibroblasts migrate into the clot and differentiate into myofibroblasts when induced by PDGF and TGFB, fibronectin and mechanical tension

  2. Myofibroblasts lay down collagen fibres, express smooth muscle actin and contractile stress fibres, form focal adhesions, and contract to pull wound edges together

  3. Myofibroblasts die by apoptosis at the end of the granulation phase
• Myofibroblasts


  Contractile fibroblasts that pull wound edges together
• Collagen III


  Disorganized collagen fibres that are replaced by parallel bundles of collagen I during remodelling
• Angiogenesis


  Endothelial cells produce new capillaries in response to macrophage-derived VEGF
• Pericytes


  Cells that line blood vessels to stabilize endothelial cells, produced in response to PDGF
• Vasculogenesis


  Formation of new blood vessels from endothelial progenitor stem cells
• Epithelial to Mesenchymal Transition (EMT)


  Process where basal epithelial cells detach from the basement membrane, convert to a mesenchymal phenotype, and migrate to repopulate the wound
• Leap-frogging


  Process where suprabasal epithelial cells loosen and 'fall' into the wound gap to repopulate it