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The sequels to cell injury

Introduction

  • Inflammation: acute and chronic
    • Driven by chemical mediators leading to local changes that promote the healing process
    • Acute: inflammation then healing
    • Chronic: healing and inflammation run in parallel

Definitions

Overview of the inflammation process
  • Healing is the process by which the body replaces damaged tissue with living tissue
    • Involves cell death which leads to inflammation

Regeneration

  • Ideal way of healing
  • Parenchymal cells that have died are replaced by replication of surviving cells
    • Several types of parenchymal cells that have different regeneration capacities
      • Labile – continuously replicating (eg: surface epithelia, skin, gut)
      • Stable – slow cell turn over by can proliferate with stimuli (eg. liver, renal tubules, secreotry glands,smooth muscle)
      • Permanent – cannot divide (eg. CNS nerves, skeletal muscle, cardiac muscle, hyaline cartilage)
  • Requires regeneration via adult stem cells – very limited
  • Regeneration involves cell replacement and structural/architectural replacement
    • Otherwise tissue will not be functionally effective
    • Structural organisation ie, the extracellular matrix (CT) also needs to be regenerated

Repair

  • When regeneration is not possible, parenchymal cells can be replaced by connective tissue - repair
    • Occurs in all tissues except in the bone and CNS etc via granulation tissue
  • Granulation tissue has three main components
    • Inflammatory cells
      • Macrophages (phagocytose cellular and protein debris and coordinate via cytokines)
        • Keep granulation process going, induce cellular migration/differentiation and angiogenesis
      • Appear round
    • Activated contractile fibroblastic cells (myofibroblasts)
      • Make matrix proteins (extracellular matrix, collagen), proteoglycans and gluycosaminoglycans
    • Blood vessels – angiogenesis

Healing in skin/mucosae – an example of repair

  • Tissue injury leads to haemorrhage/haemostasis
    • This induces an acute inflammatory response
      • This triggers the healing process
  • Healing involves restoration of the epithelial layer, requires:
    • Migration of adjacent epithelial cells
    • Proliferation to restore epithelial thickness
  • Granulation process
    • Inflammation involves presence of macrophages that induce migration and proliferation of endothelial cells and fibroblastic cells
      • Endothelial cells proliferation forming vessels/capillaries – angiogenesis
      • Fibroblastic cells synthesise the extracellular matrix – collagen
    • Over time, the vascular supply regresses, collagen is broken down and remodelled (collagenases) and the scar contracts
  • Eg: paper cut/shaving cut
    • Clot holds surfaces together
    • On the surface, cells migrate and proliferate
      • Granulation tissue collects and lays down collagen
    • Scar tissue forms, proliferation of endothelium complete
  • Eg: large wound with sutures
    • Clot is not strong enough to hold the wound together so a suture provides strength
    • Epithelium migrates to undermine the wound (overshoots and is eventually broken down)
    • Granulation tissue forms below
    • Suture track begins the healing process with epithelial migration and granulation formation
      • Need to leave the suture in long enough for the granulation process to start but before epithelium forms in the suture wound itself
  • Overall process of large wound with sutures
    • Post-operative – sutures holding epithelium together allowing granulation process to start
    • 1 week – sutures removed, dead epithelial cells are shed, vascularity due to granulation tissue andangiogenesis
    • 2 weeks – collagen remodelling reducing the size of the scar and its vascularity
    • 3 weeks – small scar, essentially invisible

Healing by primary and secondary intention

Primary intention

  • Healing with an apposed incised wound
    • Limited inflammation, rapid restoration of epithelium by migration and proliferation
  • Little formation of granulation tissue
    • Minimal scarring

Secondary intention

  • Healing with substantial tissue loss
    • Marked inflammation, delayed re-epithelialisation
    • Ingrowth of granulation tissue, wound contraction
    • Significant scarring
  • Slow process
    • Clot forms
    • Granulation tissue grows into base of wound
      • Minimal epithelial migration
      • With time, epithelium bridges gap and scar forms
  • Granulation tissue
    • Can see BVs look to the surface and return
    • Myofibroblasts are oriented perpendicularly to hold wound together
  • EG: lacerated wound
    • 3 weeks – clot, slow healing by second intention
    • 3 months – lack of hair, dense collagen and epithelium, crinkled due to scar contraction

Healing mediators

  • Mediated by sequential release of locally acting cytokines, platelets, macrophages and mast cells
    • Cytokines (proteins) in healing are often known as growth factors
  • 3 types of chemical mediators
    • Autocrine
      • Same type of cells, eg: epidermal growth factor inducing epidermal proliferation
    • Paracrine
      • Adjacent cells, eg: macrophages affecting fibroblasts, vascular endothelium etc
    • Endocrine
      • Circulating hormones – not major in healing
  • The mechanisms that stop granulation process are not well understood

Factors affecting healing

  • Systemic and local factors
    • Local is dominant:
      • Vascularity (lack means slow healing)
      • Infection, mechanical trauma, chemical injury (eg: dressings)
      • Foreign bodies, irradiation, neoplasia
    • Systemic:
      • Age, nutritional status (protein, vitamin deficiency)
      • Other diseases (diabetes, neoplasia)
      • Hormonal status (steroid therapy, eg: glucocorticoid – anti-inflammatory)