HOMEOSTASIS • When tissue is damaged by mechanical injury, disease of infection, the damaged tissue must be removed and replaced by new cells • This may involve a large area of tissues and is associated with inflammation • Cells in some tissues of higher vertebrates cannot replicate and therefore the specialised cells are not replaced e.g CNS and heart • In other instances, repair may fail after repeated injury and extensive damage e.g cirrhosis of the liver, muscular dystrophy • In these instances the tissue is replaced by fibrous and fatty connective tissue – scar tissue • Injury & inflammation (and ageing) increased fibrous connective tissue and alters the ECM environment: this can affect the fate of precursor cells e.g in dystrophic muscle, satellite cells may become fibroblasts instead of myoblasts. • Normal maintenance and renewal of differentiated cells in many tissues •This does NOT involve leukocytes. •Leukocytes and inflammation occurs in response to damage NEED FOR REPAIR
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HOMEOSTASIS NEED FOR REPAIR · HOMEOSTASIS • When tissue is damaged by mechanical injury, disease of infection, the damaged tissue must be removed and replaced by new cells •
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HOMEOSTASIS
• When tissue is damaged by mechanical injury, disease of infection, the damaged tissue must be removed and replaced by new cells
• This may involve a large area of tissues and is associated with inflammation• Cells in some tissues of higher vertebrates cannot replicate and therefore the
specialised cells are not replaced e.g CNS and heart• In other instances, repair may fail after repeated injury and extensive damage
e.g cirrhosis of the liver, muscular dystrophy• In these instances the tissue is replaced by fibrous and fatty connective tissue –
alters the ECM environment: this can affect the fate of precursor cells e.g in dystrophic muscle, satellite cells may become fibroblasts instead of myoblasts.
• Normal maintenance and renewal of differentiated cells in many tissues•This does NOT involve leukocytes. •Leukocytes and inflammation occurs in response to damage
NEED FOR REPAIR
Key events during tissue repair
1. Sealing: to limit the damage2. Inflammation: removes damaged tissue (phagocytosis), proteases
(modify the ECM), chemokines have many effects (chemotaxis, mitogens). Involves evascularisation of leukocytes (see later lecture); neutrophils followed by macrophages
3. Angiogenesis: where blood vessels are damaged they must be replaced rapidly to allow oxygen and nutrients to the new tissue(later lecture) – otherwise scar tissue results.
4. Cell proliferation: to expand cell populations5. Cell differentiation: to generate specialised cells6. Maturation and re-innervation: to restore full function
Damage to the skin and repair
1. Sealing2. Inflammation
3. Angiogenesis4. Cell proliferation
5. Differentiation6. Maturation
Examples of cellular eventsafter damage to skeletal muscle:
> PDGF-BB/AA>TGF-ßPrevented by IRRADIATIONRequires intact VASCULAR system
Bischoff (1997): TGF-ß (platelets), HGF
PDGF-AB/BB/AA, FGF-2, EGFEffect was very DOSE DEPENDENTComplex gradients of many factors
Torrente et al (2003)TNF-α : 2 fold (also in vivo)
Also acts indirectly via MMPs and ECM breakdownLeukocytes Growth Factors
Grounds MD, Davies MJ (1996) Chemotaxis in myogenesis. Basic and Applied Myology 6(6): 469-483.
Chemotactic pathways after muscle damage
PMLs from vasculature macrophages myoblasts
DAMAGED SKELETAL MUSCLE
Key events during tissue repair
1. Sealing: to limit the damage2. Inflammation: removes damaged tissue (phagocytosis),
proteases (modify the ECM), chemokines have many effects (chemotaxis, mitogens). Involves evascularisation of leukocytes (see later lecture); neutrophils followed by macrophages
3. Angiogenesis: where blood vessels are damaged they must be replaced rapidly to allow oxygen and nutrients to the new tissue – otherwise scar tissue results.
4. Cell proliferation: to expand cell populations5. Cell differentiation: to generate specialised cells6. Maturation and re-innervation: to restore full function