Module 29 - Wound Healing and Repair Flashcards
Define repair.
The body’s attempt, after injury, at restoring normal structure and function. It usually consists of two processes – tissue regeneration and fibrous organization (scar formation), in varying combinations.
Describe the two outcomes in the aftermath of an acute injury.
Repair by Regeneration:
- Parenchymal cell death (intact tissue framework)
- Superficial wounds
- Inflammatory responses
- Exp. Liver regeneration after partial hepatectomy
Repair by Scarring:
- characterized by scar formation
- Parenchymal cell death (damaged tissue framework)
- deep wounds
- Exo, Myocardium infarction
Mention and describe the three types of tissue based on their proliferative capacities.
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Labile tissue: constant proliferation to allow turnover
- Example: hematopoietic cells, surface epithelia
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Stable tissue: quiescent, but proliferation can be activated
- Example: parenchyma of most solid organs, endothelial cells, fibroblast
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Permanent tissue: no proliferation, injury is irreversible, repair leads to scar formation.
- Example: Neurons, cardiac muscle cell
How is cell proliferation regulated?
- Cell-cell contact (damaged neighbouring cells, inflammatory cells)
- Cell –ECM (integrins)
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Paracrine or Autocrine factors (cytokines, hormones)
- Receptors (cell surface)
- Transcription factors (direct outcome on gene expression) - Growth factors
Define interstitial matrix and basement membrane.
Interstitial matrix: synthesized by mesenchymal cells (eg. fibroblasts), forming an amorphous three-dimensional gel (collagens, fibronectin, elastin, proteoglycans…).
Basement membrane: highly organized around epithelial cells & endothelial cells
The ECM regulates cell proliferation, locomotion, and/or differentiation:
____________ for cell anchorage and cell migration, and maintenance of cell polarity.
Control of ____________ via growth factors and integrin signalling pathways, and is a reservoir of embedded growth factors (VEGF, FGF, HGF).
__________ for tissue renewal.
Mechanical support, cell proliferation, scaffolding
How is the immune system (especially macrophages) important to the process of tissue repair?
Inflammatory responses allow the elimination of offending agents and orchestrate the repair process. It begins when macrophages predominate at the injury site following acute inflammation.
First, M1 macrophages are responsible for the inflammation process, clearing dead tissue/debris. Then, it is replaced with M2 which initiate tissue repair itself.
Differentiate Classically Activated Macrophage (M1) and Alternatively Activated Macrophage (M2).
Classical macrophage activation (M1):
- Secrete cytokines that stimulate inflammation
- Phagocyte microbes, dead tissue, debris
- Activated by TLR-ligands & IFN-γ
Alternative macrophage activation (M2):
- Initiate the process of tissue repair (inhibit inflammation)
- Secrete growth factors that:
- Promote angiogenesis
- Activate fibroblasts and stimulate ECM synthesis
- Activated by IL-13, IL-4
Describe the characteristics of adult stem cells.
It is capable of self-renewal through asymmetric division, which refers to cell replication in which one daughter cell enters a differentiation pathway and gives rise to mature cells, whereas the other remains undifferentiated and retains its self-renewal capacity.
Explain the mechanism of tissue regeneration in labile tissues.
Labile tissues such as the epithelial tissues, when injured, will be replaced by proliferation of residual cells and differentiation of cells derived from tissue adult stem cells.
Notes:
- Residual epithelial cells produce GFs.
- The newly generated cells migrate to fill-in the gap.
- Tissue integrity and function is restored.
Explain the characteristics of tissue regeneration in stable tissues.
In parenchymal (functional) organs, cells are capable of proliferation, but usually a limited process (except for liver).
Restoration of normal tissue architecture (regeneration) only occurs if residual tissue is structurally intact (partial liver resection). If the entire tissue is damaged, the regeneration is incomplete and is accompanied by scarring (cirrhosis).
Explain the two mechanisms of liver regeneration.
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Proliferation of hepatocytes following partial hepatectomy: correction by proliferation can occur up to 90% liver resection
- Quiescent hepatocytes become competent to enter the cell cycle _in response to cytokines (IL-6) and GF_
- Replicate once or twice and then return to quiescence.
- Liver regeneration from progenitor/stem cells: if hepatocytes can’t proliferate due to chronic injury, SCs in the canals of Hering contribute to the repopulation
If the injury to the liver is severe enough to damage the ECM, what resolution will ensue?
It will initiate the deposition of connective tissue, which alongside the proliferation of the liver cells, will lead to repair by scarring.
How does tissue repair occur and is it different from regeneration? When does tissue repair occur?
It refers to the replacement of the non-regenerated tissue with connective tissue, leading to the formation of a scar. In contrast to regeneration, which involves the restitution of tissue components, scar formation is a response that “patches” rather than restore the tissue.
It occurs when:
- the underlying structure of the tissue is lost: eg. Liver cirrhosis
- loss of non-dividing permanent cells: eg. Myocardiocytes-> Myocardial infarct (MI)
How is necrosis (due to vascular occlusion) resolve in the heart? Explain how this leads to the impairment of heart muscle functionality.
Usually, necrosis will be resolved by repair by deposition of connective tissue (scar formation). This leads to a state called Myocardial Infarction (MI)
The scar is an accumulation of connective tissue and is avascular (except for some thin-walled new blood vessels)
Infarct scar contraction induces thinning of the muscle layer and increase in stiffness (reduced contraction force).
Mention the stages of chronic/severe wound repair.
- Vascular response
- Inflammation
- Cell Proliferation & Migration
- Granulation Tissue
- Contraction
- Scar
Mention what occurs during the inflammation stage of wound repair/healing.
Wounding activates coagulation pathway: stopping bleeding and prevent loss of fluid. Another characteristic feature of this process is vascular leakage, leading to tissue swelling due to ECM expansion (edema).
Chemokines (product of complement activation) will recruit neutrophils and then monocytes (differentiate to M1 and M2 macrophages) during the next 6 to 48 hours. These cells then eliminate the offending agents and clear the debris.
Mention what occurs during the proliferation phase of wound repair.
Several cell types proliferate and migrate (in response to GF and cytokines) to close the wound (could last up to 10 days), such as:
- Endothelial and other vascular cells: initiate angiogenesis (around wound edges)
- Epithelial cells: migrate and proliferate to cover the wound
- Fibroblasts: deposition of collagen fibres that form the scar
The combination of these forms the granulation tissue (GT).
Describe the mechanism of angiogenesis.
Angiogenesis is the process of new BV development from existing ones.
- Vascular leakage: tissue swelling expands ECM, edema.
- Endothelial cells proliferate and detach from the vascular wall, degrade and invade ECM (integrins, MMPs).
- Sprouting: sprouts extend in length until they encounter another cell.
- Maturation: suppression of endothelial proliferation and migration, recruitment of pericytes (Ang1, Ang2) -> formation of new vessel
Differ cutaneous wound healing by first intention and second intention.
Involves epithelial regeneration and deposition of connective scar tissue
- Healing by First Intention: Focal disruption of epithelial basement membrane Relatively little cell death Small scar, minimal wound contraction Eg. After surgical incision
- Healing by Second Intention: More extensive cell loss Extensive wound contraction (myofibroblasts) Eg.ulcer, abscess, infarction of parenchyma tissue
Explain how fibrosis arise.
ibrosis refers to the abnormal deposition of collagen due to the imbalance between ECM synthesis and ECM degradation, due to persistent injurious stimuli.
Early GT promotes wound repair, hence increasing collagen and ECM build-up. In the later stages, it promotes wound resolution, producing MMPs, which degrade ECM components.
However, chronic inflammation prolongs the activation of fibroblasts by macrophages and T helper cells.
