Tissue Repair — General Aspects
Tissue repair, commonly called tissue healing, is the body’s response to injury in an attempt to restore normal structure and function by living tissues.
It involves 2 processes which are distinguished by the type of tissue replacing the injured tissue:
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- Regeneration when healing takes place by the proliferation of surrounding undamaged specialised cells; usually it results in complete restoration of the original tissues.
- Repair when healing takes place by the formation of granulation tissue; it matures to result in fibrosis and scar tissue.
At times, both these processes take place simultaneously.
Regeneration And Repair:
1. Regeneration:
Some parenchymal cells are short-lived while others have a longer lifespan. In order to maintain proper structure of tissues, these cells are under the constant regulatory control of their cell cycle. Not all cells of the body divide at the same pace. Some mature cells do not divide at all while others complete a cell cycle every 16-24 hours.
The main difference between slowlydividing and rapidly-dividing cells is the duration of the G1 phase.
Distinguishing features between tuberculosis and sarcoidosis:
Depending upon their capacity to divide, the cells of the body can be divided into 3 groups: labile cells, stable cells, and permanent cells.
- Labile cells: These cells continue to multiply throughout life under normal physiologic conditions.
- These include: Surface epithelial cells of the epidermis, alimentary tract, respiratory tract, urinary tract, vagina, cervix, uterine endometrium, haematopoietic cells of bone marrow and cells of lymph nodes and spleen.
- Stable cells: These cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in response to stimuli throughout adult life.
- These include: Parenchymal cells of organs like liver, pancreas, kidneys, adrenal and thyroid; mesenchymal cells like smooth muscle cells, fibroblasts, vascular endothelium, bone and cartilage cells.
- Permanent cells: These cells lose their ability to proliferate around the time of birth.
- These include: Neurons of the nervous system, skeletal muscle and cardiac muscle cells.
Relationship Of Parenchymal Cells With Cell Cycle:
If the three types of parenchymal cells described above are correlated with the phase of cell cycle,
The following inferences can be drawn:
- Labile cells which are continuously dividing cells remain in the cell cycle from one mitosis to the next.
- Stable cells are in the resting phase (G0) but can be stimulated to enter the cell cycle.
- Permanent cells are non-dividing cells which have left the cell cycle and are destined to die after cell injury.
Regeneration of any type of parenchymal cells involves the following 2 processes:
- Proliferation of original cells from the margin of injury with migration so as to cover the gap.
- The proliferation of migrated cells with subsequent differentiation and maturation so as to reconstitute the original tissue.
2. Repair:
Repair is the replacement of injured tissue by fibrous tissue. Two processes are involved in
repair:
- Granulation tissue formation
- Wound contraction and strength
Repair response takes place by participation of mesenchymal cells (consisting of connective tissue stem cells, fibrocytes and histiocytes), endothelial cells, macrophages, platelets, and the parenchymal cells of the injured organ.
Granulation Tissue Formation:
The term granulation tissue derives its name from the slightly granular and pink appearance of the tissue. Each granule corresponds histologically to the proliferation of new small blood vessels which are slightly lifted on the surface and has a thin covering of fibroblasts and young collagen.
The process of granulation tissue formation can be divided into following 4 phases which are not mutually exclusive and have enough overlapping:
1. Bleeding Phase:
Following trauma, there is bleeding which may stop after a few hours (on average within 4-6 hours) but may vary, followed by clotting of blood at the site of injury.
2. Inflammatory Phase:
Inflammation is an essential component of the healing process. After blood clotting, fibrin and fibronectin remain in the tissues which form the substrate for adhesion of various inflammatory cells. Inflammatory response involves the vascular and cellular phase, and is regulated by chemical mediators.
Initially, there is infiltration by PMNs and fluid exudates within a few hours, followed by an influx of phagocytic cells (macrophages, monocytes) within 24 hours.
Dead and dying cells, necrotic debris, fibrin mesh and clot are cleared off by a combination of proteolytic enzymes liberated from neutrophils, autolytic enzymes from dead tissues cells, and phagocytic activity of macrophages. The latter events may, therefore, be referred to as the demolition phase.
3. Proliferation Phase:
This phase involves the generation of repair material that forms the initial granulation tissue. It begins within first 1-2 days after injury and reaches its peak at 2-3 weeks but qualitatively strong scar is formed much later after trauma (4-6 months).
This phaseconsists of 2 main processes: Angiogenesis or neovascularisation, and fibrogenesis.
- Angiogenesis (neovascularisation):
- Formation of new blood vessels at the site of injury takes place by proliferation of endothelial cells from the margins of severed blood vessels.
- Initially, the proliferated endothelial cells are solid buds but within a few hours develop a lumen and start carrying blood.
- The newly formed blood vessels are more leaky, accounting for the oedematous appearance of new granulation tissue. Soon, these blood vessels differentiate into muscular arterioles, thin-walled venules and true capillaries.
- The process of angiogenesis is stimulated with proteolytic destruction of the basement membrane.
- Angiogenesis takes place under the influence of the following factors:
- Vascular endothelial growth factor (VEGF) is elaborated by mesenchymal cells while its receptor, (VEGF-R) is present in endothelial cells only.
- Platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), basic fibroblast growth factor (b-FGF) and surface integrins are all associated with cellular proliferation.
- Fibrogenesis: The newly formed blood vessels are present in an amorphous ground substance or matrix. The new fibroblasts have features intermediate between those of fibroblasts and smooth muscle cells (myofibroblasts).
- By about 6th day, predominantly type III collagen fibrils appear. The myofibroblasts have surface receptors for fibronectin molecules which form bridges between collagen fibrils. As repair matures, the weak type III collagen fibrils are reabsorbed by collagenase and are replaced with type I collagen while the number of active fibroblasts and new blood vessels decreases.
4. Remodelling Phase:
This phase begins around the time when the proliferation phase is at peak (i.e. 2-3 weeks following injury). The main events in remodelling are a refinement of collagen and its associated extracellular matrix.
The replaced type I collagen fibrils have more cross-links and greater tensile strength. This results in the formation of the inactive-looking scar; this process is known as cicatrisation.
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