Lecture 13 - The role of tissue remodelling Flashcards

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1
Q

What are the dermal papillae?

A

Small extensions of the dermis into the epidermis, blood vessels in the dermal papillae nourish hair follicles and bring nutrients and oxygen into the lower levels of epidememal cells
-form the stratum basale

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2
Q

What are the Papillary dermis and Reticular dermis?

A

Papillary dermis
-uppermost layer of the dermis
-composed of fine and loosley arranged connective tissue, type III collagen fibres, few cells (mainly fibroblasts)
Reticular dermis
-the lower layer of the dermis
-composed of dense irregular connective tissue featuring densely packed type I collagen fibres, more cells (mainly fibroblasts)
-primary location of dermal elastic fibres

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3
Q

What cells are found in the Epidemis?

A
100% cellular
mainly keranocytes
some mellanocytes
dendritic cells 
very little to no ECM
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4
Q

What are the two types of wound?

A

Primary wounds

Secondary wounds

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5
Q

What features characterise a wound as primary or secondary?

A
Primary
-no lost tissue
-only two edges that need to be bought together
Secondary
-loss of tissue
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6
Q

What are the three depths a wound can be characterised by?

A

Partial
-superficial, only in outer epiderma, not below the lower limits of the hair follicles
Full
-deeper, below the limit of the base of hair follicles
Complex
-intersect other tissue types e.g. bone, muscle

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7
Q

What are the three basic overlapping phases of wound healing?

A
  1. Inflammation
  2. Proliferation and new tissue formation
  3. Maturation and remodelling
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8
Q

What is the time course of the phases of wound healing, and what do these phases contain?

A
  1. Inflammation
    - maximun response can be within a few hours, last for up to 10 days
    - initially composed of (bleeding, coagulation, platelet activation, and complement activation)
    - followed by (the recruitment of granulocytes and phagocytosis
    - overlaps with phase II
  2. Cell proliferation and matrix deposition
    - around 1 day after wound, lasts up until 30 days
    - initially (cross over with phase I) recruitment of macrophages and release of cytokines
    - followed by (fibroplasia, angiogenesis, re-repithelialation, ECM synthesis, collagens, fibronectin, Proteoglycans)
  3. Matrix remodelling
    - begins with cell proliferation and matrix deposition phase, can last up to around 300 days after wound
    - consists of extracellular matrix synthesis, degradation and remodelling
    - to increase tensile strength decrease cellularity and vascularity
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9
Q

What are the features of the inflammation phase of wound healing?

A
  • Complex process
  • involving the co-ordinated activity of a number of different cell types and enzyme cascade systems that:
  • stimulate an innflammatory response
  • provide an initial matrix to fill the wound defect
  • initiate repair
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10
Q

What are the features of the Proliferation and new tissue formation phase of wound healing?

A
  • tissue regeneration effected through re-epithelialisation and granulation tissue formation
  • initiated by chemotactic factors, growth factors, changes in matrix structure and tension, loss of nearest neighborough cell
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11
Q

What are the features of re-epithelialisation?

A
  • re-establishes the vital barrier function of the epidermis
  • initiated within hours of injury
  • stimulated by growth factors (e.g. KGF, TGFβ1, IL-1α/β, TNFα, and EGF)
  • stimulated by loss of apical-basal polarity of keranocytes at the wound edge
  • requires keranocyte proliferation and migration of an ‘epidermal tongue’ over a provisional matrix (permissable to migration) of fibrin, fibronectin, and type V collagen, disecting under desiccated tissue and eschar
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12
Q

What is the epidermal tongue?

A

A group of keranocytes migrating and disecting beneath eschar tissue in a ‘leap frog’ fashion
-happens from all edges of the wound and meet in middle

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13
Q

What chemicals do macrophages (inital stage of re-epithelialistion) and fibroblasts (later stages of re-epithelialiastion) secrete during the wound healing re-epithelialisation response?

A
Macrophages (keranocyte proliferation and migration)
-TNFα
- IL-1α/β
-TGFβ1
Fibroblasts ( fibroplasia and matrix production)
(early stage)
-KGF
-TGFβ1
(later stage)
-TNFα
- IL-1α/β
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14
Q

Why are hair follicles important in re-epithialisation?

A
  • hair follicle remnants can act as islands for re-epithelialisation in partial-thickness wounds
  • as surrounded by skin epithelial cells (keranocytes)
  • migration and proliferation of keranocytes can occur at these ‘islands’ and not just at the wound edges
  • make healing response quicker
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15
Q

What are the features of granulation tissue formation?

A
  • encompasses macrophage accumulation, fibroblast recruitment, deposition of loose connective tissue and angiogenesis, fibroplasia
  • Fibroplasia is stimulated by (FGF, EGF, PDGF, TGF-β) released by macrophages and keratinocytes
  • early wound matrix (consists predominantly of hyaluronan, fibronectin and type III collagen)
  • as healing progresses, hyluronan, fibronectin, and type II collagen content decreases and type I collagen synthesis increases
  • type I and III collagen provide the wound with tensile strength, fibres anatomically connect the wound margins
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16
Q

What is the process of wound contraction in epidermal wounds?

A
  1. Actin filaments arrange into a contunuous structure across the the cells surrrouning the wounds. Adherens junctions form at the boundries of the cells creating an ‘actin cable’.
  2. Ring of actin begins to form, damaged cells are excluded. Actin contracts to pull the wound edges together
17
Q

What is the myofibroblast and features of the myofibroblast?

A

cell between a fibroblast and a smooth muscle cell in differentiation

  • contractile fibroblastic phenotype (when epidermal wound healing in insuffient)
  • expresses α-smooth muscle actin
  • aligned along the lines of contraction
  • have large actin bundles
  • force generated is transmitted to the wound edges via cell-cell and cell-matrix interactions
  • but is not always cosmetically desirable
18
Q

What makes foetal wound healing different to adult wound healing?

A
  • heal without scarring
  • foetal fibroblasts produce more hyaluronan and type III collagen and less type I collagen than adult fibroblasts
  • more hydrated matrix for longer
  • scarless wound have virtually no myofibroblasts
19
Q

How can scar formation be inhibited?

A

TGF-β1 and TGF-β2 promote fibroplasmia and scar formation

- inhibition of these by blocking antibodies can reduce scar formation

20
Q

What is the movement by which keranocytes and fibroblasts migrate? (required for re-epithelialisation and granulation tissue formation)

A
  1. extension of the lamellipodium
  2. a new focal adhesion is laid down at the end of the lamellipodia extension
  3. cell body shifts over the new adhesion (translocation)
  4. de-adhesion at the cells rear
21
Q

How do cell surface receptors regulate RhoGTPases and consequently actin organisation?

A
  • as the leading edge progresses, focal adhesions form and become the foci for stress fibres
  • focal adhesions can activate the formation of Rho (stress fibres), Rac (lamellipodia) and Cdc42 (filopodia)
22
Q

How can α2β1 integrin aid migration following wounding?

A

α2β1 is a major integrin that recognises type I collagen

  • exposure to type I collagen matrix following wounding causes recrutiment to the basal membrane to aid migration so can bind to basal membrane
  • at intact skin, integrins are spread over the basolateral surfaces
  • at wounded skin, integrins accumulate at the basal surface of the migratory front
23
Q

How can α6β4 integrin aid migration following wounding?

A

α6β4, normally found in hemidesmosomes as part of the anchoring filaments, gets redispersed along the surface of the cells at the wound edge, leads to loosening of cell-cell and cell-matrix componants

24
Q

What are the features of phase III, maturation matrix and remodelling in the wound response?

A
  • months following wounding, matrix is constantly altered
  • to re-establish tensile strength and typical dermal architechure
  • early matric components (hyluronan, type III collagen) return to level found in non wounded tissue
  • collagen bundles become more organised and increase in size
  • scar tissue never completely reassumes prewound tissue, maximum breaking strength 30% of prewound tissue
25
Q

What is matrix remodelling dependent on and how is it largely achieved?

A
  • dependent upon the rates of matrix synthesis and matrix catabolism
  • acheived through the action of the matrix metalloproteinases (MMPs)
  • produced by fibroblasts, epidermal cells and macrophages
26
Q

What are the features of the Matrix metalloproteinases? (MMPs)

A
  • regulate ECM degradation
  • family of Zn2+ dependent proteases
  • capable of cleaving most ECM componants
  • syntesised as inactive precursors (so not constantly degrading matrix)
  • need proteolytic processing to become active
  • involved in different phases of wound healing, partiularly in remodelling the newly formed ECM
27
Q

What are the 6 types of MMPs?

A

Matilysins (Propeptide and N-terminal domain)
Collagenases, Metalloelastae, Stromelysins (Propeptide, N-terminal domain and C terminal domain (hemopexin-like repeats))
Gelatinases (Propeptide, N-terminal domain (with gelatin binding domain (fibronectin like repeats) and C terminal domain (hemopexin-like repeats)
MT-MMPs (Propeptide, N-terminal domain, C terminal domain (hemopexin-like repeats) and membrane domain)

All have a common Zn domain

28
Q

How are MT-MMPs involved in ‘path clearing’?

A

MT-MMPs are present at the leading edge of migrating keranocytes/fibroblasts and can dissect through tissue
-inhibition of MMP activity can inhibit migration

29
Q

What is the purpose of MMPs?

A

to remove unwanted ECM componants so remodelling can take place

30
Q

What are keloids?

A

when the scar tissue continues to grow outside the boundaries of the original wound
-excessive type I and type III collagen and fibronectin deposition
-decreased MMP levels
=net increase in ECM production
-keloid fibroblasts have increased proliferation with elevated levels of TGF-β1 and TGF-β2
-thickened epidermis
-more cellularity and denser structure
-STAT3 is predominant in the epidermis of keloids (promotes colagen production, cell proliferation and migration)

31
Q

What are hypertrophic scars?

A

abnormally excessive development of scar tissue during wound repair

  • within the initial wound margins
  • when repaired the tissue rises above the repaired site due to an imbalance between the matrix laid down and removed during remodelling