Lecture 15

Question 1

Provide an example of an extrinsic factor that can influence a tissues ability to repair itself:

Answer 1

1. Infection - bacterial 2. Foreign bodies - impede healing by prolonging inflammation 3. Nutritional - poor nutrition/deficiency - protein, Vitamin A and C, Zn and Cu - inhibits collagen synthesis & retards healing

Question 2

What are the intrinsic factors that can influence tissues ability to repair itself?

Answer 2

1. Poor blood supply - varies from organ to organ 2. Metabolic disturbances - e.g. diabetes 3. Glucocorticoid/steroid therapy - anti-inflammatory and immunosuppressive effects cause weak scar formation due to inhibition of TGF-B 4. Low immune status (systemic) 5. Mechanical factors - increased pressure, torsion or excessive movement causes wound dehiscence (local) 6. Cell type and extent of injury: labile, stable and permanent (local) 7. Location of injury: extensive exudates in body cavities undergo organisation with eventual scarring (adhesions)

Question 3

Briefly describe the basic steps of healing in most organs:

Answer 3

1. Haemostasis and inflammation in response to tissue injury with removal of damaged and dead tissue 2. Proliferation and migration of parenchymal and CT cells to reconstitute injured area 3. Angiogenesis and granulation tissue formation 4. Synthesis of ECM proteins and collagen 5. Tissue remodelling 6. Wound contraction (fibroblasts > myofibroblasts) 7. Acquisition of wound strength (weeks to months)

Question 4

Contrast healing of skin by first intention versus second intention:

Answer 4

1st intention: typical of surgical incisions with edges closely opposed 2nd intention: edges not closely apposed - wound defect is larger and contamination is worse

Question 5

What is the first thing that happens in healing by first intention?

Answer 5

Rapid (immediate) activation of coagulation pathways

Question 6

What happens within 24 hours of healing by first intention?

Answer 6

Inflammation (neutrophils in fibrin matrix)

Question 7

What happens in 24-48 hours in first intention healing?

Answer 7

migration and proliferation of epithelial cells with BM reconstruction & wound closure

Question 8

What happens at day 3 of first intention healing?

Answer 8

macrophages replace neutrophils, invasion of granulation tissue and angiogenesis. Collagen fibers at incision margins. Epithelial proliferation approaching normal epidermal thickness

Question 9

How does granulation tissue form?

Answer 9

At day 3, primitive granulation tissue (proliferating angioblasts, fibroblasts and myofibroblasts) begin to invade the incision space. FGF2 and VEGF from macrophages, keratinocytes and endothelial cells promote angiogenesis. Endothelial cells express new integrins so they can sprout from pre-existing capillaries. Fibroblasts = migrate and proliferate at the site of injury depositing ECM proteins. PDGF, FGF-2 and TGF-B from inflammatory cells (M2 macrophages) stmulate fibroblasts

Question 10

Briefly describe the process of angiogenesis:

Answer 10

1. Enodthelial cells activated by angiogenic factors
2. Proteolysis of BM
3. Migration of immature EC into woound
4. Adhesion molecules pull endothelial cells forward
5. Production of MMP’s initiatiate remodelling
6. Endothelial cell adhesion to adjacent cells & basal lamina + expression receptor/ligand for leukocyte adhesion cascade
7. Recruitement of pericytes for smooth muscle cells for final differentiation

Question 11

What occurs at day five of healing?

Answer 11

neovascularisation peaks and migration and proliferation of fibroblasts occurs

Question 12

What occurs at week 2 of first intention healing?

Answer 12

continued collagen accumulation/fibroblast proliferation. A reduction in inflammation and the regression of vascular channels

Question 13

What happens at 1 month of healing?

Answer 13

cellular connective tissue is devoid of inflammatory cells and covered by normal epidermis

Question 14

What is the biggest difference between first intention and second intention healing?

Answer 14

In secondary intention healing the the inflammatory reaction is much more intense. There will be nuch greater amounts of granulation tissue formation. The wound contraction is much greater. There is substantial scar formation and thinning of the epidermis.

Question 15

Briefly describe how the process of wound contraction occurs:

Answer 15

By the end of the first month a scar replaces the incision. The scar is composed of cellular connective tissue, covered by an intact epidermis. The tensile strength progressively increases.

Question 16

Why is chronic inflammation often characterised by replacement of the affected tissue by fibrosis?

Answer 16

T-lymphocytes and other lymphoid cells are the cells that generally predominate in inflammation. These release cytokines (e.g IL-13) and TGF-B and MMPs.

Question 17

How and when does the process of tissue remodelling occur?

Answer 17

During first 2 months of healing. Collagen synthesis exceeds collagen degradation. This results in the tensile strength of the skin approaching 70-80% of non-wounded skin (Type III is replaced by type one)

Extracellular matrix deposition depends upon balance between TGF-B (collagen sysnthesis) versus MMP’s (degraded BM and ECM proteins)

Question 18

How can deficient scar tissue formation occur (too little)?

Answer 18

Wound dehiscence - mechanical stress

Ulceration - deficient blood supply

Question 19

What is a complication of excessive formatiomn of repair components (provide an example and why it occurs)?

Answer 19

Proud flesh - excessive granulation tissue

Hypertrophic scar/keloid: excess collagen/excess scar tissue

Desmoids: exuberant fibroblast proliferation

Question 20

How does formation of contractures occur?

Answer 20

Deformities of the wound +/- the surrounding tissue

Question 21

What problem has caused the issue seem below?

Answer 21

Exuberant granulation tissue - not possible to rule out neoplasm without cytology

Question 22

Why do keloids form?

Answer 22

Excessive collagen Type III formation