Healing & Repair

Regeneration can be seen in what 3 renewing tissues

Epidermis

GI tract epithelium

Haematopoietic system

Regeneration can be seen in what 2 stable tissues

Liver & kidneys

What are the 3 cell types based on regenerative capacity/cell cycle

1) Continuously dividing / Labile cells

2) Stable or quiescent cells

3) Permanent (non-dividing ) cells

Describe & give examples of Labile cells

Constantly replacing dying cells

E.g. Epithelia: skin, oral cavity, exocrine ducts, GI tract & gynecological surfaces and Haematopoietic cells

Describe & give examples of Stable/Quiescent cells (what cell cycle stage are they in)

Usually in G0 but driven into G1 → rapid proliferation

E.g. parenchyma of glands: Liver, kidney & pancreas, and endothelium, fibroblast & smooth muscle connective tissue.

Describe & give examples of Permanent (non-dividing ) cells (what cell cycle stage are they in)

Permanently removed from cell cycle

Irreversible injury leads only to scar

E.g. Nerve cells, myocardium (heart)

Describe the 3 ways in which cells signal to each other

Give 5 examples of growth factors

• Epidermal growth factor (EGF)

• Fibroblast growth factors

• Vascular endothelial growth factor (VEGF)

• Transforming growth factor (TGF)

• Platelet-derived growth factor (PDGF)

Which growth factor is involved in monocyte chemotaxis

Platelet-derived growth factor (PDGF)

Which growth factor is involved in epithelial cells & fibroblasts

Epidermal growth factor (EGF)

Which growth factor is involved in fibrogenesis

Transforming growth factor (TGF)

Which growth factor is involved in Migration and proliferation of fibroblasts

Platelet-derived growth factor (PDGF)

Which growth factor is involved in smooth muscle

Platelet-derived growth factor (PDGF)

Steroid hormone receptors are ______ activated

ligand

True/False some eicosanoids signal through steroid receptors

True

Extracellular Matrix (ECM) function

ECM provides turgor, rigidity, support, adhesion substrate, reservoir for factors

ECM must remain intact for ______ healing

parenchymal healing

What are the 2 basic forms of ECM

Interstitial matrix & basement membrane

What 4 components make up Extracellular Matrix (ECM)

Collagens

Adhesive glycoproteins/Cell adhesion Molecules

Proteoglycans

Elastin

Role of Collagens in ECM

fibrous structural proteins

Which of these types of collagen are (i) interstitial/fibrillar or (ii) non-fibrillar mesh-like in basement membranes:

I-V & XI

III, V, XI: interstitial/fibrillar

IV: non-fibrillar mesh-like in basement membranes

Which form of collagen is more abundant: interstitial/fibrillar or non-fibrillar mesh-like

interstitial/fibrillar

What is the role of of Adhesive glycoproteins/Cell adhesion Molecules in the ECM

Bind ECM components to each other, and to other cells

Give some examples of Adhesive glycoproteins/Cell adhesion Molecules in the ECM

Laminin, fibronectin, thrombospondin, integrins

What are proteoglycans in ECM & what’s their role

sugars linked to proteins; form highly hydrated compressible gels (cartilage in joints)

Role of elastin in ECM

Elastic fibres allows tissue to recoil and return to normal after physical stress

Structure of elastin in ECM

Central core of elastin protein surrounded by meshlike fibrillin (glycoprotein)

What steps of Repair by Connective Tissue (Scar Formation) occur in the first 24 hrs

Formation of new blood vessels (angiogenesis)

Fibroblast migration and proliferation (lay down collagen)

What steps of Repair by Connective Tissue (Scar Formation) occur in days 3-5

Deposition of loose ECM- “Granulation tissue”: pink, soft, granular gross appearance

What steps of Repair by Connective Tissue (Scar Formation) occur after 5 days

Maturation and organization (remodeling) of fibrous tissue

In Angiogenesis, what are vessels derived from

budding of pre-existing vessels

Describe the 5 steps of Angiogenesis

– Proteolytic degradation of parent vessel BM

– Endothelial migration

– Endothelial proliferation

– Cell recruitment (pericytes and smooth muscle) to stabilise the new endothelial tube

– Endothelial maturation

What growth factors are involved in angiogenesis

• VEGF

• FGF

• ANgiopoietins

• PDGF

• TGF- β

Role of VEGF in angiogenesis

Promotes migration and proliferation of endothelial cells.

Stimulates vasodilation by increasing NO.

Role of FGF in angiogenesis

Induces proliferation of fibroblasts/endothelial cells and migration of macrophages and fibroblasts

Role of angiopoietins in angiogenesis (which angiopoietins)

Ang1 & 2 → maturation of the new vessels by recruitment of pericytes and smooth muscle cells

Role of PDGF in angiogenesis

Recruits SM cells

Role of TGF- β in angiogenesis

suppresses endothelial proliferation

enhances production of ECM protein

Role of ECM proteins in angiogenesis

Interact with integrins on endothelial cells and provide scaffold for endothelial growth. Matrix metalloproteinases degrade ECM to permit remodelling and extension of the new tube

Fibrosis (Fibroplasia) occurs where? Within what framework?

Occurs within the granulation tissue framework (new blood vessels and loose ECM)

2 steps of Fibrosis (Fibroplasia)

1) Migration and proliferation of fibroblasts into the site of injury

2) Deposition of ECM produced by these cells

In step 1 of Fibrosis, what 2 things help this stage out

– Growth factors (TGF-b, PDGF, FGF)

– Cytokines (IL-1, TNF-a)

What is the purpose of the remodelling phase of tissue repair

To strengthen the repaired tissue by reorganising and modifying the extracellular matrix after initial healing

Which enzymes are responsible for extracellular matrix breakdown during remodeling

Matrix metalloproteinases (MMPs)

Name the main types of metalloproteinases involved in tissue remodeling

Interstitial collagenases

Gelatinases

Stromelysins

Which cells produce metalloproteinases during remodeling

Macrophages, neutrophils, and fibroblasts

In what form are metalloproteinases initially produced

As inactive precursors (proenzymes)

What regulates the activity of metalloproteinases

Tissue inhibitors of metalloproteinases (TIMPs).

What happens to cellular debris during the remodeling phase

It is removed by phagocytes in a process called debridement

What happens in the 1st 1-2 days of 1st intention wound healing

epithelial basal cells grow along cut dermis

What happens @ day 3 of 1st intention wound healing

neutrophils gone, macrophages enter, granulation tissue forms

What happens @ day 5 of 1st intention wound healing

space filled with granulation tissue and collagen fibrils bridge line of closure, epidermis at pre-incision thickness

What happens @ week 2 of 1st intention wound healing

accumulation of collagen, fibroblasts, and “blanching” begins (edema inflammation vascularity reduced)

What happens @ month1 of 1st intention wound healing

connective tissue devoid of inflammation; epidermis intact

Tensile strength increases to ____% of unwounded skin in 3 months

70 - 80%

What differentiates 1st intention & 2nd intention wound healing

2nd intention is for a Large tissue defect with more intense inflammation, granulation (leads to scar) & wound contraction

For 2nd intention, regeneration of parenchymal cells alone cannot restore the tissue

5 local factors that influence repair

" Infection

" Mechanical factors

" Foreign bodies

" Size

" Location

5 general factors that influence repair

" Nutrition

" Diabetes mellitus

" Circulatory status (atherosclerosis)

" Steroid treatment

" Hydrogen Peroxide treatment

Name 2 things that can arise from deficient repair

Wound dehiscence (rupture)

Ulceration

Give example of when Wound dehiscence (rupture) could happen

often after abdominal surgery

Give example of how ulceration could happen

Poor vascularization or neuropathy (e.g.,diabetic foot)

Name 4 things that could arise from excessive repair

• Hypertrophic scars – raised, confined to injury site

• Keloids – raised scars extending beyond wound

• Exuberant granulation (proud flesh) – blocks epithelialization; needs removal

• Desmoids (aggressive fibromatoses) – rare, fibroblast proliferation with recurrence

Which of the 4 excessive repair scars can you be genetically predisposed to

Keloids

What type of injury could lead to exaggerated contraction

After severe burns