How Body Recovers from Injury

Question 1

What could be found at the site of inflammation/injury?

Answer 1

A mass of dead (necrotic) tissue

Remnants of inflammatory cells

Remnants of initial stimulus (e.g. bacteria, foreign material, …)

Question 2

Which 3 ways could the body deal with inflammtion?

Answer 2

Resolution (scavenging) of the inflammatory response

Regeneration

Repair (or incomplete regeneration) by connective tissue deposition (fibrosis) resulting in a fibrotic scar

Question 3

what is resolution?

Answer 3

the complete restoration “restitutio ad integrum” of tissue to its normal state.

it is achieved by scavenging macrophages.

Question 4

explain how macrophages carry out their scavenging role

Answer 4

Circulating monocytes migrate into the site of inflammation and become macrophages.

some go to sinusoid areas in the liver, spleen and BM.

the macrophages act as a filtering tissue and clear the insult, dead tissue and produce growth factors for proliferation of cells for healing response

Question 5

What are the different activities that macrophages carry out?

Answer 5

• Chemotaxis - Migration towards damaged tissues
• Hypertrophy - Histiocytes become larger and accumulate more cell organelles and enzymes
• Pseudopodia - Active movement
• Pinocytosis - Ingest fluid from their surroundings
• Phagocytosis - Ingest larger particles, molecules or cells

Activated macrophages/histiocytes develop receptors for abnormal molecules or abnormal cells (foreign or own)

Question 6

What is the difference between regeneration and repair?

Answer 6

Question 7

what determines whether regeneration takes place?

Answer 7

The type of tissue (and the type and extent of injury) determines the mechanisms of healing (regeneration or repair)

Regeneration is dependent on limited damage and the preserved integrity of the extracellular matrix (scaffolding) or basement membrane. Otherwise, regeneration is usually impossible and repair (scarring) occurs.

Question 8

what are the three types of cells in terms of regeneration?

Answer 8

Labile (continuously dividing) tissues e.g. skin, mucosa of GI tract

Stable (quiescent) tissues e.g. liver, kidney, endothelium

Permanent tissues e.g. heart, brain

Question 9

Adult stem cells characteristics

location

features

Answer 9

Prolonged self renewal capacity and asymmetric replication

Stem cell pools in tissues (e.g. crypts of the colonic epithelium, bone marrow, hair follicles)

Bone marrow stem cells may transdifferentiate into neurons, liver cells and others

Question 10

how does the liver and the skin regenerate?

Answer 10

Liver tissue can regenerate from stem cells if the stromal reticulin scaffolding remains intact

Epithelial tissues replenish themselves by increase in stem cell divisions and shortening of cell cycle time

Question 11

how is regeneration controlled?

Answer 11

Interactions involving macrophages and the stromal scaffolding / extracellular matrix

Cell proliferation is dependent on production of growth factors and transcription factors (mainly by macrophages) which induce:

Signaling pathways to unlock cell cycle controls

Result: Proliferation of local adjacent cells and stem cells

Question 12

When does repair occur and how?

Answer 12

Necessary when tissue damage is too extensive for resolution or regeneration (e.g. loss of reticulin network in the liver)

A response by fibroblasts to patch the damage with fibrosis thus forming a fibrotic scar

Question 13

outline the sequence of repair

Answer 13

Question 14

5 steps of repair

Answer 14

1. Formation of new blood vessels (Angiogenesis)
2. Formation of granulation tissue
3. Formation of extracellular matrix protein (collagen) by fibroblasts
4. Remodeling and contraction of the young scar
5. Final scar

Question 15

Outline the sequence of events in angiogenesis

Answer 15

Vasodilatation (acute inflammatory response, histamine, NO)

Degradation of the BM of adjacent local blood vessels - sprout

Migration of endothelial cells and recruitment of endothelial precursor cells from the bone marrow

Proliferation of endothelial cells

Maturation of endothelial cells into tubes

Development of blood vessel walls

^{Controlled by vascular endothelial growth factor (VEGF)}

Question 16

Formation of granulation tissue

Answer 16

Angiogenesis + proliferation of fibroblasts

Resulting in granulation tissue formation composed of new blood vessels, fibroblasts and remaining inflammatory cells (usually neutrophils)

New vessels are leaky leading to marked oedema

Question 17

What is present in scar tissue that is absent in granulation?

Answer 17

Collagen

Question 18

Limitations of granulation tissue

Answer 18

weak and oedematous making it prone to injury – not able to withstand the normal mechanical demands of organ function

e.g. myocardial infarction. Roughly 7-10 days to develop, this is where there is a spike in mortality after cardiac arrest, this is because this tissue that replaces the infarct is so weak that it could easily rupture

Question 19

How does scar form (start with macrophages)

Answer 19

Again growth factors from macrophages induce migration and proliferation of fibroblasts into the granulation tissue

Mainly controlled by fibroblast growth factors (FGFs)

Fibroblasts produce ECM proteins (e.g. collagen, elastin)

Mainly controlled by transforming growth factor beta (TGF-beta)

Question 20

How does scar remodeling occur?

Answer 20

Interactions of collagen deposition and degradation by matrix metalloproteinases (MMPs)

Collagen changes to type I collagen

The blood vessels disappear

Contraction of the scar tissue

The final scar consists of collagen and remaining fibroblasts

Ultimately maximum of 80% of normal skin strength

Question 21

Primary, secondary and tertiary intention

Answer 21

Primary intention

No loss of tissue

Lacerations, simple bone fractures

Secondary intention

Significant loss of tissue

Abscess

Tertiary intention

If very deep, the wound is left open

to heal from the bottom up

Question 22

local impairment of healing

Answer 22

• Cause of insult is very important (e.g. burns vs cuts)
• Local infection
• Foreign body
• Haematoma
• Denervation
• Poor blood supply or perfusion
• Mechanical stress or iatrogenic stress
• Necrotic tissue
• Site (lip vs foot)

Question 23

Give a few examples of systemic impairment of healing

Answer 23

• Age
• Anaemia
• Drugs (steroids, cytotoxics, antibiotics)
• Soft tissue genetic disorders (Ehler’s Danlos, Marfan’s, …)
• Diabetes mellitus (many blood cells shrink owing to altered osmotic pressure)
• Malignancy
• Malnutrition
• Obesity
• Systemic infection / sepsis
• Vit C deficiency
• Trace mineral deficiencies
• Trauma and shock
• Uraemia

Question 24

Complications of wound healing

Answer 24

Deficient scar formation leading to dehiscence or ulceration

Excessive scar formation (e.g. keloid)

Abdominal adhesions (e.g. Crohn’s disease, appendicitis)

Contractures (often in burns)

Question 25

What is a keloid?

Answer 25

With keloids, the fibroblasts continue to multiply even after the wound is filled in. Thus keloids project above the surface of the skin and form large mounds of scar tissue.