Medical Basic Science III

Mechanisms of Disease

Regeneration and
Fibrous Repair
Dr Nora Ramkita
Department of Pathology Anatomy
Medical Faculty of Lampung Univerrsity
May 2017

ACUTE INFLAMMATION,
CHRONIC INFLAMMATION,
OR FIBROUS SCARRING?

Acute Chronic
insult insult

Acute
inflammation

Damage Chronic
slight? No inflammation

Yes

Repair
Resolution
possible and
SCARRING

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 REGENERATION AND REPAIR

• Regeneration:
replacement of functional, differentiated cells

• Repair:
production of a fibrous scar

REGENERATION
• Labile cells:
- normal state is active cell division
- usually rapid regeneration
• Stable cells:
- not normally dividing at a significant rate
- speed of regeneration variable
• Permanent cells:
- unable to divide
- unable to regenerate

2
 Factors controlling regeneration:
Complex and poorly understood.
• ‘Growth factors’
– EGF, PDGF, FGF, IGF ...
– Hormones e.g. ACTH, estrogen, growth hormone
• Contact with basement membranes &
adjacent cells
– Signalling through integrins

• NOTE: importance of growth control in

CANCER.

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Acute damage to kidney - regeneration

Mitotic
figures

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 FIBROUS REPAIR:
The development of a fibrous scar.
• Rabbit ear chamber example.

– Blood clot forms.

– Acute inflammation around the edges.
– Chronic inflammation: Macrophages infiltrate the
clot.
– Capillaries and lymphatics sprout and infiltrate.
– Myofibroblasts infiltrate and differentiate.
– Glycoproteins and COLLAGEN are produced
– Cell population falls, vessels differentiate and are
reduced in number.
– Collagen matures AND CONTRACTS.

Rabbit Ear Chamber: Direct observation of fibrous repair.

1) Exudate clots. 2) Neutrophils infiltrate 3) Macrophages and

and digest clot lymphocytes are
recruited

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Rabbit Ear Chamber: Direct observation of fibrous repair.

4) Vessels sprout, 5) Vascular network; 6) Maturity. Cells

myofibroblasts make collagen synthesised; much reduced; collagen
glycoproteins macrophages reduced matures, contracts,
remodels

Angiogenesis

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 The Extracellular Matrix
• Collagen
– Type I - Bone, tendon, scars. Type III - ‘tissue scaffold’.
Type IV - non-fibrous, basement membranes ...
• Elastin
• Glycoproteins
– Fibronectin, Osteonectin, Tenascin,...
• Proteoglycans
– Heparan sulphate proteoglycan, ...

Specific features of fibrous

collagens
• Triple helical fibrils
• Fibrils arrange in ‘quarter stagger’ mode
to form insoluble fibres
• Relatively resistant to general
proteases; slow remodelling by specific
collagenases

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 SKIN WOUNDS:
Healing by “Primary Intention”
• Epidermis regenerates
• Dermis undergoes fibrous repair.
• Sutures out at 5-10 days: approx. 10%
normal strength.
• Maturation of scar continues up to 2 years.
• Minimal scarring, good strength
• Risk of trapping infection under skin -
produces abscess.

Healing by ‘primary intention’:

A clean, sutured wound.

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 SKIN WOUNDS:
Healing by “Secondary Intention”
• Quantitative differences.
– Initial contraction (in furry animals!)
– Clot dries to form a ‘scab’ or ESCHAR
– Epidermis regenerates beneath.
– Repair process produces GRANULATION
TISSUE
• Comparison with primary intention:
– Takes longer
– Produces a larger scar; not necessarily weaker
– Produces more late contraction

An open wound:
Healing by ‘secondary intention’

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Regeneration and repair combined:
A chronic peptic ulcer

Regeneration and repair combined:

A chronic peptic ulcer

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 CONTROL OF REPAIR
Poorly understood.
• Angiogenesis
– Various angiogenic cytokines, e.g. VEGF, bFGF ...
• Fibrosis
– various pro-fibrotic cytokines, e.g. TGF beta,
PDGF, ...
• Limitation of fibrosis and remodelling
– Hardly anything known!

FACTORS INFLUENCING WOUND

HEALING
• Local factors:
– Type, size, location of wound
– Apposition, lack of movement
– Infection: Suppuration, Gangrene, Tetanus
• (Secondary hæmorrhage)
– Blood supply: Arterial, Venous
– Foreign material: dirt, glass, sutures, necrotic
tissue
– Radiation damage

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FACTORS INFLUENCING WOUND
HEALING
• General Factors:
– Age
– General state of health
• chronic diseases e.g. diabetes, rheumatoid arthritis etc.
– Drugs (n.b. steroids) and hormones
– General cardiovascular status
– General dietary deficiencies e.g. protein
– Specific dietary deficiencies
• Vitamin C
• sulphur-containing amino acids

Complications of Repair
• Insufficient fibrosis:
– Wound dehiscence; hernia; ulceration
• Excessive fibrosis:
– Cosmetic scarring; hypertrophic scars; keloid
• Excessive contraction:
– Limitation of joint movement (Contractures);
obstruction of tubes & channels (Strictures)

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Coal worker’s pneumoconiosis

Alcoholic cirrhosis in the liver

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 Special features of healing in specific
organs
For self-directed study. As a minimum, learn
about:
• Liver (n.b. regeneration in acute versus chronic damage)
• Kidney (n.b. ‘acute tubular necrosis’)
• Heart (see ‘myocardial infarction’)
• Bone (n.b. ‘Callus’)
• Cartilage (Can it???)
• Peripheral nerve (n.b. ‘Wallerian degeneration’;
axon sprouting)
• Central nervous system (n.b. gliosis)

‘Contracture’
following a
major burn

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 Pathways of the
Reparative Response
Injury

Inflammation

No necrosis Necrosis

Tissue of Tissue of
Exudate Exudate
stable or permanent
resolved organised
labile cells cells

Framework Framework
intact destroyed

Regeneration

Normal
structure SCARRING
(RESOLUTION)

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 DAFTAR PUSTAKA

Kumar V, Cotran RS, Robbins SL. Buku ajar patologi. 6

nd ed , Vol. 1. Jakarta : Penerbit. Buku Kedokteran EGC,
2007 : 10-34.

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