Leicester Warwick Medical School

Mechanisms of Disease

Regeneration and
Fibrous Repair
Dr Peter Furness
pnf1@le.ac.uk
Department of Pathology

ACUTE INFLAMMATION,
CHRONIC INFLAMMATION,
OR FIBROUS SCARRING?
Acute
insult

Chronic
insult

Acute
inflammation
Damage
slight?

No

Chronic
inflammation

Yes
Resolution
possible

Repair
and
SCARRING

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

Factors controlling regeneration:

Complex and poorly understood.
Growth factors
EGF, PDGF, FGF, IGF ...
Hormones e.g. ACTH, strogen, growth hormone...

Contact with basement membranes & adjacent

cells
Signalling through integrins

NOTE: importance of growth control in

CANCER.

Acute damage to kidney - regeneration

Mitotic
figures

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.

RabbitEarChamber:Directobservationoffibrousrepair.

1)Exudateclots. 2)Neutrophilsinfiltrate
anddigestclot

3)Macrophagesand
lymphocytesare
recruited

RabbitEarChamber:Directobservationoffibrousrepair.

4)Vesselssprout,
myofibroblastsmake
glycoproteins

5)Vascularnetwork;
6)Maturity.Cells
collagensynthesised; muchreduced;collagen
macrophagesreduced
matures,contracts,
remodels

Angiogenesis

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

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.

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

Regeneration and repair combined:

A chronic peptic ulcer

Regeneration and repair combined:

A chronic peptic ulcer

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 hmorrhage)

Blood supply: Arterial, Venous

Foreign material: dirt, glass, sutures, necrotic
tissue
Radiation damage

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)

Coal workers pneumoconiosis

Alcoholic cirrhosis in the liver

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

Pathways of the
Reparative Response
Injury
Inflammation
Necrosis

No necrosis
Exudate
resolved

Exudate
organised

Tissue of
stable or
labile cells

Framework
intact

Tissue of
permanent
cells

Framework
destroyed

Regeneration

Normal
structure
(RESOLUTION)

SCARRING