PHYSIOLOGY 05/07/2017

TISSUE REPAIR: CELLULAR GROWTH, FIBROSIS, AND

WOUND HEALING
Tissue repair
o Regeneration implies complete restitution
Cell
Dead cells are replaced by cells of the same proliferation/
Signaling
growth
type inhibition
o Replacement by connective tissue
AKA fibroplasia scarring
Cell surface
Checkpoints
receptors
CELLULAR GROWTH
Adult individual
o Rate of proliferation is accomplished by Signal
Recruitment of quiescent cell into the cell transcription
transduction
cycle
o Cellular differentiation nucleus
o Death by apoptosis

THREE GROUPS OF CELL

They are divided into three groups according to
their
o proliferative capacity
o and relationship to the cell cycle Cell Autocrine
Labile cells are continuously dividing cells proliferation signalling
o Cells of the bone marrow
Intercellular Endocrine
o Hematopoietic cells
o Epithelial cells
signalling signalling
Quiescent cells (stable cells) paracrine
o Slow turnover signalling
o Capable of rapid division in response to stimuli
o Liver, kidney, smooth muscle, endothelial cells
Nondividing cells (permanent cells) Cell growth is initiated by binding of a signalling
o Cannot undergo division in the postnatal life agent (most commonly a growth factor) to a
Neurons, skeletal muscle, cardiac muscle specific receptor frequently located on the plasma
membrane
Autocrine signalling
Cellular
proliferation o Cells respond to signalling substance that they
secrete themselves
Paracrine signalling
o A cell produces a signalling substance that
oncogenes protooncogenes affects only a target cell of close proximity
Endocrine signalling
o Hormones are produced by cells of endocrine
glands and affect distant target cells
Normal growth Uncontrolled
control growth CELL SURFACE RECEPTORS
Receptors with intrinsic kinase activity
o Activated by ligand bonding
o Growth factors
Platelet-derived growth factor (PDGF)
Epidermal growth factor (EFG)
Fibroblast growth factor (FGF)
Receptors without intrinsic kinase activity
o Associate with and activate cytosolic protein
o Cytokines
G-protein linked receptors
o AKA seven-spanning or serpentine receptors

1|Page
PHYSIOLOGY 05/07/2017

SIGNAL TRANSDUCTION SYSTEMS

Receptors
Extracellular signals are detected and converted
into intracellular signals
Arranged as network of sequential protein Second
kinases messengers
Growth
inhibition
transcriptional
factors

Signal
transduction

GROWTH FACTORS
Growth effects
Influence cell movement, contractility and
differentiation
Examples
o ECF and TGF-: mitogenic for epithelial cells
and fibroblast
o PDGF: migration and proliferation of fibroblast
and smooth muscle cells; important in
angiogenesis

EXTRACELLULAR MATRIX AND CELL-MATRIX

INTERACTIONS
ECM
o Consists of fibrous structural proteins and
adhesive glycoproteins embedded in a gel of
REGULATION OF CELL PROLIFERATION
proteoglycan and hyaluronans
Cascade of protein phosphorylation pathways
o Interstitial matrix
o Cyclins. They are regulatory proteins whose
o Basement membrane
concentration rise and fall during the cell cycle.
ECM consists of
o Cyclin-dependent kinases (CDKs). They are
o Collagen
protein kinases that become active after
o Elastin, Fibrillin
complexing with specific cyclins.
o Adhesive matric glycoprotein and integrin
Checkpoints provides
Fibronectin
o Surveillance mechanism for ensuring that
Laminin
transitions in the cell cycle are in correct order
Integrin
o Ex: tumor-supressor gene p53
o Matricellular proteins
TUMOR-SUPRESSOR GENE P53 o Proteoglycans and hyaluronan
activated in response to DNA damage COLLAGEN
tumor-supressor gene p53 activation
14 types
increase expression of CDK inhibitor
Type 1 are the collagen of skin and bone
inhibit cell cycle progression
Type 2 are mostly collagen of cartilage
Vitamin C: improves tensile strength
GROWTH INHIBITION
o Regulate cell growth
o Polypeptide factors
ELASTIN AND FIBRILLIN
Elastin
o Provides tissue with the ability to stretch and
recoil
o 70 kD protein

2|Page
PHYSIOLOGY 05/07/2017

Fibrillin Regeneration of parenchymal cells

o Surrounds elastin Migration and proliferation of connective tissue
o Defects results in the formation of abnormal and parenchymal cells
elastic fibers like your Marfans syndrome Synthesis of ECM proteins
o 350 kD glycoprotein Remodelling
Collagenisation and acquisition of wound
MATRICELLULAR PROTEINS strength
Non-structural Wounds are classically described as healing by
Interact with matric components, cell receptors first or second intention
and other molecules
Able to disrupt cell-matric interactions HEALING BY FIRST INTENTION
Healing of a clean approximated incision
PROTEOGLYCANS AND HYALURONAN
Proteoglycans HEALING BY SECONDARY INTENTION
o Core protein linked to one or more Occurs when there is more extensive tissue
polysaccharides (glycosaminoglycans) damage
o Integral membrane protein Tissue approximation is not possible
Hyaluronan
Binds large amounts of water HEALING BY DELAYED FIRST INTENTION
Connective tissue turgor pressure and ability
to resist compression
WOUND STRENGTH
REPAIR BY CONNECTIVE TISSUES 1 week, wound strength is at 10% of normal
4 components o Largely dependent on suturing and tissue
o Angiogenesis is the formation of new blood adhesion
vessels rd
3 month, wound strength is are 70-80% of
o Migration and proliferation of fibroblasts normal
o Deposition of ECM (scar formation)
o Remodelling (maturation and reorganization SYSTEMIC FACTORS THAT INFLUENCE WOUND HEALING
of fibrous tissues into a scar) Nutritional status of the host
Metabolic status
ANGIOGENESIS Circulatory status
Formation of collateral circulation Hormones (corticosteroid)
Pre-existing blood vessels give rise to capillary
buds to produce new vessels LOCAL FACTORS THAT INFLUENCE WOUND HEALING
Vasculogenesis Infection
o Primitive vascular network during embryonic Mechanical factors
development Foreign bodies
Size, location and type of wound
FIBROSIS (FIBROPLASIA)
Occurs within the granulation tissue framework PATHOLOGIC ASPECTS OF WOUND HEALING
Fibroblast migration and proliferation Complications
ECM deposition o Deficient scar formation can lead to either
o Collagen synthesis Wound dehiscence
o Granulation tissue scaffold Ulceration
o Scar o Excessive formation of repair components
Keloid, hypertrophic scars
TISSUE REMODELLING o Formation of contractures
Interplay between collagen synthesis and
formation of matrix metalloprotinases
Synthesis vs degradation
Remodelling of connective tissue framework
Chronic inflammation and wound repair

WOUND HEALING
Induction of acute inflammatory process

3|Page