1 Healing Lec

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INFLAMMATION
Healing and repair
Dr.Kanwar
Tissue renewal & Repair
Regeneration & Healing)
(
INTRODUCTION
▶ What is dead or damaged – has to be replaced or
repaired
▶ This is critical for survival
▶ Process of repair can be broadly divided into 2
processes
◦ Regeneration
◦ Healing (tissue response)
Definitions
REGENERATION
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Growth of cells & tissues to replace lost structures
Proliferation of parenchymal cells
Usually there is complete restoration of the original
tissue
Examples
▶ Tissues with high proliferation capacity – regenerate
themselves continuously
◦ Hematopoietic system
◦ Epithelium of skin, GIT
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Liver tissue after partial hepatectomy
Healing
▶ Tissue response to
◦Wounds
◦Inflammatory processes
◦Cell necrosis in organs incapable of
regeneration
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In dermis, forms collagen scars
Even in myocardial infraction original lost tissue replaced by
collagen
Development of dense fibrous scar in the pericardium can lead
→ constrictive pericarditis (post-inflammatory thickening and
scarring of the membrane producing constriction of the cardiac
chambers)
Persistent chronic injury by helicobacter pylori
Fibrosis in liver cirrhosis, silica induced lung disease, ultimately
it is called organization
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Consists of 2 distinct processes
◦ Some amount of regeneration
◦ Laying down of fibrous tissue / scar
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In parenchymal organs replacement of inflammatory
infiltrate → granulation tissue → fibrosis →
organization
Tissue renewal & Repair
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Regeneration – require an intact connective tissue scaffold
Scarring - occurs if framework is damaged
Extracellular matrix (ECM) scaffolds essential for wound
healing
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Provides framework for cell regeneration
Maintains the correct cell polarity
Cells in ECM – source of agents critical for tissue repair
If CCl4 applied in large dose, kills 50% hepatocyte u get regeneration,
but if u give small doses u get fibrosis or healing
Control of Normal cell proliferation
Control of Normal cell proliferation
Control of Normal cell proliferation
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Homeostatic equilibrium maintained in life by
balancing
◦ Proliferation( physiological :such as endometrial cells or
thyroid gland during pregnancy) (path: nodular prostatic
hyperplasia/hypertrophy from dihydrotestosterone(DHT)
stimulation and development of nodular goiters)
◦ Differentiation
◦ Death
Cell proliferation
Stimulated by
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Physiological condition- endometrial cells in
menstrual cycle under influence of estrogen
Pathological condition- after cell death, injury etc.
Tissue Proliferation
Controlled by
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Signals (Soluble or contact dependent) from the micro
environment
Stimulators – Inhibitors
Cell growth can be accelerated by
◦ Shortening cell cycle
◦ Making the resting cells enter the cell cycle- Proliferating cell
Cell Cycle
Consists of following phases
▶ G1( Presynthetic)
▶ S ( DNA – synthesis)
▶ G2 ( Pre-mitotic phase)
▶ M ( Mitotic phase)
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Quiescent cells → G0 phase
Cell Cycle
Depending on proliferative activity tissues/ cells divided into 3
groups
▶ Labile cells ( Continuously dividing)skin, oral cavity, vagina,
cervix, line mucosa of all the excretory ducts of the glands of the
body, columnar epithelium of the GIT and uterus, urinary tract
and bone marrow
▶ Quiescent cells ( stable) parenchymal cells of the liver, kidney
and pancreas, mesenchymal cells such as fibroblast and smooth
muscle, vascular endothelial cells, and resting lymphocytes and
other leukocyte
▶ Non- dividing ( permanent)
Most mature tissues contain some combination of
▶ Continuously dividing cells
▶ Terminally differentiated cells
▶ Quiescent/ Resting cells
▶ Stem cells in some tissues
Cell Cycle
Labile / continuously dividing cells
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Cells proliferate through out life
Replace cells being destroyed
Examples
◦ Oral cavity
◦ Skin
◦ Vagina
◦ Columnar epithelium of GIT
◦ Transitional epithelium
In most of these tissues- mature cells are derived
from stem cells ( Proliferation +Differentiation)
Cell Cycle
Quiescent / Stable cells
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Normally low level of replication
Can undergo rapid division in response to stimuli i.e.
when & if required
Cells are in G0 phase
Stimulated to enter G1 phase
Quiescent / Stable cells
Examples
▶ Parenchymal cells – Liver, kidney, pancreas
▶ Mesenchymal cells
◦ Fibroblasts
◦ Endothelial cells
◦ Smooth muscle cells
◦ Lymphocytes
Cell Cycle
Non dividing / Permanent cells
▶ Cells have left the cell cycle
▶ Cannot undergo division
Examples
▶ Neurons (glial cells replace them)
▶ Skeletal muscles(have some regenerative capability
thru satellite cells)
▶ Cardiac muscles
Stem cells (totipotent cell)
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Form the core of “regenerative medicine”
Prolonged self renewal capacity and asymmetric
replication :one cell retains its self renewing property
First described in the embryo – pluripotent embryonic
stem cells
Stem cells are present in adult tissues also and
contribute to tissue homeostasis.
Bone marrow and umbilical blood – rich sources of
stem cells.
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Embryonic stem cell (ES)
The pluriopotential cells express unique transcription
factors such as homeobox protein – nanog-Tir na n’Og
and Wnt- beta-catenin-signaling in maintaining
pluripotency.
These cells used to study signal for development of
many organs
Research knockout genes and conditional gene
deficiency
Repopulate damaged genes
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Adult stem cells
have restricted differentiation capacity
Stem cells outside bone marrow are tissue stem cells
Stem cells are located in niches, and differ in different
tissues, ex in GIT- its at isthmus of stomach and base of
crypts in colon
Bone marrow contains hematopoietic cells (HSCs) and
stromal cells
HSCs can be collected from the bone marrow, umbilical cord
bld, circulating bld of individuals receiving cytokines, such as
granulocyte macrophage colony stimulating factor which
mobilize HSCs
Bone marrow stromal cells can generate chondrocytes,
osteoblasts, adipocytes and myoblasts and endothelial
precursor cells depending upon the tissue envirement.
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A change in stem cell differentiation from one cell type to another is
called trans-differentiation and the multiplicity of the stem cell
differentiation option is known as developmental plasticity
The adult bone marrow also harbors a heterogenous population of
stem cells, which appear to have very broad development abilities,
these cells are called adult progenitor cells MAPCs (multipotent
adult progenitor cells)
MAPC do not get old, and can differentiate into endothelium,
neurons, hepatocyte and other cells
MAPCs constitute a population of stem cells derived from or closely
related to ES cells
Adult stem cells reside in permanently in most organs, and some
migrate to various tissues after injury.
Liver contains stem cells in canals of hering, cells
in this area can give rise to oval cells(give rise to
hepatocytes and biliary cells), in hepatectomy the
normal cells replicate, but in fulminant hepatic
failure the oval cells replicate, oval cells also
replicate in liver carcinogenesis, chronic hepatitis,
and advanced liver cirrhosis in which hepatocyte
proliferation is blocked.
▶ Neural stem cells are also known as precursor
cells, usually found in olfactory bulb and
hippocampus, the intermediate filaments nestin
are used to identify them
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Growth and regeneration of injured skeletal muscle occur
instead by replication of satellite cells, which can be
osteogenic and adipogenic, they are not found in cardiac
muscle.
Self renewing epithelia contains stem cells, highly
proliferative intermediate cells (amplifying
compartments), cell at various stages of differentiation,
After injury self renewing cells can increase the number
of dividing stem cells,
increase replication in amplifying comp and decrease cell
cycle time for cell replication
Practical/ Applied Aspects
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Therapeutic cloning use ES
Uses in diabetes, MI and Alzheimer’s
Umbilical stem cell bank
Growth factors & Cell proliferation
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Cell proliferation initiated by action of growth factors.
Regulated by signaling mechanisms and cell cycle
events.
GROWTH FACTORS
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Large number of known polypeptide growth factors.
Some act on many cells.
Others have restricted cellular targets.
Effects of growth factors
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include
• Cell proliferation
• Cell locomotion
• Contractility
• Differentiation
• Angiogenesis
Epidermal growth factor (EGF) & Transforming
growth factor α (TGFα)
● Both belong to EGF family
● Share a common receptor
EGF
Source – platelets, macrophages, saliva, urine, milk and
plasma, in injury produced by macrophages,
keratinocytes and other inflammatory cells in the area
Functions
- Mitogenic for a variety of epithelial cells,
hepatocytes & fibroblasts. Widely distributed in
tissue secretions and fluids such as saliva, urine and
intestinal contents, used in healing of the skin
MODE OF ACTION
Binds to a receptor EGFR
↓
intrinsic tyrosine kinase activity
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triggers the signal
TGF – α
Source – macrophages, T-lymphocytes, keratinocytes
Functions – similar to EGF
↑ hepatocytes and epithelial cells
(avian erythroblastosis oncogene)
• The ErbB family of proteins contains four receptor
tyrosine kinases, These genes code for the epidermal
growth factor receptor (EGFR) family of receptors
which is important in the control of normal cell
proliferation and in the pathogenesis of human cancer.
• In humans, the family includes Her1 (EGFR, ErbB1),
Her2 (Neu, ErbB2), Her3 (ErbB3), and Her4 (ErbB4).
• Insufficient ErbB signaling in humans is associated
with the development of neurodegenerative diseases,
such as multiple sclerosis and Alzheimer's Disease,
while excessive ErbB signaling is associated with the
development of a wide variety of types of solid tumor
• Receptor tyrosine-protein kinase erbB-2, also known as CD340
(cluster of differentiation 340), proto-oncogene Neu,
• Erbb2 (rodent), or ERBB2 (human), is a protein that in humans
is encoded by the ERBB2 gene. It is also frequently called HER2
(from human epidermal growth factor receptor 2) or HER2/neu.
• HER2 is a member of the human epidermal growth factor
receptor (HER/EGFR/ERBB) family.
• Amplification or over-expression of this oncogene has been
shown to play an important role in the development and
progression of certain aggressive types of breast cancer. In
recent years the protein has become an important biomarker
and target of therapy for approximately 30% of breast cancer
patients.
• Amplification, also known as the over-expression of the ERBB2
gene, occurs in approximately 15-30% of breast cancers
Mode Of Action
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Binds to EGF receptor
(Membrane tyrosine kinase receptor)
Receptor ERB B1→ also called EGFR.The main EGFR
is referred to as EGFR1
The ERB B2 receptor AKA – HER 2/neu – over
expressed in breast Cancer and is therapeutic target
Phosphorylated tyrosine residues act as binding sites for
intracellular signal activators such as Ras. The
Ras-Raf-MAPK pathway is a major signalling route for
the ErbB family, as is the PI3-K/AKT pathway, both of
which lead to increased cell proliferation and inhibition
of apoptosis
Hepatocyte Growth Factor (HGF)
also called Scatter factor
Source – mesenchymal cell (non parenchymal cell),
fibroblasts & endothelial cells
Functions
↑ prod of
- epithelial cells: cells of biliary epi,
lung epi, and mammary gland, skin and other
tissue
- endothelial cells
- hepatocytes
↑ cell motility – migration-embryonic development
Mode of action
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Binds to a receptor
HGF receptor is a product of the proto-oncogene
C-MET
HGF required for survival during embryonic period
If overexpressed-------
Vascular Endothelial Growth Factor (VEGF)
Source – mesenchymal cell
Functions
- promotes growth of new vessels
– angiogenesis (in adults)
- vasculogenesis in embryo
Mode of action
↖ Through 3 tyrosine kinase receptors
VEGFR – 1,2&3
● VEGFR-2 located in endothelial cells and is the main
receptor for vasculogenesis & angiogenesis
● VEGFR-1 facilitate mobilization of endothelial stem
cells and has a role in inflammation.
● VEGF-c,d bind to VEGFR-3 act on lymphatic
endothelial cells to induce production of lymphatic
vessels,,
● VEGF-B bind exclusively to VEGFR-1, plays role in
myocardial function
Platelet derived growth factor (PDGF)
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Family of several closely related proteins
Consist of 2 chains A&B
Three isoforms AA, AB, BB
Bind to PDGFR alpha and beta
Stored in platelet alpha granules, released upon
platelet activation
Source – platelets, macrophages,
endothelial
cells, smooth muscle cells, many tumour cells
Functions
↖ Chemotactic for PMN, macrophages, fibroblasts & smooth
muscle cells.
↖ Activate PMN’s , macrophages & fibroblasts
↖ Mitogenic and migration for fibroblasts endothelial cells &
smooth muscle cells, monocyte
↖ Stimulate prod of MMP (matrix metalloproteinase),
fibronectin & Hyaluronic Acid
↖ Activation of hepatic stellate cells in initial steps of liver
fibrosis↖ In normal liver, hepatic stellate cells (HSCs) are
nonparenchymal, quiescent cells whose main functions is to
store vitamin A and probably to maintain the normal
basement membrane-type matrix.
Mode of action
Bind to 2 cell surface receptors – PDGFR α & β
Fibroblast Growth factor (FGF)
Source – Macrophage, mast cell, Tlymphocyte, endo cell, fibroblast
Functions
↖ Angiogenesis-fgf2
↖ Wound repair-migration of macrophage, fibroblasts,
and endothelial cell migration
↖ Development ( skeletal muscle development, lung
maturation, F6F-induce myoblast proliferation and
suppress myocyte differentiation.
↖ fgf-2 generation of angioblasts during
embryogenesis. FGF-1 and FGF-2 involved in
specification of liver from of endodermal cells)
↖ Hematopoiesis-differentiating BML and develop
stroma.
TGF (Transforming Growth Factor)–β
& Related growth factors
Belongs to a family of homologous polypeptides
▶ 3 isoforms β1, β2, β3
▶ Most important is β1-referred to as TGF- β
Sources
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◦ Platelets, lymphocytes, endothelial cells
◦ Macrophages, smooth muscle cells, fibroblasts
Functions
◦ Growth inhibitor for most epithelial cells& leucocytes, stop
cell cycle by increasing cip/kip and ink4/arf (it is against
cancer)
◦ Stimulates proliferation of smooth muscle cells & fibroblasts.
◦ TGF-beta effect on mesenchymal cells depends on conc. And
culture conditions.
◦ Potent fibrogenic agent
⚫ Fibroblast chemotaxis
⚫ Increase production of collagen, fibronectin, proteoglycans
⚫ Inhibits collagen degradation& decreases matrix proteases, and
increase protease inhibitor
◦ Strong anti – inflammatory agent
TGF –β & Related growth peptides
Mode of action
▶ Binds to 2 cell surface receptors –I & II
▶ With Serine / Threonine kinase activity
▶ Triggers phosphorylation of transcription factors
called—Smads(40 to 50 types) homologues of the Drosophila
protein, mothers against decapentaplegic (Mad) and the
Caenorhabditis elegans protein Sma▶ Which activate or inhibit gene transcription
▶ TGF –beta binds to type 2 which then forms complex with type
I, leading to phosphorylation of smad 2 and 3, forms
heterodimer with smad 4, which enter nucleus and associate
with other dna binding proteins to activate or inhibit gene
transcription
▶ TFG-B is pleiotropic
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