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Inflammation: Tissue Repair

Kinjal Shah, M.D.

Departments of Pathology and Medical Education
of Tissue
1) Regeneration
• Replacement of injured cells by cells of the same type
• Involves cell proliferation
• driven by growth factors
• dependent on the integrity of the extracellular matrix,
• relies on development of mature cells from stem cells.
•Cell types: injured tissue, endothelial cells, and fibroblasts
•Depends of the intrinsic ability of tissue to replicate:
•Labile- contantly replicating
•Stable- in G0 but can be triggered to replicate
•Permanent- cannot proliferate
• Constantly divide actively during life to replace
lost cells
• Regenerate after injury
• Source of replacement cells:
• Tissue stem cells
Labile Cells • Rapidly proliferatng immature progenitor
• Examples: hematopoietic cells in the
BM, epithelial lining of the GI tract, urinary
tract, skin, oral cavity, vagina, cervic, etc
• Normally in the G 0 stage of the cell cycle (not
• Are capable of diving/regeneration
following injury in response to growth factors
• Ex. hepatocytes, renal tubular
Stable Cells cells, parenchymal cells of many organs
and numerous mesenchymal cells (e.g.
smooth muscle, cartilage, connective tissue
& endothelium).
• Terminally differentiated nonproliferative cells
• Injury to these tissues is irreversible
• Area replaced by scar tissue, because the cells
Permanent cannot regenerate.
Cells • Ex:
• Cardiac muscle cells- heal with fibrosis/scar
• Neuron- heal with gliosis
Mechanism of Regeneration
1. Need preserved BM and relatively intact connective tissue
2. Need factors that stimulate parenchymal cell regeneration ie
growth factors
• Restoration of normal tissue architecture can occur only if
the residual tissue is structurally intact
• Cell proliferation is controlled by the cell cycle, and is stimulated by
growth factors and interactions of cells with the extracellular matrix.
• Macrophages are an imp source of these growth factors
2) Repair by Scarring

• Replacement of injured cells with connective

• Occurs if the injury is severe/chronic or has
caused destruction of the CT framework or BM.
• Steps
• Hemostasis and Inflammation
• Cell proliferation
• Remodeling
Within minutes of injury, a hemostatic plug of
platelets forms to stop the bleeding

Step 1-
Inflammation Kicks off the acute chronic inflammatory
Macrophages arrive As injury clears up,
PMNs arrive to clear up debris & macrophages start off
necrotic tissue. the repair process
Step 2: Cell proliferation
• May take upto 10 days
• You now have a clean wound- need to lay connective tissue to close
that wouldn.
• Cells that proliferate are
• Epithelial Cells- cover the wound
• Endothelial cells- angiogenesis
• Fibroblasts- lay down connective tissue and collagen fibers that form scar
• Have formation of Granulation Tissue
• Combination of new blood vessels, loose connective tissue, proliferating
fibroblasts and scatered chronic inflammatory cells
Begins 2-3 weeks after injury
and can continue for months
to years
Step 3-
Remodeling The connective tissue that has
been deposited by fibroblasts
is reorganized to produce the
stable fibrous scar .
2nd intention (secondary
1st intention (primary union)
• epithelial regeneration with • larger wounds that heal by a
minimal scarring combination of
• Ex: seen in well-apposed regeneration and scarring
surgical incisions • involves more extensive
scarring and wound

Healing by 1st intention vs 2nd intention

Healing by 2dary intention:(A) Hemostatic plug and inflammation. (B)
Proliferation of epithelial cells; formation of granulation tissue by
vessel growth and proliferating fibroblasts. (C) Remodeling to produce
the fibrous scar.
(A) Granulation tissue showing numerous blood vessels, edema, and a loose
extracellular matrix containing occasional inflammatory cells. (B) Trichrome
stain of mature scar, showing dense collagen (stained blue) and scattered
vascular channels.
Steps involved:
Dialation- NO; Permeability- VEGF
Separation of pericytes
BM degradation & start vessel sprout- MMP
Migration & proliferation of of endothelial
cells just behind the leading "tip"
Remodeling into capillary tubes
Recruitment of periendothelial cells/pericytes
to form the new vessel
Supression endothelial proliferation
• migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in
• promotes vasodilation by stimulating the production of NO and contributes to the formation of the
vascular lumen.

• proliferation of endothelial cells.
• promote the migration of macrophages and fibroblasts to the damaged area, and stimulate epithelial cell
migration to cover epidermal wounds

• Degrade the ECM to permit remodeling and extension of the vascular tube

Molecules in Angiogenesis
Activation of Fibroblasts and Deposition of
Connective Tissue
• Deposition of CT in two steps:
• (1) migration and proliferation of fibroblasts into the site of injury
• (2) deposition of ECM proteins produced by these cells

• Some of the fibroblasts differentiate into myofibroblasts, pull the

margins of the wound together by contracting
• TGF - β : most important cytokine for the synthesis and deposition of
connective tissue proteins
• stimulates fibroblast migration and proliferation, synthesis of collagen &
decreases the degradation of ECM by inhibiting MMPs
• After the scar is formed, it is remodeled to increase its strength and
contract it.
• Strenght: cross-linking of collagen, increased size of collagen fibers,
Type III coallagen to the more resilient type I collagen.
• Strength may recover to 70% to 80% of normal skin by 3 months.
• Wound contraction is initially caused by myofibroblasts and later by
cross-linking of collagen fibers.
• The connective tissue is degraded by MMPS and the scar shrinks.
• MMPs inhibited by TIMPS- balance b/w two regulates size of scar
Factors that Impair Tissue Repair

• Infection- it prolongs inflammation and potentially increases the local

tissue injury.
• Diabetes systemic cause of abnormal wound healing.
• Nutritional status- Vitamin C deficiency inhibits collagen synthesis
• Glucocorticoids (steroids)- result in weak scars because they inhibit
TGF-β production and diminish collagen deposition and fibrosis.
• Poor perfusion- diabetes or from obstructed venous drainage (e.g., in
varicose veins)
Chronic Wounds
• Venous Leg Ulcers
• develop most often in elderly people
• result of chronic venous hypertension, which may be caused by severe
varicose veins or congestive heart failure.
• ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer.
• Arterial ulcers
• Individuals with atherosclerosis of peripheral arteries, especially associated
with diabetes.
• The ischemia results in atrophy and then necrosis of the skin and underlying
• These lesions can be quite painful.
• Pressure sores
• are areas of skin ulceration and necrosis of underlying tissues caused by
prolonged compression of tissues against a bone, for example, in
bedridden, immobile elderly individuals.
• The lesions are caused by mechanical pressure and local ischemia.

• Diabetic ulcers
• affect the lower extremities, particularly the feet.
• Tissue necrosis and failure to heal are the result of small vessel disease
causing ischemia, neuropathy, systemic metabolic abnormalities, and
secondary infections.
• Histologically, these lesions are characterized by epithelial ulceration and
extensive granulation tissue in the underlying dermis
Excessive formation of the components of the
repair process can give rise to hypertrophic
scars and keloids

Hypertrophic scars- accumulation of excessive

Excessive amounts of collagen, grow rapidly and contain
abundant myofibroblasts, but they tend to
Scarring regress over several months
Keloid- scar tissue grows beyond the
boundaries of the original wound and does not
Clinical Examples of Abnormal Wound Healing
Would Healing – Tissue Mediators and Their
• Secreted by activated platelets and macrophages
• Induces vascular remodeling and smooth muscle cell migration
• Stimulates fibroblast growth for collagen synthesis
• Stimulates angiogenesis
• TGF-β
• Angiogenesis, fibrosis
• Metalloproteinases
• Tissue remodeling
• Stimulates angiogenesis
• Denotes te excessive deposition of collagen and other ECM
components in a tissues of internal organs in chronic dz.
• Persistent stimulation of collagen synthesis in chronic inflammatory
diseases leads to tissue fibrosis, often with extensive loss of the tissue
and functional impairment.
• It may be responsible for substantial organ dysfunction and even
organ failure.
of Fibrosis
What type of tissue?