patoloji-ders-notlari

Wound Healing Repair

Serdar Balcı

Wound Healing and Repair

Serdar BALCI, MD

Repair (Healing)

Restoration of tissue architecture and function after an injury

Regeneration of the injured tissue

Scar formation by the deposition of connective tissue

Regeneration

replace the damaged cells
return to a normal state
occurs by
- proliferation of residual (uninjured) cells that retain the capacity to divide
- **replacement from tissue stem cells **
skin and intestines
- rapidly dividing epithelia
liver

Robbins Basic Pathology

Robbins and Cotran Pathologic Basis of Disease

Scar formation (Nedbeleşme)

Tissues incapable of regeneration

Supporting structures of the tissue are severely damaged

Repair occurs by the laying down of connective (fibrous) tissue → scar formation

Cannot perform the function of lost parenchymal cells

Structural stability that the injured tissue is usually able to function

Extensive deposition of collagen
Lungs, liver, kidney
- Consequence of chronic inflammation
Myocardium
- Extensive ischemic necrosis (infarction)

Organization

Organizing pneumonia

Fibrosis develops in a tissue space occupied by an inflammatory exudate

Robbins and Cotran’s Pathological Basis of Diseases

Robbins Basic Pathology

Healing of Skin Wounds

Robbins Basic Pathology

Healing by First Intention

Clean, uninfected surgical incision

Approximated by surgical sutures

Focal disruption of epithelial basement membrane continuity

Death of relatively few epithelial and connective tissue cells

Epithelial regeneration is the principal mechanism of repair

A small scar is formed

There is minimal wound contraction

Incisional space first fills with fibrin-clotted blood

Rapidly invaded by granulation tissue

Covered by new epithelium

Within 24 hours

Neutrophils are seen at the incision margin, migrating to fibrin clot

Basal cells at the cut edge of the epidermis increased mitotic activity

Robbins Basic Pathology

Within 24 to 48 hours

Epithelial cells from both edges have begun to migrate and proliferate along the dermis

Deposite basement membrane components as they progress

The cells meet in the midline beneath the surface scab

A thin but continuous epithelial layer.

Robbins Basic Pathology

By day 3

Neutrophils replaced by macrophages

Granulation tissue progressively invades the incision space

Collagen fibers are evident at the incision margins, but these are vertically oriented and do not bridge the incision

Epithelial cell proliferation continues, yielding a thickened epidermal covering layer

Robbins Basic Pathology

By day 5

Neovascularization reaches its peak

Granulation tissue fills the incisional space

Collagen fibrils become more abundant and begin to bridge the incision

The epidermis recovers its normal thickness

Differentiation of surface cells yields a mature epidermal architecture with surface keratinization

Robbins Basic Pathology

Second week

Continued collagen accumulation and fibroblast proliferation

The leukocyte infiltrate, edema, and increased vascularity are substantially diminished

Increasing collagen deposition within the incisional scar

Regression of vascular channels

Robbins Basic Pathology

By the end of the first month

Scar consists of a cellular connective tissue

No inflammatory cells

Covered by a normal epidermis

Dermal appendages destroyed in the line of the incision are permanently lost The tensile strength of the wound increases with time

Robbins Basic Pathology

Healing by Second Intention

When cell or tissue loss is more extensive
Large wounds
Sites of abscess formation
Ulceration
Ischemic necrosis (infarction) in parenchymal organs
**The repair process is more complex **
- involves a combination of regeneration and scarring

Robbins Basic Pathology

Healing by Second Intention (secondary union)

Inflammatory reaction is more intense

Abundant granulation tissue

Robbins Basic Pathology

Healing by Second Intention

Accumulation of ECM and formation of a large scar

Followed by wound contraction by myofibroblasts

Robbins Basic Pathology

Healing of Skin Wounds

Wound strength

70% to 80% of normal by 3 months

Usually does not improve

Robbins Basic Pathology

Cell and Tissue Regeneration

Factors effective in Cell and Tissue Regeneration

Cell Proliferation

Growth Factors

Extracellular Matrix

The Control of Cell Proliferation

Cell types proliferating during tissue repair
the remnants of the injured tissue
- to restore normal structure
vascular endothelial cells
fibroblasts
- scar

Proliferative Capacities of Tissues

Labile (continuously dividing) tissues
- hematopoietic cells in the bone marrow
- surface epithelia, ducts
- **Gastrointestinal, Genitourinary tract **
- These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.
Stable tissues
- capable of proliferating in response to injury or loss of tissue mass
- liver, kidney, and pancreas.
- endothelial cells, fibroblasts, and smooth muscle cells
- limited capacity to regenerate after injury
  - Liver has much more capacity
Permanent tissues
- terminally differentiated and nonproliferative in postnatal life
- Neurons
  - Limited stem cell replication and differentiation
- Cardiac muscle cells
  - some evidence, may proliferate after myocardial necrosis
- Skeletal muscle
  - satellite cells attached to the endomysial sheath

Robbins and Cotran’s Pathological Basis of Diseases

Stem cells

self-renewal capacity
asymmetric replication
- one daughter cell enters a differentiation pathway and gives rise to mature cells
- the other remains an undifferentiated stem cell
Special microenvironment, stem cell niche
Regenerative medicine
Embryonic stem cells (ES cells)
- most undifferentiated stem cells
- inner cell mass of the blastocyst
- have extensive cell renewal capacity
- can be maintained in culture for over a year without differentiating
- can be induced to form specialized cells of all three germ cell layers
  - neurons, cardiac muscle, liver cells, and pancreatic islet cells.
Adult stem cells (tissue stem cells)
- less undifferentiated
- self-renewal capacity is more limited
- lineage potential is restricted to tissue, organ

Robbins Basic Pathology

Robbins and Cotran’s Pathological Basis of Diseases

Robbins Basic Pathology

Growth Factors

Proteins
stimulate the survival and proliferation of particular cells
promote migration, differentiation
Bind to specific receptors
Affect the expression of genes
promote entry of cells into cell cycle
relieve blocks on cell cycle progression
prevent apoptosis
enhance the synthesis of cellular proteins for mitosis
stimulate the function of growth control genes
- proto-oncogenes

Robbins and Cotran’s Pathological Basis of Diseases

Robbins Basic Pathology

Extracellular Matrix

Interstitial matrix
Basement Membrane
fibrous structural proteins
- collagens and elastins
- confer tensile strength and recoil
water-hydrated gels
- proteoglycans and hyaluronan
- permit resilience and lubrication
adhesive glycoproteins
- connect the matrix elements to one another and to cells
- Cell Adhesion Molecules

Robbins Basic Pathology

Functions of the Extracellular Matrix

**Mechanical support **
- cell anchorage and cell migration
- cell polarity
Control of cell proliferation
- binding and displaying growth factors
- signaling through cellular receptors of the integrin family
Scaffolding for tissue renewal
Establishment of tissue microenvironments
An intact ECM is required for tissue regeneration
If the ECM is damaged → scar formation

Scar Formation

Severe, chronic injury

Nondividing cells are injured

repair occurs with connective tissue → scar

combination of regeneration of some cells and scar formation

Inflammatory response
Angiogenesis
Granulation tissue
- Migration and proliferation of fibroblasts
- Deposition of connective tissue
Remodelling
- Maturation and reorganization of the fibrous tissue
Stable fibrous scar

Robbins Basic Pathology

Repair begins within 24 hours of injury

emigration of fibroblasts

induction of fibroblast and endothelial cell proliferation

Robbins Basic Pathology

Granulation Tissue

abundant vessels

interspersed leukocytes

pink, granular appearance macroscopically

Robbins Basic Pathology

Angiogenesis

Process of new blood vessel development
__ Existing vessels__
- primarily venules

Robbins Basic Pathology

Active research area for therapies
To fascilitate
- to improve blood flow to a heart in atherosclerosis
**To inhibit **
- **Stop tumor growth **
- **Block pathologic vessel growth **
  - diabetic retinopathy

Robbins Basic Pathology

Vasodilation
- NO, VEGF
Separation of pericytes
Migration of endothelial cells
Proliferation of endothelial cells
Remodeling into capillary tubes
Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel
Suppression of endothelial proliferation and migration and deposition of the basement membrane

Robbins and Cotran Pathologic Basis of Disease

Robbins Basic Pathology

Activation of Fibroblasts and Deposition of Connective Tissue

Migration and proliferation of fibroblasts into the site of injury

**Deposition of ECM proteins produced by these cells. **

Transforming growth factor-β (TGF-β)

Platelet-derived growth factor (PDGF)

Cytokines

Remodelling of Connective Tissue

Synthesis and degredation of ECM at the same time

The degradation of collagens and other ECM components by matrix metalloproteinases (MMPs), dependent on zinc ions for activity

inhibited by tissue inhibitors of metalloproteinases (TIMPs)

Factors that influence tissue repair

Infection
Nutrition
- Vit C
Glucocorticoids
Mechanical effects
Poor perfusion
- Arteriosclerosis, diabetes, venous obstruction
Foreign bodies
Type of injured tissue
Location of injury (cavity, solid organ)
Aberrations of cell growth and ECM production
- Keloid formation (excess fibroblastic growth)
- Exuberant granulation tissue (prevent epithelialization)

Robbins Basic Pathology

Fibrosis in Parenchymal Organs

Excessive deposition of collagen and other ECM components in a tissue

Deposition of collagen in chronic diseases.

The basic mechanisms of fibrosis are the same as those of scar formation during tissue repair

Tissue repair occurs after a short-lived injurious stimulus, follows an orderly sequence of steps

**Fibrosis is induced by persistent injurious stimuli **

Responsible for organ dysfunction and even organ failure

Robbins and Cotran’s Pathological Basis of Diseases