General Pathology for Lecture7 Dr. Mukhallad A.

Ramadhan
College of Dentistry

INFLAMMATION AND REPAIR

III. Tissue Repair: Cell Regeneration and Fibrosis

Stimuli that induce death in some cells can trigger the activation of replication
pathways in others.

Recruited inflammatory cells not only clean up the necrotic debris but also elaborate
mediators that drive the synthesis of new extracellular matrix (ECM).

Thus, repair begins very early in the process of inflammation and involves two
dichotomous processes:

• Regeneration of injured tissue by parenchymal cells of the same type.

• Replacement by connective tissue (fibrosis), resulting in a scar.

Commonly, tissue repair (healing) involves a combination of both processes.

The Proliferative Potential of Different Cell Types

The cells of the body are divided into three groups on the basis of their regenerative
capacity and their relationship to the cell cycle.

1. Labile cells: These are continuously dividing (and continuously dying).

Regeneration occurs from a population of stem cells with relatively unlimited
capacity to proliferate.

EX.

A. Hematopoietic cells in the bone marrow.

B. Surface epithelia including the stratified squamous surfaces of the skin, oral
cavity, vagina, and cervix; the cuboidal epithelia of the ducts draining
exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar
epithelium of the gastrointestinal tract, uterus, and fallopian tubes; and the
transitional epithelium of the urinary tract.

2. Stable cells: These are considered to be quiescent (or have only low-level
replicative capacity) in their normal state but are capable of undergoing rapid
division in response to injury.

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

EX.

A. Parenchymal cells. of most solid glandular tissues, including liver, kidney,

and pancreas, as well as endothelial cells lining blood vessels.
B. Mesenchymal cells. fibroblast and smooth muscle connective tissue cells.
3. Permanent cells: These are considered to be terminally differentiated and no
proliferative in postnatal life.

EX. The majority of neurons and cardiac muscle cells belong to this category. Thus,
injury to brain or heart is irreversible and results in only scar since the tissues cannot
proliferate.

Extracellular Matrix and Cell-Matrix Interactions

1. Interstitial matrix:

This is present in the spaces between cells in connective tissue, and between
epithelium and supportive vascular and smooth muscle structures; it is
synthesized by fibroblasts.

2. Basement membrane:

The random array of interstitial matrix in connective tissues becomes highly

organized around epithelial cells, endothelial cells, and smooth muscle cells,
forming the specialized basement membrane. The BM is synthesized by
overlying epithelium and underlying mesenchymal cells.

WOUND HEALING

Wound healing is a complex but generally orderly process. Sequential waves of

specialized cell types first clear the inciting injury and then progressively build the
scaffolding to fill in any resulting defect. The events are orchestrated by an interplay
of soluble growth factors and ECM. Wound healing may ultimately be reduced to a
sequence of processes:

• Induction of an acute inflammatory response by the initial injury

• Parenchymal cell regeneration (where possible)

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

• Migration and proliferation of both parenchymal and connective tissue cells

• Synthesis of ECM proteins

• Remodeling of parenchymal elements to restore tissue function

• Remodeling of connective tissue to achieve wound strength

Generally wound healing occurs by one of these processes:

1. Healing by First Intention: wound repair is the healing of a clean, uninfected

surgical incision approximated by surgical sutures.

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

2. Healing by Second Intention: When cell or tissue loss is more extensive, as in

infarction, inflammatory ulceration, abscess formation, or even just large
wounds, the reparative process is more complex. In these situations, regeneration
of parenchymal cells alone cannot restore the original architecture. As a result,
there is extensive ingrowth of granulation tissue from the wound margin,
followed in time by accumulation of ECM and scarring.

REPAIR BY CONNECTIVE TISSUE (FIBROSIS)

Severe or persistent tissue injury with damage both to parenchymal cells and to the
stromal framework leads to a situation in which repair cannot be accomplished by
parenchymal regeneration alone. Under these conditions, repair occurs by
replacement of the nonregenerated parenchymal cells with connective tissue. There
are four general components of this process:

• Formation of new blood vessels (angiogenesis).

• Migration and proliferation of fibroblasts.

• Deposition of ECM.

• Maturation and reorganization of the fibrous tissue (remodeling).

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

Repair begins within 24 hours of injury by the emigration of fibroblasts and the
induction of fibroblast and endothelial cell proliferation. By 3 to 5 days, a specialized
type of tissue that is characteristic of healing, called granulation tissue, is apparent.
The term granulation tissue derives from the pink, soft, granular gross appearance,
such as that seen beneath the scab of a skin wound. Its

histologic appearance is characterized by proliferation of fibroblasts and new thin-

walled, delicate capillaries, in a loose ECM. Granulation tissue then progressively
accumulates connective tissue matrix, eventually resulting in dense fibrosis, which
may further remodel over time.

Formation of new blood vessels (angiogenesis)

Angiogenesis is induced by the action of several factors, the most important between
them are basic fibroblast growth factor (bFGF) and vascular endothelial growth
factor (VEGF).

Four general steps occur in the development of a new capillary vessel:

• Proteolytic degradation of the parent vessel BM, allowing formation of a

capillary sprout

• Migration of endothelial cells from the original capillary toward an

angiogenic stimulus

• Proliferation of the endothelial cells behind the leading edge of migrating cells

• Maturation of endothelial cells with inhibition of growth and organization into

capillary tubes; this includes recruitment and proliferation of pericytes (for
capillaries) and smooth muscle cells (for larger vessels) to support the
endothelial tube and provide accessory functions.

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

Fibrosis (Scar Formation)

Fibrosis, or scar formation, builds on the granulation tissue framework of new

vessels and loose ECM that develop early at the repair site.

The process of fibrosis occurs in two steps:

(1) Emigration and proliferation of fibroblasts into the site of injury.

(2) Deposition of ECM by these cells. The recruitment and stimulation of fibroblasts
is driven by many of the growth factors described later, including platelet-derived
growth factor (PDGF), bFGF, and TGF-β. One source of these factors is the
activated endothelium and by inflammatory cells (Macrophages).

Ultimately, the granulation tissue scaffolding evolves into a scar composed of

largely inactive, spindle-shaped fibroblasts, dense collagen, fragments of elastic
tissue, and other ECM components. As the scar matures, vascular regression
eventually transforms the highly vascularized granulation tissue into a pale, largely
avascular scar.

Scar Remodeling

The transition from granulation tissue to scar involves shifts in the composition of
the ECM; even after its synthesis and deposition, scar ECM continues to be modified
and remodeled. The outcome at each stage is a balance between ECM synthesis and
degradation.

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General Pathology for Lecture7 Dr. Mukhallad A. Ramadhan
College of Dentistry

PATHOLOGIC ASPECTS OF REPAIR:

1. Infection: is the single most important cause of delay in healing, by prolonging the
inflammation phase of the process and potentially increasing the local tissue injury.

2. The type (and volume) of injured tissue: is a critical factor, Complete repair can
occur only in tissues composed of stable and labile cells.

3. The location of the injury, or the character of the tissue in which the injury occurs,
is also important. For example, inflammations arising in tissue spaces (e.g., pleural,
peritoneal, synovial cavities) develop extensive exudates.

4. Aberrations of cell growth and ECM production may occur even in what begins as
normal wound healing. For example, the accumulation of exuberant amounts of
collagen can give rise to prominent, raised scars known as keloids.

5. The mechanisms underlying the disabling fibrosis associated with chronic

inflammatory diseases such as rheumatoid arthritis, pulmonary fibrosis, and
cirrhosis are essentially identical to those that are involved in normal wound healing.

6. Diabetes.

7. Nutritional status.

8. Glucocorticoids (steroids).

9. Poor perfusion.

10. Mechanical factors.

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