Porth's Essentials of Pathophysiology, 4e - page 99

C h a p t e r 4
Cell Proliferation and Tissue Regeneration and Repair
79
formation of capillary buds, and proliferation of endothe-
lial cells, followed by fusion and remodeling of the endo-
thelial cells into capillary tubes. Several growth factors
induce angiogenesis, but the most important are VEGF
and basic FGF-2. In angiogenesis, VEGF stimulates both
proliferation and motility of endothelial cells, thus initiat-
ing the process of capillary sprouting. FGF-2 participates
in angiogenesis mainly by stimulating the proliferation of
endothelial cells. During angiogenesis, new blood vessels
are leaky because of incompletely formed interendothe-
lial cell junctions and because VEGF increases vascu-
lar permeability. This leakiness explains the edematous
appearance of granulation tissue and accounts in part for
the swelling that may persist in healing wounds long after
the acute inflammation has subsided.
Emigration of Fibroblasts and Deposition
of Extracellular Matrix
Scar formation builds on the granulation tissue frame-
work of new vessels and loose ECM. The process occurs
in two phases: emigration and proliferation of fibroblasts
into the site of injury, and deposition of extracellular
matrix by these cells. The recruitment and proliferation
of fibroblasts is mediated by a number of growth factors
including FGF-2 and TGF-
β
. These growth factors are
released from endothelial cells and from inflammatory
cells that are present at the site of injury.
As healing progresses, the number of proliferating
fibroblasts and formation of new vessels decrease and
there is increased synthesis and deposition of collagen.
Collagen synthesis is important to the development of
strength in the healing wound site. Ultimately, the gran-
ulation tissue scaffolding evolves into a scar composed
of largely inactive spindle-shaped fibroblasts, dense col-
lagen fibers, fragments of elastic tissue, and other ECM
components. As the scar matures, vascular degeneration
eventually transforms the highly vascular granulation
tissue into a pale, largely avascular scar.
Maturation and Remodeling of the
FibrousTissue
The transition from granulation to scar tissue involves
shifts in the modification and remodeling of the ECM.
The outcome of the repair process is, in part, a bal-
ance between previously discussed ECM synthesis and
degradation. The rate of collagen synthesis diminishes
until it reaches equilibrium with collagen degradation.
The degradation of collagen and other ECM proteins
is achieved through a family of metalloproteinases,
which require zinc for their activity. The metallopro-
teinases are produced by a variety of cell types (fibro-
blasts, macrophages, synovial cells, and some epithelial
cells), and their synthesis and secretion are regulated
by growth factors, cytokines, and other agents.
10,11
Their synthesis may be suppressed pharmacologically
by corticosteroids. Metalloproteinases are typically
released as inactive precursors that require activation
by enzymes, such as proteases, that are present at sites
of injury.
Cutaneous Wound Healing
Thus far, this chapter has focused on general aspects of
tissue repair and wound healing. The following section
specifically addresses healing of skin wounds (cutane-
ous wound healing). This is a process that involves both
epithelial cell regeneration and connective tissue scar
formation, and thus is illustrative of general principles
that apply to all tissues.
Healing by Primary and Secondary Intention
Depending on the extent of tissue loss, wound closure
and healing occur by primary or secondary intention
(Fig. 4-6). A sutured surgical incision is an example of
healing by primary intention. Larger wounds (e.g., burns
and large surface wounds) that have a greater loss of
tissue and contamination heal by secondary intention.
Healing by secondary intention is slower than healing by
primary intention and results in the formation of larger
FIGURE 4-5.
Granulation tissue.
(A)
A foot covered by
granulation tissue.
(B)
A photomicrograph of granulation tissue
shows the thin-walled vessels (arrows) embedded in a loose
connective tissue matrix containing mesenchymal cells and
occasional inflammatory cells. (From Sephal GC, Davidson JM.
Repair, regeneration, and fibrosis. In: Rubin R, Strayer DS, eds.
Rubin’s Pathology: Clinicopathologic Foundations of Medicine.
6th ed. Philadelphia, PA: Wolters Kluwer Health | Lippincott
Williams &Wilkins; 2012:94.)
A
B
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