TISSUE REPAIR
Overview of Tissue Repair
Critical
to the survival of an organism is the ability to repair the damage caused by
toxic insults and inflammation. In fact, the inflammatory response to microbes
and injured tissues not only serves to eliminate these dangers but also sets
into motion the process of repair.
Repair of damaged tissues occurs by two types of reactions: regeneration by
proliferation of residual (uninjured) cells and maturation of tissue stem cells, and the deposition of connective
tissue to form a scar.
• Regeneration. Some tissues are able
to replace the damaged components and essentially return to a normal state; this process
is called regeneration.
Regeneration occurs
by proliferation of cells that survive the injury and
retain the capacity to proliferate, for example, in the
rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver.
• Connective
tissue deposition (scar formation). If the injured
tissues are incapable of complete restitution, or if the supporting structures
of the tissue are severely damaged, repair occurs by the laying down of
connective (fibrous) tissue, a process that may result in formation of a scar. Although the fibrous scar is
not normal, it provides enough structural stability that the injured tissue is
usually able to function. The term fibrosis
is most often used to describe the extensive deposition of collagen
that occurs in the lungs, liver, kidney, and other organs as a consequence of
chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarction).
If fibrosis develops in a tissue space occupied by an inflammatory exudate, it
is called organization
(as in
organizing pneumonia affecting the lung).
After many
common types of injury, both regeneration and scar formation contribute in
varying degrees to the ultimate repair. Both processes involve the
proliferation of various cells, and close interactions between cells and the extracellular
matrix (ECM). We first discuss the general mechanisms of cellular proliferation
and regeneration, and then the salient features of regeneration and healing by scar
formation, and conclude with a description of cutaneous wound healing and fibrosis
(scarring) in parenchymal organs as illustrations of the repair process.
Cell and Tissue
Regeneration
The
regeneration of injured cells and tissues involves cell proliferation, which is
driven by growth factors and is critically dependent on the integrity of the
extracellular matrix, and by the development of mature cells from stem cells.
Cell
Proliferation: Signals and Control Mechanisms
Several cell
types proliferate during tissue repair. These include the remnants of the
injured tissue (which attempt to restore normal structure), vascular
endothelial cells (to create new vessels that provide the nutrients needed for the
repair process), and fibroblasts (the source of the fibrous
tissue that
forms the scar to fill defects that cannot be corrected by regeneration).
The ability of
tissues to repair themselves is determined, in part, by their intrinsic
proliferative capacity
.
Cell
proliferation is driven by signals provided by growth factors and from the
extracellular matrix. Many different growth factors have been described, some
of which act on multiple cell types, while others are cell-type specific.
.
Mechanisms
of Tissue Regeneration
The importance
of regeneration in the replacement of injured tissues varies in different types
of tissues and with the severity of injury.
• In epithelia
of the intestinal tract and skin, injured cells are rapidly replaced by
proliferation of residual cells and differentiation
of cells derived from tissue stem cells,
providing the underlying basement membrane is intact.
The residual epithelial cells produce the growth factors involved in these processes. The newly generated cells migrate to fill the defect created by the injury,
and
tissue integrity is restored .
•
Tissue regeneration can occur in parenchymal organs whose cells are capable of
proliferation, but with the exception of the liver, this is usually a limited
process. Pancreas, adrenal, thyroid, and lung have some regenerative capacity.
Liver Regeneration
The human liver has a remarkable capacity to regenerate, as
demonstrated by its growth after partial hepatectomy, which may be performed for tumor resection or for living donor hepatic transplantation.
.
Regeneration of the liver occurs by two major mechanisms: proliferation
of remaining hepatocytes and repopulation from progenitor cells. Which mechanism plays the
dominant role depends on the nature of the injury.
Repair by
Scarring
If repair cannot be accomplished by regeneration alone, it occurs
by replacement of the injured cells with connective tissue, leading to the
formation of a scar, or by a combination of regeneration of some residual cells
and scar formation.
Steps
in Scar Formation
Repair
by connective tissue deposition consists of a series of sequential steps that
follow tissue injury (Fig. 3.24).
•
Within minutes after injury, a hemostatic plug comprised of platelets is formed, which stops
bleeding
and provides a scaffold for infiltrating inflammatory cells.
• Inflammation. This step is
comprised of the typical acute and chronic inflammatory responses. Breakdown products
of complement activation, chemokines released from activated platelets, and
other mediators produced at the site of injury function as chemotactic agents
to recruit neutrophils and then monocytes during the next 6 to 48 hours. As
described earlier, these inflammatory cells eliminate the offending agents,
such as microbes that may have entered through the wound, and clear the debris.
Macrophages are the central cellular players in the repair
process—M1 macrophages
clear
microbes and necrotic tissue and promote inflammation in a positive feedback
loop, and M2 macrophages produce growth factors that stimulate the proliferation
of many cell types in the next stage of repair. As the injurious agents and
necrotic cells are cleared, the
inflammation
resolves; how this inflammatory flame is extinguished in most situations of
injury is still not well defined.
• Cell proliferation. In the
next stage, which takes up to 10 days, several cell types, including epithelial
cells, endothelial and other vascular cells, and fibroblasts, proliferate and
migrate to close the now-clean wound.
• Remodeling. The connective tissue
that has been deposited by fibroblasts is reorganized to produce the stable fibrous
scar. This process begins 2 to 3 weeks after injury
and
may continue for months or years.
Angiogenesis
Angiogenesis is the process of new blood vessel development from
existing vessels. It is critical in healing at
sites of injury, in the development of collateral circulations at sites of ischemia, and in
allowing tumors to increase in size
beyond the constraints of their original blood supply.
Angiogenesis
involves sprouting of new vessels from existing ones, and consists of the
following steps (Fig. 3.25):
•
Vasodilation in response to NO and increased permeability induced by VEGF
•
Separation of pericytes from the abluminal surface and breakdown of the basement
membrane to allow formation of a vessel sprout
•
Migration of endothelial cells toward the area of tissue injury
•
Proliferation of endothelial cells just behind the leading front (“tip”) of
migrating 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
The process of angiogenesis
involves several signaling pathways, cell–cell interactions, ECM proteins, and
tissue enzymes.
• Growth
factors. VEGFs,
mainly VEGF-A , stimulates both migration and proliferation of endothelial cells,
thus initiating the process of capillary sprouting in angiogenesis. It promotes
vasodilation by stimulating the production of NO and contributes to the
formation of
the vascular lumen. Fibroblast growth factors (FGFs),
mainly FGF-2, stimulate the proliferation of endothelial
cells. They also promote the migration of macrophages
and fibroblasts to the damaged area, and stimulate
epithelial cell migration to cover epidermal wounds.
Activation of
Fibroblasts and Deposition of Connective Tissue
The
laying down of connective tissue occurs in two steps:
(1)
migration and proliferation of fibroblasts into the site of injury and (2) deposition
of ECM proteins produced by these cells
TGF-β is the most
important cytokine for the synthesis and deposition of connective tissue
proteins. It is produced
by most of the cells in granulation tissue, including
alternatively activated macrophages.
.
Remodeling
of Connective Tissue
After
the scar is formed, it is remodeled to increase its strength and contract it. Wound
strength increases because of
cross-linking of collagen and increased size of collagen
fibers.
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