Cell Regeneration

7/31/2019 Cell Regeneration

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WOUND HEALING

Wound healing, or wound repair is an intricate process in which the skin (or

another organ) repairs itself after injury. In normal skin, the epidermis (outermost layer)

and dermis (inner or deeper layer) exists in steady-state equilibrium, forming a protectivebarrier against the external environment. Once the protective barrier is broken, the normal

(physiologic) process of wound healing is immediately set in motion. The classic model of

wound healing is divided into three or four sequential, yet overlapping, phases:

(1) Hemostasis, (2) Inflammatory, (3) Proliferative and (4) Remodeling.

HEMOSTASIS

Upon injury to the skin, a set of complex biochemical events takes place in a

closely orchestrated cascade to repair the damage. Within minutes post-injury, platelets

(thrombocytes) aggregate at the injury site to form a fibrin clot. This clot acts to control

active bleeding. When tissue is first wounded,blood comes in contact with collagen,

triggering blood platelets to begin secreting inflammatory factors. Platelets also

express glycoproteins on theircell membranes that allow them to stick to one another and

to aggregate, forming a mass. Fibrin and fibronectin cross-link together and form a plug

that traps proteins and particles and prevents further blood loss. This fibrin-fibronectin plug

is also the main structural support for the wound until collagen is deposited. Migratory

cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete

factors. The clot is eventually lysed and replaced with granulation tissue and then later withcollagen.

Platelets

Platelets, the cells present in the highest numbers shortly after a wound occurs,

release a number of things into the blood, including ECM proteins and cytokines,

including growth factors. Growth factors stimulate cells to speed their rate of division.

Platelets also release other proinflammatory factors like serotonin,

bradykinin,prostaglandins, prostacyclins, thromboxane, and histamine, which serve a

number of purposes, including to increase cell proliferation and migration to the area and tocauseblood vessels to become dilated and porous.

INFLAMMATORY PHASE

In the inflammatory phase,bacteria and debris are phagocytosed and removed, and

factors are released that cause the migration and division of cells involved in the
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proliferative phase. The cellular phase follows the early phase, and involves several types

of cells working together to mount an inflammatory response.

Vasoconstriction and vasodilation

Immediately after a blood vessel is breached, ruptured cell membranes release

inflammatory factors like thromboxanes andprostaglandins that cause the vessel to spasm

to prevent blood loss and to collect inflammatory cells and factors in the area.

This vasoconstriction lasts five to ten minutes and is followed by vasodilation, a widening

of blood vessels, which peaks at about 20 minutes post-wounding. Vasodilation is the

result of factors released by platelets and other cells. The main factor involved in causing

vasodilation is histamine. Histamine also causes blood vessels to become porous, allowing

the tissue to become edematous because proteins from the bloodstream leak into the

extravascular space, which increases its osmolar load and draws water into the

area. Increased porosity of blood vessels also facilitates the entry of inflammatory cells

like leukocytes into the wound site from thebloodstream.

Polymorphonuclear neutrophils

Within an hour of wounding,polymorphonuclear neutrophils (PMNs) arrive at the wound

site and become the predominant cells in the wound for the first two days after the injury

occurs, with especially high numbers on the second day. They are attracted to the site by

fibronectin, growth factors, and substances such as kinins. Neutrophils phagocytise debris

and bacteria and also kill bacteria by releasing free radicals in what is called a 'respiratory

burst'. They also cleanse the wound by secretingproteases that break down damaged tissue.Neutrophils usually undergo apoptosis once they have completed their tasks and are

engulfed and degraded by macrophages.

Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause

more T cells to divide and to increase inflammation and enhance vasodilation and vessel

permeability.[10][16] T cells also increase the activity of macrophages.[10]

Macrophages

Macrophages are essential to wound healing. They replace PMNs as the predominant cells

in the wound by two days after injury. Attracted to the wound site by growth factors

released by platelets and other cells, monocytes from the bloodstream enter the area

through blood vessel walls. Numbers of monocytes in the wound peak one to one and a

half days after the injury occurs. Once they are in the wound site, monocytes mature into

macrophages. The spleen contains half the body's monocytes in reserve ready to be

deployed to injured tissue.
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The macrophage's main role is to phagocytize bacteria and damaged tissue and they also

debride damaged tissue by releasing proteases. Macrophages also secrete a number of

factors such as growth factors and other cytokines, especially during the third and fourth

post-wounding days. These factors attract cells involved in the proliferation stage of

healing to the area, although they may restrain the contraction phase. Macrophages are

stimulated by the low oxygen content of their surroundings to produce factors that induce

and speed angiogenesis. and they also stimulate cells that reepithelialize the wound, create

granulation tissue, and lay down a new extracellular matrix. By secreting these factors,

macrophages contribute to pushing the wound healing process into the next phase.

Decline of inflammatory phase

As inflammation dies down, fewer inflammatory factors are secreted, existing ones

are broken down, and numbers of neutrophils and macrophages are reduced at the wound

site. These changes indicate that the inflammatory phase is ending and the proliferative

phase is underway. The presence of macrophages actually delays wound contraction and

thus the disappearance of macrophages from the wound may be essential for subsequent

phases to occur. Inflammation can lead to tissue damage if it lasts too long.[4] Thus the

reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as

long as there is debris in the wound. Thus the presence of dirt or other objects can extend

the inflammatory phase for too long, leading to a chronic wound.

PROLIFERATIVE PHASE

About two or three days after the wound occurs, fibroblasts begin to enter the

wound site, marking the onset of the proliferative phase even before the inflammatory

phase has ended. As in the other phases of wound healing, steps in the proliferative phase

do not occur in a series but rather partially overlap in time. The proliferative phase is also

called the reconstruction phase.

The proliferative phase is characterized by angiogenesis, collagen deposition,

granulation tissue formation, epithelialization, and wound contraction. In angiogenesis,

new blood vessels are formed by vascular endothelial cells. In fibroplasia and granulation

tissue formation, fibroblasts grow and form a new, provisional extra-cellular matrix (ECM)

by secreting collagen and fibronectin. Concurrently, re-epithelialization of the epidermis

occurs, in which epithelial cellsproliferate and 'crawl' atop the wound bed, providing cover

for the new tissue. In contraction, the wound is made smaller by the action

ofmyofibroblasts, which establish a grip on the wound edges and contract themselves
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using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to

complete, unneeded cells undergo apoptosis.

In the maturation and remodeling phase, collagen is remodeled and realigned along

tension lines and cells that are no longer needed are removed by apoptosis. However, this

process is not only complex but fragile, and susceptible to interruption or failure leading to

the formation of chronic non-healing wounds. Factors which may contribute to this include

diabetes, venous or arterial disease, old age, and infection.

Angiogenesis

Also called neovascularization, the process of angiogenesis occurs concurrently

with fibroblast proliferation when endothelial cells migrate to the area of the

wound Because the activity of fibroblasts and epithelial cells requires oxygen and nutrients,

angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast

migration. The tissue in which angiogenesis has occurred typically looks red

(is erythematous) due to the presence ofcapillaries.[27]

Stem cells ofendothelial cells, originating from parts of uninjured blood vessels,

developpseudopodia and push through the ECM into the wound site to establish new blood

vessels. Endothelial cells are attracted to the wound area by fibronectin found on the fibrin

scab and chemotactically by angiogenic factors released by other cells, e.g. from

macrophages and platelets when in a low-oxygen environment. Endothelial growth and

proliferation is also directly stimulated by hypoxia, and presence oflactic acid in the

wound.

To migrate, endothelial cells need collagenases andplasminogen activatorto

degrade the clot and part of the ECM. Zinc-dependent metalloproteinases digest basement

membrane and ECM to allow cell migration, proliferation and angiogenesis. When

macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic

acid-filled environment, they stop producing angiogenic factors. Thus, when tissue is

adequatelyperfused, migration and proliferation of endothelial cells is reduced. Eventually

blood vessels that are no longer needed die by apoptosis.

Fibroplasia and granulation tissue formation

Simultaneously with angiogenesis, fibroblasts begin accumulating in the wound

site. Fibroblasts begin entering the wound site two to five days after wounding as the

inflammatory phase is ending, and their numbers peak at one to two weeks post-

wounding. By the end of the first week, fibroblasts are the main cells in the

wound Fibroplasia ends two to four weeks after wounding.
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In the first two or three days after injury, fibroblasts mainly migrate and proliferate,

while later, they are the main cells that lay down the collagen matrix in the wound

site. Origins of these fibroblasts are thought to be from the adjacent uninjured cutaneous

tissue. Initially fibroblasts utilize the fibrin cross-linking fibers (well-formed by the end of

the inflammatory phase) to migrate across the wound, subsequently adhering to fibronectin.[Fibroblasts then deposit ground substance into the wound bed, and later collagen, which

they can adhere to for migration.

Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells,

endothelial cells, myofibroblasts, and the components of a new, provisional extracellular

matrix (ECM). Granulation tissue functions as rudimentary tissue, and begins to appear in

the wound already during the inflammatory phase, two to five days post wounding and

continues growing until the wound bed is covered.

Growth factors (PDGF, TGF-) and fibronectin encourage proliferation, migration to the

wound bed and production of ECM molecules by fibroblasts. Fibroblasts also secrete

growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to

fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit

their growth and deposition of ECM components, and can lead to excessive,

fibrotic scarring.

Collagen deposition

One of fibroblasts' most important duties is the production ofcollagen. Fibroblasts

begin secreting appreciable collagen by the second or third post-wounding day, and its

deposition peaks at one to three weeks. Collagen production continues rapidly for two to

four weeks, after which its destruction matches its production and so its growth levels off.

Collagen deposition is important because it increases the strength of the wound;

before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot,

which does not provide much resistance to traumatic injury. The cells involved in

inflammation, angiogenesis, and connective tissue construction attach to, grow and

differentiate on the collagen matrix laid down by fibroblasts. Even as fibroblasts are

producing new collagen, collagenases and other factors degrade it. Shortly after wounding,

synthesis exceeds degradation, so collagen levels in the wound rise. Later production and

degradation become equal so there is no net collagen gain. This homeostasis signals the

onset of the maturation phase. Granulation gradually ceases and fibroblasts decrease in

number in the wound once their work is done. At the end of the granulation phase,
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fibroblasts begin to commit apoptosis, converting granulation tissue from an environment

rich in cells to one that consists mainly of collagen.

Epithelialization

The formation of granulation tissue in an open wound allows the re-

epithelialization phase to take place, as epithelial cells migrate across the new tissue to

form a barrier between the wound and the environment. Basalkeratinocytes from the

wound edges are the main cells responsible for the epithelialization phase of wound

healing. They advance in a sheet across the wound site and proliferate at its edges, ceasing

movement when they meet in the middle.

If the basement membrane is not breached, epithelial cells are replaced within three

days by division and upward migration of cells in the stratum basale in the same fashion

that occurs in uninjured skin. If the wound is very deep, skin appendages may also be

ruined and migration can only occur from wound edges. Migration of keratinocytes over

the wound site is stimulated by lack ofcontact inhibition and by chemicals such as nitric

oxide.

As keratinocytes migrate, they move over granulation tissue but underneath

the scab (if one was formed), separating it from the underlying tissue. Until the entire

wound area is resurfaced, the only epithelial cells to proliferate are those at the at the

wound edges.

Contraction

Contraction is a key phase of wound healing. If contraction continues for too long,

it can lead to disfigurement and loss of function.Contraction commences approximately a

week after wounding, when fibroblasts have differentiated into myofibroblasts. In full

thickness wounds, contraction peaks at 5 to 15 days post wounding. Contraction can last

for several weeks and continues even after the wound is completely reepithelialized.

Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction.

Myofibroblasts contain the same kind of actin as that found in smooth muscle cells. As the

actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay

down collagen to reinforce the wound as myofibroblasts contract

Maturation and Remodeling
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The maturation phase can last for a year or longer, depending on the size of the wound and

whether it was initially closed or left open.During maturation, type III collagen, which is

prevalent during proliferation, is gradually degraded and the strongertype I collagen is laid

down in its place. Originally disorganized collagen fibers are rearranged, cross-linked, and

aligned along tension lines. As the phase progresses, the tensile strength of the wound

increases, with the strength approaching 50% that ofnormal tissue by three months after

injury and ultimately becoming as much as 80% as strong as normal tissue.

Healing by first intension and healing by secondary intension
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The least complicated example of wound repair is the healing of a clean, uninfected

surgical incision approximated by surgical sutures. Such healing is referred to as primary

union or healing by first intension. Here, there is only death of a limited number of

epithelial cells and connective tissue cells as well as disruption of the epithelial basement

membrane continuity. The narrow incisional space immediately fills with clotted blood

containing fibrin and blood cells; dehydration of the surface clot forms the well-known

scab that covers the wound.

Within 24 hours, neutrophils appear at the margins of the incision, moving toward

the fibrin clot. The epidermis at its cut edges thickens as a result of mitotic activity of basal

cells, and within 24 to 48 hours spurs of epithelial cells from the edges both migrate and

grow along the cut margins of the dermis, depositing basement membrane of the dermis,

depositing basement membrane components as they move. They fuse in the mid-

components are they move. They fuse in the midline beneath the surface scab, thusproducing a continuous but thin epithelial layer.

By day 3, the neutrophils have been largely replaced by macrophages. Granulation

tissue progressively invades the incision space. Collagen fibers are now present in the

margins of the incision, but at first these are vertically oriented and do not bridge the

incision. Epithelial cell proliferation continues, thickening the epidermal covering layer.

By day 5, the incisional space is filled with granulation tissue. Neovascularization

is maximal. Collagen fibrils become more abundant and begin to bridge the incision. The

epidermis recovers its normal thickness, and differentiation of surface cells yields a mature

epidermal architecture with surface keratinisation.

During the second week, there is continued accumulation of collagen and

proliferation of fibroblasts. The leukocytic infiltrate, edema, and increased vascularity have

largely disappeared. At this time, the long process of blanching begins, accomplished by

the increased accumulation of collagen within the incisional scar, accompanied by

regression of vascular channels.

By the end of the first month, the scar comprise a cellular connective tissue devoid

of inflammatory infiltrate, covered now by intact epidermis. The dermal appendages that

have been destroyed in the like of the incision are permanently lost. Tensile strength of the

wound increases thereafter, but it may take months for the wounded are to obtain its

maximal strength.

When there is more extensive loss of cells and tissue, as occurs in infarction,

inflammatory ulceration, abscess formation, and surface wounds that create large defects,


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the reparative process is more complicated. The common denominator in all these

situations is a large tissue defect that must be filled. Regeneration of parenchymal cells

cannot completely reconstitute the original architecture. Abundant granulation tissue grows

in from the margin to complete the repair. This form of healing is referred to as secondary

union or healing by second intention.

Secondary healing differs from primary healing in several respects.

1. Inevitably, large tissue defects initially have more fibrin and more necrotic debris

and exudate that must be removed. Consequently, the inflammatory reaction is more

intense.

2. Much larger amounts of granulation tissue are formed. When a large defect

occurs in deeper tissues, such as in a viscous, granulation tissue with its numerous

scavenger white cells bears the full responsibility for its closure, because draining to thesurface cannot occur.

3. Perhaps the feature that most clearly differentiates primary from secondary

healing is the phenomenon of would contraction, which occurs in large surface wounds.

Large defects in the skin of a rabbit are reduced in approximately 6 weeks to 5 to 10 % of

their original size, largely by contraction. Contraction has been ascribed, at least in part, to

the presence of myofibroblastsaltered fibroblasts that have the ultrastructural

characteristics of smooth muscle cells.

The Role of Growth Factors: Growth factors are polypeptides, and are involved in repair.

Some of them are competence factors, that is, they do not stimulate DNA synthesis but


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render cells in Go or G2 competent to do so. Others are progression factors, which stimulate

DNA synthesis in competent cells. Certain growth factors also initiate cell migration,

differentiation, and tissue remodeling. Those involved in various stages of wound healing

and repair are as follows:

(1) Epidermal Growth Factor (EGF): It is a polypeptide, purified from submaxillary

glands of mice, or from human urine. EGF is mitogenic (i.e. causes proliferation) for a

variety of epithelial cells and fibroblasts in vitro It is a progression factor, and stimulates

cell division by binding to specific tyrosine kinase receptors on the cell membrane,

followed by the changes described later under molecular events in cell growth.

(ii) Platelet-derived Growth Factor (PDGF): This is highly cationic protein,

composed of two chains A and B. PDGF is stored in the platelet alpha granules, and

released upon platelet activation. It is also produced by activated macrophages, endothelial

and smooth muscle cells, and a variety of tumour cells. PDGF causes both migration and

proliferation of fibroblasts, smooth muscle cells, and monocytes.

(iii) Fibroblast Growth Factors (FGFs): Fibroblast growth factors represent a family

of polypeptide growth factors that have, in particular, the ability to induce all the steps

necessary for new blood vessel formation (angiogenesis), both in vivo and in vitro. FGFs

are elaborated by activated macrophges.

(iv) Transforming Growth Factors Alpha and Beta (TGF-alpha and beta): These

factors were initially extracted from sarcoma virus-transformed cells, and were thought to

be involved in transformation of normal cells to cancer. TGF-alpha has a similarity to EGF,

binds to EGF receptors, and produces most of the biological activities of EGF.

TGF-beta, on the other hand, is a growth inhibitor to most epithelial cell types in

culture, and inhibits cell growth after partial hepatctomy. However, it stimulates fibroblast

chemotaxis and the production of collagen and fibronectin, favouring fibrogenesis. TGF-

beta is produced by various cells, including macrophages, platelets, endothelium and T-

lymphocytes.

(v) Cytokines: Many cytokines are growth factors, examples being interleukin-I(IL-I) and tumour necrosis factor (TNF). IL-I and TNF are mitogenic and chemotactic for

fibroblasts, and they stimulate the synthesis of both collagen and collagenases by

fibroblasts. They are knowns as the fibrogenic cytokines. TNF also induces new blood

vessel formation (angiogenesis) in vivo.

To summarise


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(a) In addition to growth stimulators, a number of growth inhibitors are produced in

inflammation. Besides TGF-beta, others include: alpha-interferon, prostaglandin E2, and

heparin. All three inhibit fibroblast and smooth muscle proliferation in vitro.

(b) Growth factors also have effects on cell locomotion, contractility, and

differentiation. These effects are as important in repair and wound healing, as the growth-

promoting effects.

(c) Macrophages, which are abundant in health wounds, play a central role in these

processes because they can be induced to secrete growth factors (PDGF, FGF), fibrogenic

cytokinds (IL-I, TNF), growth inhibitors (TGF-beta, prostaglandins), and enzymes

involved in tissue degradation and organisation.

(d) Growth Factors Induce their Effects in Three Ways: (i) They act on the same

cell that produces them- autocrine effect. Examples: Interleukin-2 produced by activated T-lymphocyte promotes T-cell growth, (ii) they affect other cells in their vicinity paracrine

effect. Examples: when interleukin-1 produced by antigen-presenting cells affects T-cells

during the induction of an immune response, and (iii) they affect many cells systematically

endocrine effect. Examples: IL-1 and TNF produce the acute-phase response during

inflammation.

Paracrine stimulation is most common in connective tissue repair of healing

wounds. In this a factor produced by one cell type has its growth effect on adjacent cells,

usually of a different cell type; for example, macrophage-derived growth factor acting on

fibroblasts.

(e) The genes that encode for some of these growth factors (PDGF, EGF), or their

receptors, show extensive sequence homology (similarity) with oncogenes, suggesting

involvement of these growth factors in cancer formation.

Interactions between Extracellular Matrix (ECM) and the Cells

ECM forms a significant proportion of the volume of any tissue. Structurally, ECM

occurs in two forms: (1) fibrous structural proteins (collagen, elastin), and (2) adhesive


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glycoproteins (laminin, fibronectin), they glue various components. Both, fibrous proteins

and adhesive glycoproteins, are embedded in a gel (more solid form of sol, like jelly)

composed of (3) proteoglycans.

Proteoglycans have diverse role in regulating connective tissue structure and

permeability. The main function of ECM is to maintain the normal shape and volume of the

connective tissue, and also to provide rigidity to skeletal tissues. In addition, it provides a

substratum an underlying support, foundation) to which cells can adhere, migrate, and

proliferate, and directly influences the form and function of cells.

The three biochemical components of ECM, namely (1) structural proteins, (2)

adhesive glycoproteins, and (3) proteoglycans will now be discussed.

(1) Structural proteins

a. Collagen : Collagen is the most common protein in the body and provides theextracellular framework. It is the major component of fibrous tissue, basement membrane,

bone and cartilage. It is a product of the fibroblast and provides tensile strength to the

healing wounds. The basic unit of collagen is the tropocollagen. Each collagen molecule is

made up of three separate polypeptide alpha chains wrapped tightly together into a triple

helix. Biochemically, 15 distinct types of collagen are recognized. The synthesis of

collagen is initiated by DNA transcription from specific genes coding for the polypeptide

chains. Among the series of biochemical changes, the most important one is the

hydroxylation of the aminoacid-proline. This hydroxylation is dependent on the availability

of vitamin C and is important because it is necessary to hold the three alpha chains inside

the rough endoplasmic reticulum. Another important biochemical modification is lysine

oxidation. This results in cross linkages between the alpha chains of the neighbouring

molecule and is the basis of the structural stability of collagen.

(b) Elastin : Fibroblasts also synthesis elastic fibres. Elastic fibers consist of two

proteins, the amorphous elastin and elastic microfibril.

(2) Adhesive Glycoproteins

These structurally diverse proteins bind with the other ECM components and on the

other hand bind with specific cell membrane proteins and thereby linking ECM

components to one another and to cells. They include fibronectin, laminin,

thrombospondin.

(3) Proteoglycans


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Proteoglycans consist of glycosaminoglycans (like hyaluronic acid, heparin and

chondroitin) linked covalently to a protein core. Proteoglycans retain fluid in the tissues

and maintain the normal shape and volume of the connective tissue. Thus, they regulate

connective tissue structure and permeability and modulate cell growth and differentiation.

FACTORS AFFECTING WOUND HEALING

Many general (systemic) and local factors influence quality of the inflammatory-

reparative response. These are:


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General Factors (Systemic Influences)

(1) Nutrition plays a very important role in healing, especially proteins. Low

protein levels in the diet have an adverse effect on healing. Of special importance are the

two sulphur-containing aminoacids, methionine and cystine. In the absence of these

aminoacids, connective tissue of weak tensile strength is formed. Methionine also increases

the rate of utilization of the protein, and its sulphur radicle may also be used for the

formation of chondroitin sulphate which imparts firmness to the ground substance. In

protein deficiency, few fibroblasts form and synthesis of collagen is inhibited, and healing

retarded.

(ii) Vitamin C (Ascorbic Acid): Its deficiency is an important cause of poor and

delayed wound healing. As mentioned earlier, vitamin C enhances the conversion of

praline tohydrioxyproline, and of lysine to hydroxylysine. Thus, deficiency of vitamin C

results in impaired synthesis of normal collagen. Absence of hydroxyproline will result in

failure to achieve fibril formation (fibrillogenesis). Consequently, fibroblasts produce little

collagen, and what is produced is of poor quality.

(iii) Zinc: Many enzymes, such as the metalloenzymes and DNA and RNA

polymerases, are zinc dependent. Wound healing is delayed in patients with zinc

deficiency, and is restored to normal by zinc administration.

(iv) Age: It is generally believed that with advancing age, the rate of healing may

be considerably impaired, an important factor being the inadequate blood supply in the old

age due to generalized vascular disease (arteriosclerosis). However, recent observations

suggest that age is probably not a major influence of healing, since there are little

controlled data in the experimental animal to support this notion.

(v) Glucocorticosteroids : Glucocorticosteroids have well-documented anti-

inflammatory effects, and influence various component of inflammation and fibroplasia.

Steroids block or retard the process of repair. It probably does so by inducing chemical

changes in the mucopolysaccharides of the ground substance of connective tissue. Besides,

during its presence less collagen and fewer blood vessels are fomed.

Local Factor (Local Influences)


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(1) Local Irritant: These, such as bacterial infection, presence of necrotic debris,

pus or foeign bodies in a wound markedly interfere with healing. Of these, infection is the

most important local cause of delayed healing.

(ii) Inadequate Blood Supply (Ischaemia): Ischaemia is a local anaemia, a cutting

off of the arterial blood supply to a part. Under such conditions normal healing cannot

occur. Arterial disease that limits blod flow (usually arteriosclerosis), and venous

abnormalities that retard drainage, also impair healing.

(iii) Foreign Bodies such as unnecessary sutures, or fragments of wood, steel, glass,

and even bone interfere with healing.

(iv) Mechanical factors such as increased abdominal pressure may cause rupture of

abdominal wound, this is called wound dehiscence.

Healing of Some Special Tissues

Epithelium can, in general, regenerate with considerable ease. Like fibrous tissue,

the epithelium of the skin, alimentary, respiratory and urogenital tracts, has retained its

regenerative properties. When the epithelium is lost, repair occurs by proliferation of

epithelium from the margin of the wounds. Secretory epithelium of glands, gastric glands,

seminiferous tubules, etc. In the liver, epithelial cells regenerate to a limited extent. In the

kidney, no new nephrons can be formed. The cells can undergo only hypertrophy.

Mesothelium of the serous surface is quickly regenerated.

Connective Tissue: Fibroblasts proliferate rapidly, replacing its own kind and other

which are not able to regenerate. When the formed connective tissue is young it is more

cellular and rich in young capillaries. With age, it becomes denser and less vascular.

Cartilage and Bone: Due to a vascularity, repair in cartilage is very slow and

imperfect. It is usually replaced by fibrous tissue. Repair is very good and complete in the

bone, osteoblasts playing the key role.

Tendon and ligaments regenerate slowly but completely.

Elastic Tissue is also replaced rather slowly but completely.

Blood Vessels are easily replaced by newly formed capillaries. However, the

muscular coat (characteristic of arteries and veins) is seldom added.

Muscle : Lost muscles are reunited by fibrous tissue. Skeletal and cardiac muscle

never regenerate. A certain amount of regeneration sometimes occurs in smooth muscle.


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Nerve Cell: Cannot be replaced; once destroyed it is lost for ever.

Neuroglia proliferate readily. Nerves: if the nerve cell is intact, repair of the

peripheral nerves can occur. When a peripheral nerve is cut, the distal portion first dies but

is slowly regenerated by new growth from the proximal end; and, although rarely, union

can occur between proximal and the original distal dies and is not replaced. The peripheral

nerve then undergoes a series of retrogressive changes known as `Wallerian degeneration.

--------------------------------------------------------------------------------------

REGENERATION

Healing is the process whereby the body restores the injured part to as near its

previous normal condition as possible. The lower an animal in evolution, the greater are the


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powers of repair. For example, when an earthworm is severed, a new part grows in its

place. Similarly, the tail of a salamander (a lizard-like amphibian), or the limb of an

amphibian will grow when amputated. Tissue or organ involved also influences the process

of healing. If the tissue or organ is very highly specialized, it has less ability to regenerate.

For example, in brain and spinal cord the lost nerve cells cannot be replaced. Similarly, the

age of an animal also influences healing. The younger the animal the more rapid and

complete is healing. Before healing can take place, the products of inflammation such as

exudate and dead cells have to be removed from the area. This is accompanied by

liquefaction of the dead tissue. This, in turn, is attained by the autolytic enzymes of the

dead tissue itself (autolysis), and also by the enzymes derived from inflammatory

leukocytes (heterolysis). The liquefied material (fluid) is then readily absorbed into lymph

and blood, and paves the way for healing.

Repair involves two distinct processes: (1) repair by regeneration. In this, the lostcells and tissues are replaced by other cells of the same type; and (2) replacement by

connective tissue (fibroplasia), which in its permanent state constitutes a scar. In most

instances, both processes contribute to repair.

The cells of the body are divided into three groups on the basis of their regenerative

capacity and their relationship to the cell growth cycle: labile, stable and permanent cells.

(1) Labile Cells (or Continuously Dividing Cells): Labile cells continue to

proliferate throughout the life, to replace cells that are constantly being destroyed. They

include: surface epithelia such as stratified squamous epithelium of the skin, oral cavity,

vagina and cervix; the lining mucosa of the excretory ducts of glands (e.g., salivary glands,

pancreas, biliary tract); the columnar epithelium of the gastro-intestinal tract, uterus, and

Fallopian tubes; the transitional epithelium of the urinary tract, and cells of the splenic,

lymphoid, and haematopoietic tissues.

(2) Stable (or Quiescent) Cells: Stable cells normally demonstrate a low level of

proliferation (replication). However, these cells can undergo rapid division in response to a

variety of stimuli. Thus, they can reconstitute the tissue of origin. Examples: parenchymal

cells of glands, such as liver, kidney and pancreas; mesenchymal cels such as fibroblasts,

smooth muscle cells, osteoblasts, and chondroblasts; and vascular endothelial cells. Liver

regenerates after hepatectomy, and following toxic, viral or chemical injury.

For labile and stable cells to reconstitute normal structure, it is essential that the

underlying framework, or supporting stroma of the organ or tissue, must be present to

permit orderly replacement. The basement membrane (BM) is the main structural


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component necessary for organized regeneration. It functions as scaffold for accurate

regeneration of parenchymal cells, and pre-existing structures. When BM is disrupted, cells

proliferate in a haphazard manner, and produce disorganized masses with no resemblance

to the original arrangement, or scarring (fibrosis) may occur. For example, in liver,

hepatitis virus destroys only parenchymal cells without injuring connective tissue cells, or

framework of the liver lobule. Thus, after viral hepatitis, regeneration of liver cells

completely reconstitutes liver lobule. On the other hand, a large liver abscess destroys

hepatocytes and connective tissue framework. This is followed by scarring only.

(3) Permanent (or Non-dividing Cells): These are those cells which have left the

cell cycle, and cannot undergo mitotic division in postnatal life. To this group belong the

nerve cells, and the skeletal and cardiac muscle cells. Their regenerative attempts are of no

practical importance. Thus, neurons destroyed in the central nervous system (CNS) are

permanently lost. They are replaced by the proliferation of the glial cells.

To conclude, except for tissues composed solely of non-dividing cells, most tissues

of adults consist of a mixture of all the three cell types, i.e., continuously dividing cells,

quiescent cells, and non-dividing cells.

Cell cycle

The cell cycle can be divided into four phases: G1 (presynthetic), S (DNA

synthesis), G2 and M (mitotic). G1 is the time of gap between the end of mitosis and the

start of DNA synthesis; S is the period of DNA synthesis and the beginning of mitosis. In a

cell with a cycle of 16 hours G1 = 5 hours, S = 7 hours, G2 = 3 hours, and mitosis = 1 hour.

Thus, mitosis represents only a small part of the life cycle of a cell (about 1 hour in most

cells). The cell spends most of its lifetime in interphase (i.e. S + G1 + G2 phases combined

together), the period during which it replicates its DNA and doubles in size. The most

variable period is G1. Depending on the type of cell, it may last days, months, or years.

Cells that stop proliferating become arrested at a specific point of G1 and remain withdrawn

from the cell cycle in the G0 state.

Continuously dividing (labile) cells follow the cell cycle from one mitosis to the

next. Quiescent (stable) cells are in the G0 state. They are neither cycling nor dying; and

can be induced to enter the cycle at G1by appropriate stimulus. Non-dividing (permanent)

cells have left the cycle for ever and are destined to die without dividing again.

Molecular Events in Cell Growth


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(i) Ligand-receptor binding: Cell growth is initiated when a growth factor (ligand)

binds to specific receptors present on the cell surface. These receptors are transmembrane

glycoproteins, and their intracellular domains interact with elements of the cytoskeleton to

signal cell locomotion or differentiation.

(ii) Growth Factor Receptor Activation: Most receptors of growth factors (EGF,

PDGF), present on the cell surface, contain the enzyme tyrosinase kinase. This enzyme is

activated after ligand binding. The enzyme tyrosinase kinase, in turn, leads to activation of

a protein phosphorylation cascade, which stimulates stable (quiescent) cells to enter the

growth cycle.

(iii) Signal Transduction and Second Messenger: Tyrosine kinase are essential for

signal transduction (transfer of messages). First, the enzyme phospholipase C is activated,

and it then catalyzes the degradation of phosphatidyl inositol biphosphate (PIP2). This

results in the generation of two second messengers: (i) inositol triphosphate (IP 3), which

release intracellular calcium, and III) diacylglycerol (DAG). DAG, in turn, activates the

enzyme protein kinase C (PKC), present in the plasma membrane. The second enzymes

that is phosphorylated by tyrosine kinase is the guanosine triphosphatase (GTPase)

activating protein (GAP). IP3, DAG and GAP act as second messengers within the cell and

are implicated in the regulation of cell proliferation.

(iv)Transcription Factors: Second messengers lead to the activation of transcription

factors. Cellular phosphatases (i.e. transcription factors) have emerged as regulators of cell

growth. Activation or inactivation of these phosphatases correlates respectively with

inhibition or stimulation of cell growth. When stable (quiescent) cells are exposed to

growth factors, a large number of cellular genes are induced. These have been divided into

early growth-regulated genes, and late growth-regulated genes.

(v) Cyclins: The signals that trigger the events that lead to DNA replication, and

nuclear and cell division are controlled, in part, by changes in the intracellular

concentration of a group of proteins called cyclins, which are induced during the cell cycle.

To summarise, growth factors first bind to their receptors and activate them. These

receptors possess kinase activity. Their activation phosphorylates several substrates that are

involved in the generation of second messengers. These in turn transmit the signals to the

nucleus where activation of transcription factors leads to the initiation of DNA synthesis,

and cell division. This process of cell cycle appears to be controlled partly by a family of

proteins, called cyclins.

Growth Inhibition


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The other aspect of cell growth control is growth inhibition. The idea of growth

inhibitory signals came from the observation that population of cells in culture, or in vivo,

can limit one anothers growth, e.g., contact inhibition of growth in cell cultures. There is

also in vivo evidence for growth suppression. In partial hepatectomy (partial removal of

liver), the liver cells stop multiplying when the liver attains its normal size and

configuration. This suggested the action of an inhibitory signal.

Growth inhibition, like growth stimulation, utilizes polypeptide factors and signal

transducers, including cell surface receptors, cytoplasmic second messengers, and

transcription regulators. One growth factor that acts as a growth inhibitor of many cell

types is transforming growth factor-beta (TGF-beta).

REPAIR BY REGENERATION

This type of repair is governed by the fact whether the cells possess the capacity toproliferate or not. If the cells have lost their capacity, they cannot repair themselves by

regeneration. The power of regeneration differs widely with different cells. Those tissues

where the cells have retained their powers to proliferate, healing occurs by regeneration,

but in tissues where the cells have lost this capacity, the place of such cells is filled by less

specialized connective tissue.

Wound Repair Versus Regeneration

There is a subtle distinction between repair and regeneration'. An injury is an

interruption of morphology and/or functionality of a given tissue. Repair refers to the

physiologic adaptation of an organ after injury in an effort to re-establish continuity

without regards to exact replacement of lost/damaged tissue. True tissue regeneration refers

to the replacement of lost/damaged tissue with an exact copy, such that both morphology

and functionality are completely restored. Mammals do not regenerate spontaneously. In

some instances, such as skin, partial regeneration may be induced by the use of scaffolds.[1]

Pathological aspects of inflammation and repair

The usual manifestation of inflammation and repair and the orderly healing of

wounds in normal presons are modified by a number of known influences and some

unknown ones, frequently impairing the quality and adequacy of both inflammation and

repair. Aberrations of growth may also occur even in what may begin initially as normal

wound healing. Accumulation of excessive amount of collagen may give rise to raised
http://en.wikipedia.org/wiki/Wound_healing#cite_note-Nguyen-0%23cite_note-Nguyen-0http://en.wikipedia.org/wiki/Wound_healing#cite_note-Nguyen-0%23cite_note-Nguyen-0


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tumorous scars known as a Keloid. Keloid formation appears to be an individual

predisposition and this aberration is most common in blacks.

Another important deviation in wound healing is the formation of excessive

amounts of granulation tissue, which protrudes above the level of surrounding skin and in

fact blocks re-epithelialization this has been called as exuberant granulation or proud

flesh.

Overview of inflammatory-reparative responses

Not all injuries results in permanent damage. Some are resolved with almost perfect

repair. Most often the injury and inflammatory response results in residual scarring.

Although it is functionally imperfect the scarring provides a permanent patch that permits

the residual parenchyma more or less to continue functioning. Sometimes the scar itself is


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so large or so situated that it may cause permanent dysfunction as in a healed myocardial

infarct.

Injury

Vascular and cellular responses

Acute inflammatoryexudation

Stimulus promptlydestroyed

No or minimal necrosis of cells Necrosis of cell

Exudationresolved

Exudationorganized

Stable orlabile cells

Frameworkintact

Frameworkdestroyed

Restitution ofnormal structureExampleMild head injury

ScarringExample

Fibrinopurulent,pericarditis, peritonitis

Regenaration&restitution ofnormal structure

ScarringExample

Bacterial abscess

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Cell Regeneration