Path 6: Tissue Repair

Question 1

Repair occurs by what two types of reactions?

Answer 1

regeneration of the injured tissue and scar formation by the deposition of connective tissue

Question 2

How does regeneration of injured tissue work?

Answer 2

Some tissues are able to replace the damaged cells and essentially return to a normal state; this process is called regeneration. Regeneration occurs by proliferation of residual (uninjured) cells that retain the capacity to divide, and by replacement from tissue stem cells.

Question 3

Regeneration is the typical response to injury where?

Answer 3

In the rapidly dividing epithelia of the skin and intestines, and some parenchymal organs, notably the liver.

Question 4

How does scar formation work?

Answer 4

If the injured tissues are incapable of regeneration, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that results in scar formation.

Question 5

What is the main benefit for scar tissue?

Answer 5

Although the fibrous scar cannot perform the function of lost parenchymal cells, it pro- vides enough structural stability that the injured tissue is usually able to function.

Question 6

What is fibrosis?

Answer 6

process of 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).

Question 7

What is ‘organization’?

Answer 7

When fibrosis develops in a tissue space occupied by an inflammatory exudate

Question 8

Several cell types proliferate during tissue repair, namely:

Answer 8

1) remnants of the injured tissue (which attempt to restore normal structure),
2) vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process), and
3) fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration).

The proliferation of these cell types is driven by proteins called growth factors

Question 9

The ability of tissues to repair themselves is critically influenced by their intrinsic proliferative capacity. On the basis of this criterion, the tissues of the body are divided into three groups:

Answer 9

1) Labile (continuously dividing) tissues
2) Stable tissues
3) Permanent tissues

Question 10

What are labile tissues?

Answer 10

Cells of these tissues are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells.

Labile cells include hematopoietic cells in the bone marrow and the majority of surface epithelia, such as 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. These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.

Question 11

What are stable tissues?

Answer 11

Cells of these tissues are quiescent and have only minimal replicative activity in their normal state. However, these cells are capable of proliferating in response to injury or loss of tissue mass. Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas.

They also include endothelial cells, fibroblasts, and smooth muscle cells; the proliferation of these cells is particularly important in wound healing.

With the exception of liver, stable tissues have a limited capacity to regenerate after injury.

Question 12

What are permanent tissues?

Answer 12

The cells of these tissues are considered to be terminally differentiated and nonproliferative in postnatal life. Most neurons and cardiac muscle cells belong to this category.

Thus, injury to brain or heart is irreversible and results in a scar, because neurons and cardiac myocytes cannot regenerate. Limited stem cell replication and differentiation occur in some areas of the adult brain, and there is some evidence that cardiac stem cells may proliferate after myocardial necrosis.

Never- theless, whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue regenera- tion after injury. Skeletal muscle is usually classified as a permanent tissue, but satellite cells attached to the endomysial sheath provide some regenerative capacity for this tissue. In permanent tissues, repair is typically dominated by scar formation.

Question 13

With the exception of tissues composed primarily of non-dividing permanent cells (e.g., cardiac muscle, nerve), most mature tissues contain variable proportions of three cell types: continuously dividing cells, quiescent cells that can return to the cell cycle, and cells that have lost replicative ability.

Answer 13

With the exception of tissues composed primarily of non- dividing permanent cells (e.g., cardiac muscle, nerve), most mature tissues contain variable proportions of three cell types: continuously dividing cells, quiescent cells that can return to the cell cycle, and cells that have lost replicative ability.

Question 14

Stem cells are characterized by what two important properties?

Answer 14

self- renewal capacity and asymmetric replication

Question 15

What is asymmetric replication? Self-renewal?

Answer 15

Asymmetric replication means that when a stem cell divides, one daughter cell enters a differentiation pathway and gives rise to mature cells, while the other remains an undifferentiated stem cell that retains its self-renewal capacity

Self-renewal enables stem cells to maintain a functional population of precursors for long periods of time.

Question 16

What are the two fundamental kinds of stem cells?

Answer 16

1) Embryonic stem cells (ES cells)

2) Adult stem cells

Question 17

What are ES cells?

Answer 17

are the most undifferentiated stem cells. They are present in the inner cell mass of the blastocyst and have extensive cell renewal capacity. Hence they can be maintained in culture for over a year without differentiating. Under appropriate culture conditions, ES cells can be induced to form specialized cells of all three germ cell layers, including neurons, cardiac muscle, liver cells, and pancreatic islet cells.

Question 18

What are Adult stem cells?

Answer 18

also called tissue stem cells, are less undifferentiated than ES cells and are found among dif- ferentiated cells within an organ or tissue. Although, like ES cells, they also have self-renewal capacity, this property is much more limited. In addition, their lineage potential (ability to give rise to specialized cells) is restricted to some or all of the differentiated cells of the tissue or organ in which they are found.

Question 19

What keeps ES stem cells quiescent and undifferentiated?

Answer 19

signals from other cells in stem cell niches

Question 20

Where are mesenchymal stem cells found and what can they form?

Answer 20

Found in bone marrow and can give rise to a variety of mesenchymal cells, such as chondroblasts, osteoblasts, and myoblasts

Question 21

Why would introduction of ES cells into a recipient body as part of regenerative therapy be bad?

Answer 21

ES cells are derived from blastocysts (typically produced from in vitro fertilization), their progeny carry histocompatibility molecules (human leukocyte antigen [HLA] in people) of the donors of the egg and sperm. Thus, they are likely to evoke immunologi- cally mediated rejection by the host, just as organs trans- planted from genetically disparate hosts do.

Question 22

Induced pluripotent stem cells (iPS cells)?

Answer 22

The expressed genes in ES cells and differentiated cells have been compared and a handful of genes that are critical for the “stem-cell-ness” of ES cells have been identified. Introduction of such genes into fully differentiated cells, such as fibroblasts or skin epithelial cells, leads, quite remarkably, to reprogramming of the somatic cell nucleus, such that the cells acquire many of the properties of ES cells.

Question 23

Most growth factors are proteins that stimulate the survival and proliferation of particular cells, and may also promote migration, differentiation, and other cellular responses.

Answer 23

Most growth factors are proteins that stimulate the survival and proliferation of particular cells, and may also promote migration, differentiation, and other cellular responses.

Question 24

How do most growth factors work?

Answer 24

Most growth factors function by binding to specific cell- surface receptors and triggering biochemical signals in cells. The major intracellular signaling pathways induced by growth factor receptors are similar to those of many other cellular receptors that recognize extracellular ligands. In general, these signals lead to the stimulation or repres- sion of gene expression. Signaling may occur directly in the same cell that produces the factor (autocrine signaling), between adjacent cells (paracrine signaling), or over greater distances (endocrine signaling).

Question 25

On the basis of their major signaling transduction pathways, plasma membrane receptors fall into three main types:

Answer 25

1) Receptors with intrinsic kinase activity
2) G protein–coupled receptors.
3) Receptors without intrinsic enzymatic activity

Question 26

Receptors with intrinsic kinase activity.

Answer 26

Binding of ligand to the extracellular portion of the receptor causes dimer- ization and subsequent phosphorylation of the receptor subunits. Once phosphorylated, the receptors can bind and activate other intracellular proteins (e.g., RAS, phos- phatidylinositol 3[PI3]-kinase, phospholipase Cγ [PLC- γ]) and stimulate downstream signals that lead to cell proliferation, or induction of various transcriptional programs.

Growth factors such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF) bind to receptors with intrinsic kinase activity, triggering a cascade of phos- phorylating events through MAP kinases, which culminate in transcription factor activation and DNA replication.

Think EGF, VEGF, FGF, and HGF

Question 27

G protein–coupled receptors.

Answer 27

These receptors contain seven-transmembrane α-helix segments and are also known as seven-transmembrane receptors. After ligand binding, the receptors associate with intracellular gua- nosine triphosphate (GTP)-binding proteins (G proteins) that contain guanosine diphosphate (GDP). Binding of the G proteins causes the exchange of GDP with GTP, resulting in activation of the proteins. Among the several signaling pathways activated through G protein– coupled receptors are those involving cyclic AMP (cAMP), and the generation of inositol 1,4,5-triphosphate (IP3), which releases calcium from the endoplasmic reticulum

Chemokines utilize such receptors.

Question 28

Receptors without intrinsic enzymatic activity.

Answer 28

These are usually monomeric transmembrane molecules with an extracellular ligand-binding domain; ligand interaction induces an intracellular conformational change that allows association with intracellular protein kinases called Janus kinases (JAKs). Phosphorylation of JAKs activates cytoplasmic transcription factors called STATs (signal transducers and activators of transcription), which shuttle into the nucleus and induce transcription of target genes.

Cytokines generally bind to receptors without kinase activity; such receptors interact with cytoplasmic transcription factors that move into the nucleus.

Question 29

ECM occurs in two basic forms: ___ and ___.

Answer 29

Interstitial matrix and basement membrane

Question 30

Describe interstitial matrix.

Answer 30

This form of ECM is present in the spaces between cells in connective tissue, and between epithelium and supportive vascular and smooth muscle structures. It is synthesized by mesenchymal cells (e.g., fibroblasts) and tends to form a three-dimensional, amorphous gel. Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, proteoglycans, hyaluronate, and other elements

Question 31

Describe basement membrane.

Answer 31

The seemingly 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 basement membrane lies beneath the epithelium and is synthesized by overlying epithelium and underlying mesenchymal cells; it tends to form a platelike “chicken wire” mesh.

Its major constituents are amorphous nonfibrillar type IV collagen and laminin, proteoglycan

Question 32

Name the three basic components of ECM.

Answer 32

(1) fibrous structural proteins such as collagens and elastins, which confer tensile strength and recoil;
(2) water-hydrated gels such as proteoglycans and hyaluronan, which permit resilience and lubrication; and
(3) adhesive glycoproteins that connect the matrix elements to one another and to cells

Question 33

Extensive regeneration or compensatory hyperplasia can occur only if the residual connective tissue framework is structurally intact, as after partial surgical resection. By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring

Answer 33

Extensive regeneration or compensatory hyperplasia can occur only if the residual connective tissue framework is structurally intact, as after partial surgical resection. By contrast, if the entire tissue is damaged by infection or inflammation, regeneration is incomplete and is accompanied by scarring

For example, extensive destruction of the liver with collapse of the reticulin framework, as occurs in a liver abscess, leads to scar formation even though the remaining liver cells have the capacity to regenerate.

Question 34

As discussed earlier, if tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as the connective tissue, or if nondividing cells are injured, repair cannot be accomplished by regeneration alone. Under these conditions, repair occurs by replacement of the nonregenerated cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some cells and scar formation.

Answer 34

As discussed earlier, if tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as the connective tissue, or if nondividing cells are injured, repair cannot be accomplished by regeneration alone. Under these conditions, repair occurs by replacement of the nonregenerated cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some cells and scar formation.

Question 35

Repair by connective tissue deposition consists of sequential processes that follow the inflammatory response:

Answer 35

• Formation of new blood vessels (angiogenesis)

• Migration and proliferation of fibroblasts and deposition of connective tissue, which, together with abundant vessels and interspersed leukocytes, has a pink, granular
appearance and hence is called granulation tissue

• Maturation and reorganization of the fibrous tissue (remodeling) to produce the stable fibrous scar

Repair begins within 24 hours of injury by the emigration of fibroblasts and the induction of fibroblast and endothe- lial cell proliferation. By 3 to 5 days, the specialized granu- lation tissue that is characteristic of healing is apparent.

Question 36

Angiogenesis is the process of new blood vessel development from existing vessels, primarily _____.

Answer 36

Venules. 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.

Question 37

Angiogenesis involves sprouting of new vessels from existing ones and consists of the following steps:

Answer 37

• Vasodilation occurring in response to NO and increased permeability induced by VEGF
• Separation of pericytes from the abluminal surface
• Migration of endothelial cells toward the area of tissue injury
• Proliferation of endothelial cells just behind the leading front 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

Question 38

Several growth factors contribute to angiogenesis; the most important are __ and ___. What’s another important player?

Answer 38

VEGF and basic fibroblast growth factor (FGF-2)

Angiopoietins Ang1 and Ang2 also play roles

Question 39

What does VEGF-A do?

Answer 39

is generally referred to as VEGF and is the major inducer of angiogenesis after injury and in tumors

Question 40

What do VEGF-B and PlGF do?

Answer 40

involved in vessel development in the embryo

Question 41

What do VEGF-C and -D do?

Answer 41

stimulate both lymphangiogenesis and angiogenesis

Question 42

Where are VEGFs expressed?

Answer 42

expressed in most adult tissues, with the highest expression in epithelial cells adjacent to fenestrated epithelium (e.g., podocytes in the kidney, pigment epithelium in the retina)

Question 43

How do VEGFS work? What are they made by?

Answer 43

They bind to a family of tyrosine kinase recep- tors (VEGFR-1, -2, and -3). The most important of these receptors for angiogenesis is VEGFR-2, which is expressed by VEGF target cells, especially endothelial cells.

These are made by mesenchymal cells. In general they cause proliferation of endothelial cells and increase vascular permeability

Question 44

Of the many inducers of VEGF, ___ is the most important. Others? (3)

Answer 44

hypoxia; others are platelet-derived growth factor (PDGF), TGF-α, and TGF-β.

Question 45

What do VEGFs promote?

Answer 45

1) stimulates both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis.
2) Promotes vasodilation by stimulating the production of NO, and contributes to the formation of the vascular lumen.

Question 46

What does basic fibroblast growth factor (FGF-2) do in terms of angiogenesis?

Answer 46

participates in angiogenesis mostly by:

1) stimulating the proliferation of endothelial cells.
2) It also promotes the migration of macrophages and fibroblasts to the damaged area, and
3) stimulates epithelial cell migration to cover epidermal wounds.

Question 47

How are Angiopoietins Ang1 and Ang2 involved in angiogenesis?

Answer 47

These help stabilize newly formed vessels by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue.

Question 48

The growth of blood vessels during embryonic development is called ____.

Answer 48

vasculogenesis

Question 49

How is the ECM rearranged o accommodate angiogenesis?

Answer 49

Enzymes in the ECM, notably the matrix metalloproteinases (MMPs), degrade the ECM to permit remodeling and extension of the vascular tube.

Question 50

Why are newly formed vessels considerably more leaky than mature vessels?

Answer 50

Because of incomplete interendothelial junctions and because VEGF increases vascular permeability.

Question 51

The laying down of connective tissue (second step in scar formation after angiogenesis) in the scar occurs in two steps:

Answer 51

(1) migration and proliferation of fibroblasts into the site of injury and
(2) deposition of ECM proteins produced by these cells.

Question 52

How are fibroblasts recruited and activated to synthesize connective tissue proteins and the ECM in scar tissue?

Answer 52

growth factors PDGF, FGF-2 (described in card 46), TGF-β.

Cytokines are also involved

The major source of these factors is inflammatory cells, particularly macrophages, which are present at sites of injury and in granulation tissue.

Question 53

As healing progresses, the number of proliferating fibroblasts and new vessels decreases. So how does scar formation continue?

Answer 53

The fibroblasts progressively assume a more synthetic phenotype, so there is increased deposition of ECM. Collagen synthesis, in particular, is critical to the development of strength in a healing wound site.

Ultimately, the granulation tissue 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, there is progressive vascular regression, which eventually transforms the highly vascularized granulation tissue into a pale, largely avascular scar.

Question 54

What role does Transforming growth factor-β (TGF-β) play in ECM deposition and scar formation?

What is this made by?

Answer 54

1) TGF-β stimulates the production of collagen, fibronectin, and proteoglycans, and it inhibits collagen degradation by both decreasing proteinase activity and increasing the activity of tissue inhibitors of proteinases known as TIMPs. TGF-β is involved not only in scar formation after injury but also in the development of fibrosis in lung, liver, and
kidneys that follows chronic inflammation.

2) TGF-β is an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses. It does so by inhibiting lymphocyte proliferation and the activity of other leukocytes.

Made by fibroblasts

Question 55

What role does Platelet-derived growth factor (PDGF) play in ECM deposition and scar formation?

Answer 55

PDGF is stored in platelets and released on platelet activation (and is also produced by endothelial cells, activated macrophages, smooth muscle cells, and many tumor cells.)

PDGF causes migration and proliferation of fibroblasts and smooth muscle cells and may contribute to the migration of macrophages.

Question 56

What other cytokines are involved in ECM deposition and scar formation?

Answer 56

IL-1 and IL-13, for example, act on fibroblasts to stimulate collagen synthesis, and can also enhance the proliferation and migration of fibroblasts.

Epidermal growth factor helps stimulate formation of granulation tissue

Question 57

After its synthesis and deposition, the connective tissue in the scar continues to be modified and remodeled. Thus, the outcome of the repair process is a balance between synthesis and degradation of ECM proteins. The degradation of collagens and other ECM components is accomplished by the family of ____.

Answer 57

matrix metalloproteinases (MMPs),

MMPs include interstitial collagenases, which cleave fibrillar collagen (MMP-1, -2, and -3); gelatinases (MMP-2 and -9), which degrade amorphous collagen and fibronectin; and stromelysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibronectin, and amorphous collagen.

Question 58

What do MMPs require for their function?

Answer 58

dependent on zinc ions for their activity

Question 59

T or F. The activity of the MMPs is tightly controlled.

Answer 59

T. MMPs are produced by a variety of cell types (fibro- blasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regu- lated by growth factors, cytokines, and other agents. The activity of the MMPs is tightly controlled. They are produced as inactive precursors (zymogens) that must be first activated

Question 60

What activates MMPs?

Answer 60

proteases (e.g., plasmin) likely to be present only at sites of injury.

Question 61

What inhibits the activity of MMPs?

Answer 61

(TIMPs), produced by most mesenchymal cells.

Thus, during scarring, MMPs are activated to remodel the deposited ECM, and then their activity is shut down by the TIMPs.

Question 62

Tissue repair may be altered by a variety of influences, frequently reducing the quality or adequacy of the reparative process, namely:

Answer 62

• Infection is clinically the most important cause of delay in healing; it prolongs inflammation and potentially increases the local tissue injury.
• Nutrition has profound effects on repair; protein deficiency, for example, and especially vitamin C deficiency inhibit collagen synthesis and retard healing.
• Glucocorticoids (steroids) have well-documented anti- inflammatory effects, and their administration may result in weakness of the scar because of inhibition of TGF-β production and diminished fibrosis. In some instances, however, the anti-inflammatory effects of glu- cocorticoids are desirable. For example, in corneal infec- tions, glucocorticoids are sometimes prescribed (along with antibiotics) to reduce the likelihood of opacity that may result from collagen deposition.

Diabetes, mechanical variables (pressure or torsion), poor perfusion, location of the injury, etc.

Question 63

Cutaneous wound healing is a process that involves both epithelial regeneration and the formation of connective tissue scar and is thus illustrative of the general principles that apply to healing in all tissues.

Depending on the nature and size of the wound, the healing of skin wounds is said to occur by first or second intention. Describe first intention.

Answer 63

One of the simplest examples of wound repair is the healing of a clean, uninfected surgical incision approximated by surgical sutures. This is referred to as primary union, or healing by first intention. The incision causes only focal disruption of epithelial basement membrane continuity and death of relatively few epithelial and connective tissue cells. As a result, epithelial regeneration is the principal mechanism of repair.

A small scar is formed, but there is minimal wound contraction. The narrow incisional space first fills with fibrin-clotted blood, which then is rapidly invaded by granulation tissue and covered by new epithelium.

Question 64

What are the steps of first intention healing?

Answer 64

• Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot. Basal cells at the cut edge of the epidermis begin to show increased mitotic activity. Within 24 to 48 hours, epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane com- ponents as they progress. The cells meet in the midline beneath the surface scab, yielding a thin but continuous epithelial layer.
• By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space. Collagen fibers are now 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.
• By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. Collagen fibrils become more abundant and begin to bridge the incision. The epidermis recovers its normal thickness as differentiation of surface cells yields a mature epidermal archi- tecture with surface keratinization.
• During the second week, there is continued collagen accumulation and fibroblast proliferation. The leukocyte infiltrate, edema, and increased vascularity are substantially diminished. The long process of “blanching” begins, accomplished by increasing collagen deposition within the incisional scar and the regression of vascular channels.
• By the end of the first month, the scar consists of a cellular connective tissue, largely devoid of inflammatory cells, covered by an essentially normal epidermis. However, the dermal appendages destroyed in the line of the incision are permanently lost. The tensile strength of the wound increases with time.

Question 65

When is Healing by Second Intention common?

Answer 65

When cell or tissue loss is more extensive, such as in large wounds, at sites of abscess formation, ulceration, and isch- emic necrosis (infarction) in parenchymal organs, the repair process is more complex and involves a combination of regeneration and scarring.

Question 66

Secondary healing differs from primary healing in several respects:

Answer 66

• A larger clot or scab rich in fibrin and fibronectin forms at the surface of the wound.
• Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. Consequently, large defects have a greater potential for secondary, inflammation-mediated, injury.
• Larger defects require a greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium. A greater volume of granulation tissue generally results in a greater mass of scar tissue.
• Secondary healing involves wound contraction. Within 6 weeks, for example, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction. This process has been ascribed to the presence of myofibroblasts, which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.

Question 67

Notes on Wound Strength

Answer 67

Carefully sutured wounds have approximately 70% of the strength of normal skin, largely because of the placement of sutures. When sutures are removed, usually at 1 week, wound strength is approximately 10% of that of unwounded skin, but this increases rapidly over the next 4 weeks. The recovery of tensile strength results from collagen synthesis exceeding degradation during the first 2 months, and from structural modifications of collagen (e.g., cross-linking, increased fiber size) when synthesis declines at later times. Wound strength reaches approximately 70% to 80% of normal by 3 months and usually does not improve substantially beyond that point.

Question 68

Deposition of collagen is part of normal wound healing. So what is fibrosis again?

Answer 68

he term fibrosis is used to denote the excessive deposition of collagen and other ECM components in a tissue. The terms scar and fibrosis are used interchangeably, but fibrosis most often refers to the deposition of collagen in chronic diseases.

Question 69

What is the difference between scar formation and fibrosis?

Answer 69

The basic mechanisms of fibrosis are the same as those of scar formation during tissue repair. However, tissue repair typically occurs after a short-lived injurious stimu- lus and follows an orderly sequence of steps, whereas fibrosis is induced by persistent injurious stimuli such as infections, immunologic reactions, and other types of tissue injury. The fibrosis seen in chronic diseases such as pulmonary fibrosis is often responsible for organ dysfunction and even organ failure.

Question 70

Whos a punk biotch?

Answer 70

Barrett