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Flashcards in chapter3 tissue renewal and regeneration Deck (146):

Results in the complete restitution of the lost damage or tissue.



The process by which there is extensive deposition of collagen.



The following are examples of labile tissues EXCEPT:A. Skin epitheliaB. Oral cavityC. Parenchymal cells of the liverD. Lining mucosa of all the excretory ducts

C. Parenchymal cells of the liver


Mechanism of stem cells in which with each stem cell division, one of the daughter cells retains its self-renewing capacity while the other enters differentiation.

Obligatory asymmetric replication


Stem cell mechanism in which there is a balance between self-renewing and differentiated cells.

Stochastic differentiation


A change in differentiation of a cell from one type to another is known as ________________.



The capacity of a cell to transdifferentiate into diverse lineages is referred to as ___________.

Developmental plasticity


Somatic stem cells generate rapidly dividing cells called __________.

Transit amplifying cells


The liver contains stem cells/progenitor cells in the _____________.

Canals of Hering


Neural precursor cells are found in which two areas of the adult brain.

Subventricular zone and dentate gyrus of the hippocampus


This is the rate limiting step for replication in the cell cycle.

Restriction point between G1 and S.


This step in cell cycle monitors the integrity of DNA BEFORE replication.

G1/S checkpoint


Aids in cell scattering and proliferation.

HGF/Scatter factor


Most potent growth factor for vasculogenesis and angiogenesis.



Growth factor responsible for migration and proliferation of fibroblasts, smooth muscles



Growth factor that acts as a growth inhibitor and a potent fibrinogenic agent.



The following are biochemical pathways that utilize intrinsic tyrosine kinase activity EXCEPT:A. PI3 Kinase PathwayB. MAP-kinase PathwayC. IP3 PathwayD. cAMP Pathway

D. cAMP Pathway


Mobilization of endothelial stem cells and has a role in inflammation.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Acts on lymphatic endothelial cells to induce lymphangiogenesis.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Located in endothelial cells and many other cells types and considered to be the main receptors for vasculogenic and angiogenic effect on VEGF.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Also known as the wear and tear pigment.



Provide resilience and lubrication to many types of CT (cartilage in joints).



This is the most abundant glycoprotein in BM.



Mobilization of endothelial stem cells and has a role in inflammation.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Acts on lymphatic endothelial cells to induce lymphangiogenesis.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Located in endothelial cells and many other cells types and considered to be the main receptors for vasculogenic and angiogenic effect on VEGF.A. VEFGR-1B. VEFGR-2C. VEFGR-3D. None of the above



Also known as the wear and tear pigment.



Provide resilience and lubrication to many types of CT (cartilage in joints).



This is the most abundant glycoprotein in BM.



What is REPAIR?

Repair, sometimes called healing, refers to the restoration
of tissue architecture and function after an injury.


(By convention, the term repair is often used for parenchymal
and connective tissues and healing for surface epithelia,
but these distinctions are not based on biology and we
use the terms interchangeably.)

Critical to the survival of
an organism is the ability to repair the damage caused by
toxic insults and inflammation. Hence, 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:

1. regeneration by proliferation of residual (uninjured)
cells and maturation of tissue stem cells,

2. and the deposition of connective tissue to form a scar


What is 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. In other
cases, tissue stem cells may contribute to the restoration
of damaged tissues.

However, mammals have a limited
capacity to regenerate damaged tissues and organs, and
only some components of most tissues are able to fully
restore themselves


What happens in 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 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


The regeneration of injured cells and tissues involves___________, which is driven by growth factors and is
critically dependent on the integrity of the extracellular
matrix, and by the _____________.

Before describing examples of repair by regeneration,
the general principles of cell proliferation are

  •  cell proliferation 
  • development of mature cells from stem cells


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.
Based on this criterion, the tissues of the body are divided
into three groups.

  • Labile (continuously dividing) tissues
  • Stable tissues
  • Permanent tissues.


What are Labile tissues?

Labile (continuously dividing) tissues.


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

Labile cells include:

  1. hematopoietic cells in the bone marrow and the
  2. majority of surface epithelia,
    • such as the stratified squamous epithelia 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.


What are Stable tissues? 

Cells of these tissues are quiescent (in the
G0 stage of the cell cycle) and have only minimal proliferative activity in their normal state.

However, these
cells are capable of dividing 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.


What are Permanent tissues? 

The cells of these tissues are considered
to be terminally differentiated and nonproliferative
in postnatal life.

The majority of neurons and cardiac
muscle cells belong to this category.

Thus, injury to the
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 heart muscle cells may proliferate after myocardial
necrosis. Nevertheless, whatever proliferative capacity may exist in these tissues, it is insufficient to
produce tissue regeneration after injury. Skeletal muscle
is usually classified as a permanent tissue, but satellite
cells attached to the endomysial sheath provide some
regenerative capacity for muscle. In permanent tissues,
repair is typically dominated by scar formation.


Cell proliferation is driven by signals provided by

growth factors and from the extracellular matrix


different growth factors have been described; some act on
multiple cell types and others are cell-selective (Chapter 1,
Table 1-1). Growth factors are typically produced by cells
near the site of damage.
The most important sources of
these growth factors are________ that are activated by
the tissue injury, but epithelial and stromal cells also
produce some of these factors. Several growth factors bind
to ECM proteins and are displayed at high concentrations.



All growth factors activate signaling pathways that ultimately
induce the production of proteins that are involved
in driving cells through the cell cycle and other proteins
that release blocks on the cell cycle (checkpoints
) (Chapter
1). In addition to responding to growth factors, cells use
integrins to bind to ECM proteins, and signals from the
integrins can also stimulate cell proliferation.


Also, we now realize that cell
proliferation is only one pathway of regeneration and that
stem cells contribute to this process in important ways.


In the process of regeneration, proliferation of residual
cells is supplemented by development of mature cells
from stem cells.

In Chapter 1 we introduced the major
types of stem cells. In adults, the most important stem cells
for regeneration after injury are___________

 tissue stem cells.

stem cells live in specialized niches, and it is believed
that injury triggers signals
in these niches that activate
quiescent stem cells to proliferate and differentiate into
mature cells that repopulate the injured tissue.


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 labile tissues, such as the epithelia of the intestinal
tract and skin, injured cells are rapidly replaced by proliferation
of residual cells and differentiation of tissue
stem cells provided the underlying basement membrane

is intact.


The growth factors involved in these
processes are not defined.

Loss of blood cells is corrected
by proliferation of hematopoietic stem cells in the
bone marrow and other tissues, driven by growth
factors called colony-stimulating factors (CSFs), which
are produced in response to the reduced numbers of
blood cells.


Tissue regeneration can occur in parenchymal organs
with stable cell populations, but with the exception of
the_______ this is usually a limited process. Pancreas,
adrenal, thyroid, and lung have some regenerative

The surgical removal of a kidney elicits in
the remaining kidney a compensatory response that consists of both hypertrophy and hyperplasia of proximal
duct cells. The mechanisms underlying this response
are not understood, but likely involve local production
of growth factors and interactions of cells with the ECM.
The extraordinary capacity of the liver to regenerate has
made it a valuable model for studying this process, as
described below.



Restoration of normal tissue structure can occur only if
the residual tissue is structurally___________ as after partial
surgical resection.




By contrast, if the entire tissue is
damaged by infection or inflammation, regeneration is

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.

incomplete and is accompanied by scarring


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 livingdonor
hepatic transplantation. The mythologic image of
liver regeneration is the regrowth of the liver of Prometheus,
which was eaten every day by an eagle sent by Zeus as
punishment for stealing the secret of fire, and grew back
overnight. The reality, although less dramatic, is still quite


Regeneration of the liver occurs by two major mechanisms:
__________. Which mechanism plays the
dominant role depends on the nature of the injury.

  • proliferation of remaining hepatocytes
  • and repopulation from progenitor cells


In humans, resection of up to 90% of the liver can
be corrected by __________
This classic model of tissue regeneration has been used
experimentally to study the initiation and control of the

proliferation of the residual hepatocytes.


Hepatocyte proliferation in the regenerating liver is
triggered by the combined actions of_____________

 cytokines and
polypeptide growth factors.


Hepatocyte proliferation in the regenerating liver is
triggered by the combined actions of cytokines and
polypeptide growth factors.

The process occurs in distinct

  • first, or priming
  • second, or growth factor, phase,
  • final, termination, phase,


What happens in the first step of heptocyte proliferation?

In the first, or priming, phase,
cytokines such as IL-6 are produced mainly by Kupffer
and act on hepatocytes to make the parenchymal
cells competent to receive and respond to growth factor


What happens in the second step of hepatocyte proliferation?

In the second, or growth factor, phase, growth
factors such as HGF and TGF-α, produced by many
cell types, act on primed hepatocytes to stimulate cell
metabolism and entry of the cells into the cell cycle.

Because hepatocytes are quiescent cells, it takes them
several hours to enter the cell cycle, progress from G0 to
and reach the S phase of DNA replication.

all hepatocytes replicate during liver regeneration
after partial hepatectomy.

The wave of hepatocyte replication
is followed by replication of nonparenchymal
cells (Kupffer cells, endothelial cells, and stellate cells).

During the phase of hepatocyte replication, more than
70 genes are activated; these include genes encoding
transcription factors, cell cycle regulators, regulators
of energy metabolism, and many others.


What happens in the final step of hepatocyte proliferation
termination, phase? 

hepatocytes return to quiescence.
The nature of the stop signals is poorly understood;antiproliferative
cytokines of the TGF-β family are likely


When does liver regeneration from progenitor cells happen?

 In situations
where the proliferative capacity of hepatocytes is
such as after chronic liver injury or inflammation,
progenitor cells in the liver contribute to repopulation.
In rodents, these progenitor cells have been called
oval cells because of the shape of their nuclei. Some of
these progenitor cells reside in specialized niches called
canals of Hering
, where bile canaliculi connect with larger
bile ducts. The signals that drive proliferation of progenitor
cells and their differentiation into mature hepatocytes
are topics of active investigation


When does repair by Connective Tissue Deposition happens?

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.


When does scarring may happen?

 if the tissue injury is severe or chronic and results in
damage to parenchymal cells and epithelia as well as to
the connective tissue framework, or if nondividing cells
are injured. 


In contrast to regeneration, which involves
the restitution of tissue components, scar formation is a
response that_____________

 “patches” rather than restores the tissue.

The term scar is most often used in connection to wound healing
in the skin, but may also be used to describe the replacement
of parenchymal cells in any tissue by collagen, as in
the heart after myocardial infarction.


Steps in Scar Formation

Repair by connective tissue deposition consists of sequential
processes that follow tissue injury and the inflammatory

1. Angiogenesis

2. Formation of Granulation of tissue

3.  Remodelling of Connective Tissue



What is Angiogenesis? 

It is  is the formation of new blood vessels,
which supply nutrients and oxygen needed to support
the repair process.



Why are newly formed vessels are leaky? 

because of incomplete interendothelial junctions and
because VEGF, the growth factor that drives angiogenesis,
increases vascular permeability.

This leakiness
accounts in part for the edema that may persist in
healing wounds long after the acute inflammatory
response has resolved.


What is the growth factor that drives angiogenesis?



What happens in the formation of granulation tissue. 

Migration and proliferation
of fibroblasts and deposition of loose connective
tissue, together with the vessels and interspersed leukocytes,
form granulation tissue.

The term granulation tissue
derives from its pink, soft, granular gross appearance,
such as that seen beneath the scab of a skin wound.


What is the histologic appearance of granulation tissue?

histologic appearance is characterized by proliferation
of fibroblasts and new thin-walled, delicate capillaries
(angiogenesis), in a loose extracellular matrix, often
with admixed inflammatory cells, mainly macrophages
(Fig. 3-27A).

Granulation tissue progressively invades
the site of injury; the amount of granulation tissue that
is formed depends on the size of the tissue deficit created
by the wound and the intensity of inflammation.


How does remodeling of connective tissue happens? 

Maturation and reorganization
of the connective tissue (remodeling) produce
the stable fibrous scar. The amount of connective tissue
increases in the granulation tissue, eventually resulting in the formation of a scar (Fig. 3-27B), which may
remodel over time.


Figure 3-27 A, Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells. Collagen
is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen, with
only scattered vascular channels.


How does macrophage play a role in repair?

Macrophages play a central role in repair by clearing
offending agents and dead tissue
, providing growth
factors for the proliferation of various cells
, and secreting
cytokines that stimulate fibroblast proliferation and connective
tissue synthesis and deposition.



What are the mostly type of macrophage involved in repair?


The macrophages
that are involved in repair are mostly of the alternatively
activated (M2) type. It is not clear how the classically activated
macrophages that dominate during inflammation,
and are involved in getting rid of microbes and dead
tissues, are gradually replaced by alternatively activated
macrophages that serve to terminate inflammation and
induce repair


Repair begins within ________of injury by the emigration
of fibroblasts and the induction of fibroblast and
endothelial cell proliferation.

24 hours 


 By _______days, the specialized
granulation tissue that is characteristic of healing is
We next describe the steps in the formation of granulation
tissue and the scar.

3 to 5 


________ is the process of new blood vessel development
from existing vessels. 



Angiogenesis is critical in the

  • 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

  • Angiogenesis involves sprouting of new vessels from

      existing ones, and consists of the following steps (Fig. 3-28):

  • • Vasodilation in response to nitric oxide and increased

permeability induced by vascular endothelial growth
factor (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


  • • 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

  • Growth factors.
  • Notch signaling,
  • ECM proteins
  • Enzymes


What are the growth factors involve in angiogenesis?

  • VEGF-A
  • Fibroblast growth factors (FGFs)
  • Angiopoietins
    1 and 2 (Ang 1 and Ang 2
  • PDGF and


What does Vascular endothelial growth factors
(VEGFs), mainly VEGF-A (Chapter 1) does?,

 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.


What does Fibroblast growth factors (FGFs),
mainly FGF-2 does?

It stimulates the proliferation of endothelial

It also promotes the migration of macrophages
and fibroblasts to the damaged area, and stimulates epithelial
cell migration to cover epidermal wounds.


What does Angiopoietins
1 and 2 (Ang 1 and Ang 2) does?

are growth factors that
play a role in angiogenesis and the structural maturation
of new vessels.

Newly formed vessels need to be
stabilized by the recruitment of pericytes and smooth
muscle cells and by the deposition of connective tissue.


Ang1 interacts with a tyrosine kinase receptor on endothelial
cells called _________



The growth factors ____________ also participate in the stabilization process:


PDGF and


What is the role of PDGF in angiogenesis?

recruits smooth muscle cells


What is TGF-β role in angiogenesis? 

It suppresses endothelial proliferation and migration, and enhances
the production of ECM proteins.


What does Notch signaling pathway do?

Through “cross-talk” with VEGF, the
Notch signaling pathway regulates the sprouting and
branching of new vessels and thus ensures that the new
vessels that are formed have the proper spacing to effectively
supply the healing tissue with blood.


What is the role of ECM proteins in angiogenesis?

ECM proteins participate in the process of vessel sprouting
in angiogenesis, largely through interactions with
integrin receptors in endothelial cells and by providing
the scaffold for vessel growth.


Enzymes in the ECM, notably the matrix metalloproteinases
(MMPs) function to in angiogenesis to? 

degrade the ECM to permit remodeling
and extension of the vascular tube.


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.



These processes are orchestrated by locally
produced cytokines and growth factors, including PDGF,
FGF-2, and TGF-β. The major sources of these factors are
inflammatory cells, particularly alternatively activated
(M2) macrophages, which are present at sites of injury and
in granulation tissue. Sites of inflammation are also rich in
mast cells, and in the appropriate chemotactic milieu lymphocytes
may also be present. Each of these can secrete
cytokines and growth factors that contribute to fibroblast
proliferation and activation.


___________ is the most
important cytokine for the synthesis and deposition of
connective tissue proteins

Transforming growth factor-β (TGF-β)


 It is produced by most of the cells in granulation tissue, including alternatively activated macrophages.


The levels of TGF-β in tissues are primarily
regulated not by the transcription of the gene but by the
posttranscriptional activation of latent TGF-β, the rate of
secretion of the active molecule, and factors in the ECM,
notably integrins, that enhance or diminish TGF-β activity.



What are the function of TGF-β ?

  1.  stimulates fibroblast migration and proliferation
  2. increased synthesis of collagen and fibronectin,
  3. decreased degradation of ECM due to inhibition of metalloproteinases.
  4. involved not only in scar formation
    after injury but also in the development of fibrosis in lung,
    liver, and kidneys that follows chronic inflammation.
  5. TGF-β is also an antiinflammatory cytokine that serves to limit and terminate inflammatory responses. It does this by inhibiting lymphocyte proliferation and the activity other leukocytes. 


As healing progresses, the number of proliferating
fibroblasts and new vessels decreases; however, the fibroblasts
progressively assume a more synthetic phenotype,
and hence there is increased deposition of ECM.

______, in particular, is critical to the development of
strength in a healing wound site

Collagen synthesis


synthesis by fibroblasts begins early in wound
healing (days 3 to 5) and continues for several weeks,
depending on the size of the wound


Net collagen accumulation,
however, depends not only on increased synthesis
but also on diminished collagen degradation
later). Ultimately, the granulation tissue evolves into a scar
composed of largely inactive, spindle-shaped fibroblasts,
dense collagen, fragments of elastic tissue, and other ECM


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, what happens? 

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

Some of the fibroblasts also acquire
features of smooth muscle cells, including the presence of
actin filaments, and are called myofibroblasts.


The outcome of the repair process is influenced by a
balance between synthesis and degradation of ECM proteins.


After its deposition, the connective tissue in the scar
continues to be modified and remodeled. The degradation
of collagens and other ECM components is accomplished
by a family of ___________, so called
because they are dependent on metal ions (e.g., zinc) for
their activity.

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.


What cells producecd MMPs ____________ and their synthesis and secretion are regulated
by growth factors, cytokines, and other agents

are produced by a variety of cell types (fibroblasts,
macrophages, neutrophils, synovial cells, and some
epithelial cells),


 The activity of the MMPs is tightly controlled. They are produced
as inactive precursors (zymogens) that must be first
activated; this is accomplished by proteases (e.g., plasmin)
likely to be present only at sites of injury.



In addition, activated
collagenases can be rapidly inhibited by specific
tissue inhibitors of metalloproteinases (TIMPs), produced
by most mesenchymal cells. Thus, during scar formation,
MMPs are activated to remodel the deposited ECM and
then their activity is shut down by the ________



A family of enzymes related to MMPs is called ADAM
(a disintegrin and metalloproteinase). ADAMs are anchored
to the plasma membrane and cleave and release extracellular
domains of cell-associated cytokines and growth
factors, such as TNF, TGF-β, and members of the EGF


Factors That Influence Tissue Repair

  • Infection 
  • • Diabetes 
  • • Nutritional status
  • • Glucocorticoids (steroids) 
  • • Mechanical factors such as increased local pressure or
  • torsion may cause wounds to pull apart, or dehisce.
  • • Poor perfusion
  • • Foreign bodies 
  • • The type and extent of tissue injury affects the subsequent
  • repair.
  • • The location of the injury


__________ is clinically one of the most important causes
of delay in healing; it prolongs inflammation and potentially
increases the local tissue injury.



______________is a metabolic disease that compromises tissue
repair for many reasons (Chapter 24), and is one of the
most important systemic causes of abnormal wound



Glucocorticoids (steroids) have well-documented antiinflammatory
effects, and their administration may
result in weakness of the scar due to inhibition of ______
production and diminished fibrosis.


In some instances,
however, the anti-inflammatory effects of glucocorticoids
are desirable. For example, in corneal infections,
glucocorticoids are sometimes prescribed (along with
antibiotics) to reduce the likelihood of opacity that may
result from collagen deposition



Mechanical factors such as _________ may cause wounds to pull apart, or dehisce.

increased local pressure or


The type and extent of tissue injury affects the subsequent

Complete restoration can occur only in
tissues composed of _________; even then,
extensive injury will probably result in incomplete
tissue regeneration and at least partial loss of function.

Injury to tissues composed of permanent cells must
inevitably result in scarring with, at most, attempts at
functional compensation by the remaining viable elements.
Such is the case with healing of a myocardial

stable and labile cells


The location of the injury and the character of the tissue
in which the injury occurs are also important.

example, inflammation arising in tissue spaces (e.g.,
pleural, peritoneal, synovial cavities) develops extensive

Subsequent repair may occur by digestion
of the exudate, initiated by the proteolytic enzymes
of leukocytes and resorption of the liquefied exudate.
This is called ________, and in the absence of cellular
necrosis, normal tissue architecture is generally restored.
However, in the setting of larger accumulations, the
exudate undergoes organization: granulation tissue
grows into the exudate, and a fibrous scar ultimately



two clinically significant types of

  • the healing of skin wounds (cutaneous woundhealing)
  • and fibrosis in injured parenchymal organs.


What is Healing of Skin Wounds

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


What is healing by 1st intention?

Healing by First Intention
When the injury involves only the epithelial layer, 


What is the principal mechanism in the healing process of first intention?

principal mechanism of repair is epithelial regeneration,
also called primary union or healing by first intention. 


Give an example of first intention healing?

of the simplest examples of this type of wound repair is
the healing of a clean, uninfected surgical incision approximated
by surgical sutures (Fig. 3-29). 


healing of a clean, uninfected surgical incision approximated
by surgical sutures (Fig. 3-29).

The incision causes
only focal disruption of epithelial basement membrane
continuity and death of relatively few epithelial and connective
tissue cells



The repair of first intention consists of three connected

  • inflammation,
  • proliferation of epithelial and other cells,
  • and maturation of the connective tissue scar.


What happens in the healing of first intention within 24 hrs?

Within 24 hours, neutrophils are seen at the incision
margin, migrating toward the fibrin clot.

They release
proteolytic enzymes that begin to clear the debris.

cells at the cut edge of the epidermis begin to show
increased mitotic activity.




What happens Within 24 to 48 hours in first intention healin?

epithelial cells from both edges have begun to migrate and
proliferate along the dermis, depositing basement membrane
components as they progress.

The cells meet in
the midline beneath the surface scab, yielding a thin but
continuous epithelial layer that closes the wound.


What happens in day 3 of first intention healing?

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. Epithelial cell proliferation continues, forming
a covering approaching the normal thickness of the



As mentioned earlier, ______
are key cellular constituents of tissue repair,
clearing extracellular debris, fibrin, and other foreign
material, and promoting angiogenesis and ECM deposition.



What happens by day 5 in first intention healing?

By day 5, neovascularization reaches its peak as granulation
tissue fills the incisional space.

These new vessels
are leaky,
allowing the passage of plasma proteins and
fluid into the extravascular space. Thus, new granulation
tissue is often edematous

Migration of fibroblasts
to the site of injury is driven by chemokines, TNF,
PDGF, TGF-β, and FGF.
Their subsequent proliferation
is triggered by multiple growth factors, including
PDGF, EGF, TGF-β, and FGF, and the cytokines IL-1 and TNF

The epidermis recovers
its normal thickness as differentiation of surface cells
yields a mature epidermal architecture with surface


What are _____are the main source for these PDGF, EGF, TGF-β, and FGF, and the cytokines IL-1 and TNF?


although other inflammatory cells and platelets may

also produce them.



What produces the______ ECM proteins,
and collagen fibrils become more abundant and
begin to bridge the incision.


 The fibroblasts


What happens during the second week in first intention healing?

During the second week, there is continued collagen
accumulation and fibroblast proliferation

The leukocyte
infiltrate, edema, and increased vascularity are
substantially diminished.

The process of “blanching”
begins, accomplished by increasing collagen deposition
within the incisional scar and the regression of vascular


What happens by the end of first month in first healing intention?

By the end of the first month, the scar comprises a
cellular connective tissue largely devoid of inflammatory
cells and 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, as described


What is healing by second intention?

Healing by Second Intention
When cell or tissue loss is more extensive, such as in large
wounds, abscesses, ulceration, and ischemic necrosis

(infarction) in parenchymal organs, the repair process
involves a combination of regeneration and scarring.
In healing of skin wounds by second intention, also known
as healing by secondary union, the inflammatory reaction is more intense, there is development
of abundant granulation tissue
, accumulation of
ECM and formation of a large scar, and wound contraction
by the action of myofibroblasts.


Secondary healing differs from primary healing in
several respects:

• In wounds causing large tissue deficits, the fibrin clot is
larger, and there is more exudate and necrotic debris in
the wounded area. 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.
• Much larger amounts of granulation tissue are formed.
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.
• At first a provisional matrix containing fibrin, plasma
fibronectin, and type III collagen is formed, but in about
2 weeks this is replaced by a matrix composed primarily
of type I collagen. Ultimately, the original granulation
tissue scaffold is converted into a pale, avascular
scar, composed of spindle-shaped fibroblasts, dense
collagen, fragments of elastic tissue, and other ECM
components. The dermal appendages that have been destroyed in the line of the incision are permanently
lost. The epidermis recovers its normal thickness and

By the end of the first month, the scar is
made up of acellular connective tissue devoid of inflammatory
infiltrate, covered by intact epidermis.
Wound contraction generally occurs in large surface
. The contraction helps to close the wound by
decreasing the gap between its dermal edges and by
reducing the wound surface area. Hence, it is an important
feature in healing by secondary union. The initial
steps of wound contraction involve the formation, at the
edge of the wound, of a network of myofibroblasts, which
are modified fibroblasts exhibiting many of the ultrastructural
and functional features of contractile smooth
muscle cells. Within 6 weeks, large skin defects may be
reduced to 5% to 10% of their original size, largely by


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 _____of that of unwounded
skin, but this increases rapidly over the next 4 weeks.




recovery of tensile strength results from the excess of collagen
synthesis over collagen degradation during the first
2 months of healing,
and, at later times, from structural modifications of collagen fibers (cross-linking, increased
fiber size) after collagen synthesis ceases.

Wound strength
reaches approximately _______of normal by 3 months
but usually does not substantially improve beyond that

70% to 80% 


Deposition of collagen is part of normal wound healing? Tor F



What is fibrosis?

The term fibrosis is used to denote the excessive deposition
of collagen and other ECM components in a tissue.

already mentioned, the terms scar and fibrosis are used
interchangeably, but fibrosis most often refers to the abnormal deposition of collagen that occurs in internal organs
in chronic diseases


What are the basic mechanism of fibrosis?

. The basic mechanisms of fibrosis are
the same as those of scar formation in the skin during
tissue repair.

Fibrosis is a pathologic process induced by
persistent injurious stimuli such as chronic infections and
immunologic reactions, and is typically associated with
loss of tissue (Fig. 3-31). It may be responsible for substantial
organ dysfunction and even organ failure.


As discussed earlier, the major cytokine involved in
fibrosis is _______.



The mechanisms that lead to the activation

of TGF-β in fibrosis are not precisely known, but cell
death by necrosis or apoptosis and the production of reactive
oxygen species seem to be important triggers of the

activation, regardless of the tissue.

Similarly, the cells that
produce collagen under TGF-β stimulation may vary
depending on the tissue.



In most organs, such as in lung
and kidney, _______ are the main source of collagen,



______________are the major collagen producers in
liver cirrhosis.

stellate cells 


Fibrotic disorders include diverse chronic and debilitating
diseases such as . 

  • liver cirrhosis,
  • systemic sclerosis (scleroderma),
  • fibrosing diseases of the lung (idiopathic pulmonary fibrosis, pneumoconioses,
  • and drug-, radiationinduced pulmonary fibrosis),
  • end-stage kidney disease,
  • and constrictive pericarditis

These conditions are discussed
in the appropriate chapters throughout the book.
Because of the tremendous functional impairment caused
by fibrosis in these conditions, there is great interest in the
development of antifibrotic drugs.


Abnormalities in Tissue Repair

  • Inadequate formation of granulation tissue or formation
    of a scar can lead to two types of complications:
    wound dehiscence and ulceration.
  • Excessive formation of the components of the repair
    process can give rise to hypertrophic scars and keloids.
  • Exuberant granulation
  • Contraction problems


Inadequate formation of granulation tissue or formation
of a scar can lead to two types of complications:

  1. wound dehiscence
  2. and ulceration.


Dehiscence or
rupture of a wound, although not common, occurs most
frequently after __________. 

abdominal surgery and is due to increased abdominal pressure

 Vomiting, coughing, or ileus can generate mechanical stress on the abdominal


Wounds can ulcerate because of ________ 

vascularization during healing.



For example, lower
extremity wounds in individuals with atherosclerotic
peripheral vascular disease typically ulcerate

Nonhealing wounds also form in areas devoid of
sensation. These neuropathic ulcers are occasionally
seen in patients with diabetic peripheral neuropathy


Excessive formation of the components of the repair
process can give rise to _________

hypertrophic scars and keloids.


What is a hypertophic scar?

The accumulation of excessive amounts of collagen may
give rise to a raised scar known as a hypertrophic scar;

Hypertrophic scars generally develop after thermal or
traumatic injury that involves the deep layers of the


What  is a keloid formation?

The accumulation of excessive amounts of collagen may
give rise to a raised scar known as a hypertrophic scar;
if the scar tissue grows beyond the boundaries of the
original wound and does not regress,
it is called a keloid
(Fig. 3-32). Keloid formation seems to be an individual
predisposition, and for unknown reasons this aberration
is somewhat more common in African Americans.


What is exuberant granulation?

Exuberant granulation is another deviation in wound
healing consisting of the formation of excessive amounts
of granulation tissue, which protrudes above the level
of the surrounding skin and blocks reepithelialization

(this process has been called, with more literary fervor,
proud flesh). Excessive granulation must be removed by
cautery or surgical excision to permit restoration continuity of the epithelium.




Fortunately rarely, incisional
scars or traumatic injuries may be followed by
exuberant proliferation of fibroblasts and other connective
tissue elements that may, in fact, recur after excision.
Called _________, or aggressive fibromatoses, these
neoplasms lie in the interface between benign and
malignant (though low-grade) tumors.



Contraction in the size of a wound is an important
part of the normal healing process. An exaggeration of
this process gives rise to _______

contracture and results in
deformities of the wound and the surrounding tissues.


Contractures are particularly prone to develop on the

palms, the soles, and the anterior aspect of the thorax.
Contractures are commonly seen after serious burns
and can compromise the movement of joints.


Decks in 2H. Pathology Class (49):