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Flashcards in Chapter 3 Tissue Repair Deck (144):

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 restorationof tissue architecture and function after an injury. (By convention, the term repair is often used for parenchymaland connective tissues and healing for surface epithelia,but these distinctions are not based on biology and weuse the terms interchangeably.)Critical to the survival ofan organism is the ability to repair the damage caused bytoxic insults and inflammation. Hence, the inflammatoryresponse to microbes and injured tissues not only serves toeliminate these dangers but also sets into motion theprocess 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 thedamaged components and essentially return to a normalstate; this process is called regeneration.  Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate, for example, in therapidly dividing epithelia of the skin and intestines, andin some parenchymal organs, notably the liver. In othercases, tissue stem cells may contribute to the restorationof damaged tissues. However, mammals have a limitedcapacity to regenerate damaged tissues and organs, andonly some components of most tissues are able to fullyrestore themselves


What happens in Connective tissue deposition (scar formation)?

 If theinjured tissues are incapable of complete restitution, orif the supporting structures of the tissue are severelydamaged, repair occurs by the laying down of connective(fibrous) tissue, a process that may result in scarformation. Although the fibrous scar is not normal, itprovides enough structural stability that the injuredtissue is usually able to function.


 The term fibrosis ismost often used to describe the: 

 extensive depositionof collagen that occurs in the lungs, liver, kidney, andother organs as a consequence of chronic inflammation,or in the myocardium after extensive ischemicnecrosis (infarction). 


If fibrosis develops in a tissuespace occupied by an inflammatory exudate, it iscalled ________

organization (as in organizing pneumonia affectingthe lung


The regeneration of injured cells and tissues involves___________, which is driven by growth factors and iscritically dependent on the integrity of the extracellularmatrix, and by the _____________.Before describing examples of repair by regeneration,the general principles of cell proliferation arediscussed.

 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 dividedinto three groups.

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


What are Labile tissues?

Labile (continuously dividing) tissues. Cells of thesetissues are continuously being lost and replaced bymaturation from tissue stem cells and by proliferationof mature cells.Labile cells include:
* hematopoietic cells in the bone marrow and the 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 thepool of stem cells is preserved.


What are Stable tissues? 

Cells of these tissues are quiescent (in theG0 stage of the cell cycle) and have only minimal proliferative activity in their normal state.However, thesecells are capable of dividing in response to injury or lossof tissue mass. Stable cells constitute the parenchyma ofmost solid tissues, such as liver, kidney, and pancreas.They also include endothelial cells, fibroblasts, andsmooth muscle cells; the proliferation of these cells isparticularly important in wound healing. With theexception of liver, stable tissues have a limited capacityto regenerate after injury.


What are Permanent tissues? 

The cells of these tissues are consideredto be terminally differentiated and nonproliferativein postnatal life.The majority of neurons and cardiacmuscle cells belong to this category.Thus, injury to thebrain or heart is irreversible and results in a scar, becauseneurons and cardiac myocytes cannot regenerate.Limited stem cell replication and differentiation occurin some areas of the adult brain, and there is some evidencethat heart muscle cells may proliferate after myocardialnecrosis. Nevertheless, whatever proliferative capacity may exist in these tissues, it is insufficient toproduce tissue regeneration after injury. Skeletal muscleis usually classified as a permanent tissue, but satellitecells attached to the endomysial sheath provide someregenerative 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


Manydifferent growth factors have been described; some act onmultiple cell types and others are cell-selective (Chapter 1,Table 1-1). Growth factors are typically produced by cellsnear the site of damage. The most important sources ofthese growth factors are________ that are activated bythe tissue injury, but epithelial and stromal cells alsoproduce some of these factors. Several growth factors bindto ECM proteins and are displayed at high concentrations. 



All growth factors activate signaling pathways that ultimatelyinduce the production of proteins that are involvedin driving cells through the cell cycle and other proteinsthat release blocks on the cell cycle (checkpoints) (Chapter1). In addition to responding to growth factors, cells useintegrins to bind to ECM proteins, and signals from theintegrins can also stimulate cell proliferation.


Also, we now realize that cellproliferation is only one pathway of regeneration and thatstem cells contribute to this process in important ways. In the process of regeneration, proliferation of residualcells is supplemented by development of mature cellsfrom stem cells.In Chapter 1 we introduced the majortypes of stem cells. In adults, the most important stem cellsfor regeneration after injury are___________

 tissue stem cells.Thesestem cells live in specialized niches, and it is believedthat injury triggers signals in these niches that activatequiescent stem cells to proliferate and differentiate intomature cells that repopulate the injured tissue.


Mechanisms of Tissue RegenerationThe importance of regeneration in the replacement ofinjured tissues varies in different types of tissues and withthe severity of injury. 

• In labile tissues, such as the epithelia of the intestinaltract and skin, injured cells are rapidly replaced by proliferationof residual cells and differentiation of tissuestem cells provided the underlying basement membraneis intact. The growth factors involved in theseprocesses are not defined.Loss of blood cells is correctedby proliferation of hematopoietic stem cells in thebone marrow and other tissues, driven by growthfactors called colony-stimulating factors (CSFs), whichare produced in response to the reduced numbers ofblood cells.


Tissue regeneration can occur in parenchymal organswith stable cell populations, but with the exception ofthe_______ this is usually a limited process. Pancreas,adrenal, thyroid, and lung have some regenerativecapacity.The surgical removal of a kidney elicits inthe remaining kidney a compensatory response that consists of both hypertrophy and hyperplasia of proximalduct cells. The mechanisms underlying this responseare not understood, but likely involve local productionof growth factors and interactions of cells with the ECM.The extraordinary capacity of the liver to regenerate hasmade it a valuable model for studying this process, asdescribed below.



Restoration of normal tissue structure can occur only ifthe residual tissue is structurally___________ as after partialsurgical resection. 



By contrast, if the entire tissue isdamaged by infection or inflammation, regeneration is__________.For example,extensive destruction of the liver with collapse of the reticulinframework, as occurs in a liver abscess, leads to scarformation even though the remaining liver cells have thecapacity 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 livingdonorhepatic transplantation. The mythologic image ofliver regeneration is the regrowth of the liver of Prometheus,which was eaten every day by an eagle sent by Zeus aspunishment for stealing the secret of fire, and grew backovernight. The reality, although less dramatic, is still quiteimpressive.


Regeneration of the liver occurs by two major mechanisms:__________. Which mechanism plays thedominant 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 canbe corrected by __________This classic model of tissue regeneration has been usedexperimentally to study the initiation and control of theprocess.

proliferation of the residual hepatocytes.


Hepatocyte proliferation in the regenerating liver istriggered by the combined actions of_____________

 cytokines andpolypeptide growth factors.


Hepatocyte proliferation in the regenerating liver istriggered by the combined actions of cytokines andpolypeptide growth factors.The process occurs in distinctstages

* 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 Kupffercells and act on hepatocytes to make the parenchymalcells competent to receive and respond to growth factorsignals.


What happens in the second step of hepatocyte proliferation?

In the second, or growth factor, phase, growthfactors such as HGF and TGF-α, produced by manycell types, act on primed hepatocytes to stimulate cellmetabolism and entry of the cells into the cell cycle.Because hepatocytes are quiescent cells, it takes themseveral hours to enter the cell cycle, progress from G0 toG1, and reach the S phase of DNA replication.Almostall hepatocytes replicate during liver regenerationafter partial hepatectomy.The wave of hepatocyte replicationis followed by replication of nonparenchymalcells (Kupffer cells, endothelial cells, and stellate cells).During the phase of hepatocyte replication, more than70 genes are activated; these include genes encodingtranscription factors, cell cycle regulators, regulatorsof energy metabolism, and many others.


What happens in the final step of hepatocyte proliferationtermination, phase? 

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


When does liver regeneration from progenitor cells happen?

 In situationswhere the proliferative capacity of hepatocytes isimpaired, such as after chronic liver injury or inflammation,progenitor cells in the liver contribute to repopulation.In rodents, these progenitor cells have been calledoval cells because of the shape of their nuclei. Some ofthese progenitor cells reside in specialized niches calledcanals of Hering, where bile canaliculi connect with largerbile ducts. The signals that drive proliferation of progenitorcells and their differentiation into mature hepatocytesare topics of active investigation


When does repair by Connective Tissue Deposition happens? 

If repair cannot be accomplished by regeneration aloneit occurs by replacement of the injured cells with connectivetissue, leading to the formation of a scar, or by acombination of regeneration of some residual cells andscar formation.


When does scarring may happen?

 if the tissue injury is severe or chronic and results indamage to parenchymal cells and epithelia as well as tothe connective tissue framework, or if nondividing cellsare injured. 


In contrast to regeneration, which involvesthe restitution of tissue components, scar formation is aresponse that_____________

 “patches” rather than restores the tissue. The term scar is most often used in connection to wound healingin the skin, but may also be used to describe the replacementof parenchymal cells in any tissue by collagen, as inthe heart after myocardial infarction.


Steps in Scar FormationRepair by connective tissue deposition consists of sequentialprocesses that follow tissue injury and the inflammatoryresponse

1. Angiogenesis2. Formation of Granulation of tissue3.  Remodelling of Connective Tissue 


What is Angiogenesis? 

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


Why are newly formed vessels are leaky? 

because of incomplete interendothelial junctions andbecause VEGF, the growth factor that drives angiogenesis,increases vascular permeability.This leakinessaccounts in part for the edema that may persist inhealing wounds long after the acute inflammatoryresponse has resolved.


What is the growth factor that drives angiogenesis?



What happens in the formation of granulation tissue. 

Migration and proliferationof fibroblasts and deposition of loose connectivetissue, together with the vessels and interspersed leukocytes,form granulation tissue. The term granulation tissuederives 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?

Itshistologic appearance is characterized by proliferationof fibroblasts and new thin-walled, delicate capillaries(angiogenesis), in a loose extracellular matrix, oftenwith admixed inflammatory cells, mainly macrophages(Fig. 3-27A). Granulation tissue progressively invadesthe site of injury; the amount of granulation tissue thatis formed depends on the size of the tissue deficit createdby the wound and the intensity of inflammation.


How does remodeling of connective tissue happens? 

Maturation and reorganizationof the connective tissue (remodeling) producethe stable fibrous scar. The amount of connective tissueincreases in the granulation tissue, eventually resulting in the formation of a scar (Fig. 3-27B), which mayremodel over time.


How does macrophage play a role in repair?

Macrophages play a central role in repair by clearingoffending agents and dead tissue, providing growthfactors for the proliferation of various cells, and secretingcytokines that stimulate fibroblast proliferation and connectivetissue synthesis and deposition. 


What are the mostly type of macrophage involved in repair? 

The macrophagesthat are involved in repair are mostly of the alternativelyactivated (M2) type. It is not clear how the classically activatedmacrophages that dominate during inflammation,and are involved in getting rid of microbes and deadtissues, are gradually replaced by alternatively activatedmacrophages that serve to terminate inflammation andinduce repair


Repair begins within ________of injury by the emigrationof fibroblasts and the induction of fibroblast andendothelial cell proliferation.

24 hours 


 By _______days, the specializedgranulation tissue that is characteristic of healing isapparent.We next describe the steps in the formation of granulationtissue and the scar.

3 to 5 


________ is the process of new blood vessel developmentfrom 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 fromexisting 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 growthfactor (VEGF)
* • Separation of pericytes from the abluminal surface and
breakdown of the basement membrane to allow formationof 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) toform the mature vessel
* • Suppression of endothelial proliferation and migration
and deposition of the basement membrane.


The process of angiogenesis involves several signalingpathways, cell-cell interactions, ECM proteins, and tissueenzymes.

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


What are the growth factors involve in angiogenesis?

* Fibroblast growth factors (FGFs) Angiopoietins 1 and 2 (Ang 1 and Ang 2 PDGF and TGF-β


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

 stimulates bothmigration and proliferation of endothelial cells, thusinitiating 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 endothelialcells. It also promotes the migration of macrophagesand fibroblasts to the damaged area, and stimulates epithelialcell migration to cover epidermal wounds.


What does Angiopoietins1 and 2 (Ang 1 and Ang 2) does?

are growth factors thatplay a role in angiogenesis and the structural maturationof new vessels. Newly formed vessels need to bestabilized by the recruitment of pericytes and smoothmuscle cells and by the deposition of connective tissue. 


Ang1 interacts with a tyrosine kinase receptor on endothelialcells called _________



The growth factors ____________ also participate in the stabilization process: 



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 enhancesthe production of ECM proteins.


What does Notch signaling pathway do?

Through “cross-talk” with VEGF, theNotch signaling pathway regulates the sprouting andbranching of new vessels and thus ensures that the newvessels that are formed have the proper spacing to effectivelysupply the healing tissue with blood.


What is the role of ECM proteins in angiogenesis?

ECM proteins participate in the process of vessel sproutingin angiogenesis, largely through interactions withintegrin receptors in endothelial cells and by providingthe scaffold for vessel growth.


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

degrade the ECM to permit remodelingand extension of the vascular tube.


The laying down of connective tissue occurs in two steps: 

(1) migration and proliferation of fibroblasts into the siteof injury and (2) deposition of ECM proteins produced by these cells.  These processes are orchestrated by locallyproduced cytokines and growth factors, including PDGF,FGF-2, and TGF-β. The major sources of these factors areinflammatory cells, particularly alternatively activated(M2) macrophages, which are present at sites of injury andin granulation tissue. Sites of inflammation are also rich inmast cells, and in the appropriate chemotactic milieu lymphocytesmay also be present. Each of these can secretecytokines and growth factors that contribute to fibroblastproliferation and activation.


___________ is the mostimportant cytokine for the synthesis and deposition ofconnective 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 primarilyregulated not by the transcription of the gene but by theposttranscriptional activation of latent TGF-β, the rate ofsecretion 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 ? 

 stimulates fibroblast migration and proliferation increased synthesis of collagen and fibronectin, decreased degradation of ECM due to inhibition of metalloproteinases. involved not only in scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation. 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 proliferatingfibroblasts and new vessels decreases; however, the fibroblastsprogressively assume a more synthetic phenotype,and hence there is increased deposition of ECM.______, in particular, is critical to the development ofstrength in a healing wound site

Collagen synthesis collagensynthesis by fibroblasts begins early in woundhealing (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 synthesisbut also on diminished collagen degradation (discussedlater). Ultimately, the granulation tissue evolves into a scarcomposed of largely inactive, spindle-shaped fibroblasts,dense collagen, fragments of elastic tissue, and other ECMcomponents


Ultimately, the granulation tissue evolves into a scarcomposed of __________

largely inactive, spindle-shaped fibroblasts,  dense collagen, fragments of elastic tissue, and other ECM components


As the scar matures, what happens? 

there is progressivevascular regression, which eventually transformsthe highly vascularized granulation tissue into a pale,largely avascular scar.Some of the fibroblasts also acquirefeatures of smooth muscle cells, including the presence ofactin filaments, and are called myofibroblasts.


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


After its deposition, the connective tissue in the scarcontinues to be modified and remodeled. The degradationof collagens and other ECM components is accomplishedby a family of ___________, so calledbecause they are dependent on metal ions (e.g., zinc) fortheir 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 regulatedby growth factors, cytokines, and other agents

are produced by a variety of cell types (fibroblasts,macrophages, neutrophils, synovial cells, and someepithelial cells),  The activity of the MMPs is tightly controlled. They are producedas inactive precursors (zymogens) that must be firstactivated; this is accomplished by proteases (e.g., plasmin)likely to be present only at sites of injury. 


In addition, activatedcollagenases can be rapidly inhibited by specifictissue inhibitors of metalloproteinases (TIMPs), producedby most mesenchymal cells. Thus, during scar formation,MMPs are activated to remodel the deposited ECM andthen their activity is shut down by the ________



A family of enzymes related to MMPs is called ADAM(a disintegrin and metalloproteinase). ADAMs are anchoredto the plasma membrane and cleave and release extracellulardomains of cell-associated cytokines and growthfactors, such as TNF, TGF-β, and members of the EGFfamily.


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 causesof delay in healing; it prolongs inflammation and potentiallyincreases the local tissue injury.



______________is a metabolic disease that compromises tissuerepair for many reasons (Chapter 24), and is one of themost important systemic causes of abnormal woundhealing.



Glucocorticoids (steroids) have well-documented antiinflammatoryeffects, and their administration mayresult in weakness of the scar due to inhibition of ______production and diminished fibrosis. In some instances,however, the anti-inflammatory effects of glucocorticoidsare desirable. For example, in corneal infections,glucocorticoids are sometimes prescribed (along withantibiotics) to reduce the likelihood of opacity that mayresult from collagen deposition



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

increased local pressure ortorsion


The type and extent of tissue injury affects the subsequentrepair.Complete restoration can occur only intissues composed of _________; even then,extensive injury will probably result in incompletetissue regeneration and at least partial loss of function.Injury to tissues composed of permanent cells mustinevitably result in scarring with, at most, attempts atfunctional compensation by the remaining viable elements.Such is the case with healing of a myocardialinfarct.

stable and labile cells


The location of the injury and the character of the tissuein which the injury occurs are also important.Forexample, inflammation arising in tissue spaces (e.g.,pleural, peritoneal, synovial cavities) develops extensiveexudates.Subsequent repair may occur by digestionof the exudate, initiated by the proteolytic enzymesof leukocytes and resorption of the liquefied exudate.This is called ________, and in the absence of cellularnecrosis, normal tissue architecture is generally restored.However, in the setting of larger accumulations, theexudate undergoes organization: granulation tissuegrows into the exudate, and a fibrous scar ultimatelyforms.



two clinically significant types ofrepair—?

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 regenerationand the formation of connective tissue scar and is thusillustrative of the general principles that apply to healingin all tissues.Based on the nature and size of the wound, the healingof skin wounds is said to occur by first or secondintention


What is healing by 1st intention?

Healing by First IntentionWhen the injury involves only the epithelial layer, 


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

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


Give an example of first intention healing?

Oneof the simplest examples of this type of wound repair isthe healing of a clean, uninfected surgical incision approximatedby surgical sutures (Fig. 3-29).  healing of a clean, uninfected surgical incision approximatedby surgical sutures (Fig. 3-29). The incision causesonly focal disruption of epithelial basement membranecontinuity and death of relatively few epithelial and connectivetissue cells. 


The repair of first intention consists of three connectedprocesses: 

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 incisionmargin, migrating toward the fibrin clot.They releaseproteolytic enzymes that begin to clear the debris.Basalcells at the cut edge of the epidermis begin to showincreased mitotic activity.   


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

epithelial cells from both edges have begun to migrate andproliferate along the dermis, depositing basement membranecomponents as they progress. The cells meet inthe midline beneath the surface scab, yielding a thin butcontinuous epithelial layer that closes the wound.


What happens in day 3 of first intention healing?

By day 3, neutrophils have been largely replaced bymacrophages, and granulation tissue progressivelyinvades the incision space. Collagen fibers are now evident at the incisionmargins. Epithelial cell proliferation continues, forminga covering approaching the normal thickness of theepidermis. 


As mentioned earlier, ______are key cellular constituents of tissue repair,clearing extracellular debris, fibrin, and other foreignmaterial, and promoting angiogenesis and ECM deposition. 



What happens by day 5 in first intention healing?

By day 5, neovascularization reaches its peak as granulationtissue fills the incisional space.These new vesselsare leaky, allowing the passage of plasma proteins andfluid into the extravascular space. Thus, new granulationtissue is often edematous.Migration of fibroblaststo the site of injury is driven by chemokines, TNF,PDGF, TGF-β, and FGF. Their subsequent proliferationis triggered by multiple growth factors, includingPDGF, EGF, TGF-β, and FGF, and the cytokines IL-1 and TNFThe epidermis recoversits normal thickness as differentiation of surface cellsyields a mature epidermal architecture with surfacekeratinization


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

Macrophages although other inflammatory cells and platelets mayalso produce them.  


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

 The fibroblasts


What happens during the second week in first intention healing?

During the second week, there is continued collagenaccumulation and fibroblast proliferation.The leukocyteinfiltrate, edema, and increased vascularity aresubstantially diminished.The process of “blanching”begins, accomplished by increasing collagen depositionwithin the incisional scar and the regression of vascularchannels. 


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

By the end of the first month, the scar comprises acellular connective tissue largely devoid of inflammatorycells and covered by an essentially normal epidermis.However, the dermal appendages destroyed in theline of the incision are permanently lost. The tensilestrength of the wound increases with time, as describedlater.


What is healing by second intention?

Healing by Second IntentionWhen cell or tissue loss is more extensive, such as in largewounds, abscesses, ulceration, and ischemic necrosis(infarction) in parenchymal organs, the repair processinvolves a combination of regeneration and scarring.In healing of skin wounds by second intention, also knownas healing by secondary union, the inflammatory reaction is more intense, there is developmentof abundant granulation tissue, accumulation ofECM and formation of a large scar, and wound contractionby the action of myofibroblasts.


Secondary healing differs from primary healing inseveral respects: 

• In wounds causing large tissue deficits, the fibrin clot islarger, and there is more exudate and necrotic debris inthe wounded area. Inflammation is more intense becauselarge tissue defects have a greater volume of necroticdebris, exudate, and fibrin that must be removed.Consequently, large defects have a greater potential forsecondary, inflammation-mediated, injury.• Much larger amounts of granulation tissue are formed.Larger defects require a greater volume of granulationtissue to fill in the gaps and provide the underlyingframework for the regrowth of tissue epithelium. Agreater volume of granulation tissue generally results ina greater mass of scar tissue.• At first a provisional matrix containing fibrin, plasmafibronectin, and type III collagen is formed, but in about2 weeks this is replaced by a matrix composed primarilyof type I collagen. Ultimately, the original granulationtissue scaffold is converted into a pale, avascularscar, composed of spindle-shaped fibroblasts, densecollagen, fragments of elastic tissue, and other ECMcomponents. The dermal appendages that have been destroyed in the line of the incision are permanentlylost. The epidermis recovers its normal thickness andarchitecture. By the end of the first month, the scar ismade up of acellular connective tissue devoid of inflammatoryinfiltrate, covered by intact epidermis.• Wound contraction generally occurs in large surfacewounds. The contraction helps to close the wound bydecreasing the gap between its dermal edges and byreducing the wound surface area. Hence, it is an importantfeature in healing by secondary union. The initialsteps of wound contraction involve the formation, at theedge of the wound, of a network of myofibroblasts, whichare modified fibroblasts exhibiting many of the ultrastructuraland functional features of contractile smoothmuscle cells. Within 6 weeks, large skin defects may bereduced to 5% to 10% of their original size, largely bycontraction.


Carefully sutured wounds have approximately 70% of thestrength of normal skin, largely because of the placementof sutures. When sutures are removed, usually at 1 week,wound strength is approximately _____of that of unwoundedskin, but this increases rapidly over the next 4 weeks.  



Therecovery of tensile strength results from the excess of collagensynthesis over collagen degradation during the first2 months of healing, and, at later times, from structural modifications of collagen fibers (cross-linking, increasedfiber size) after collagen synthesis ceases.Wound strengthreaches approximately _______of normal by 3 monthsbut usually does not substantially improve beyond thatpoint.

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 depositionof collagen and other ECM components in a tissue.Asalready mentioned, the terms scar and fibrosis are usedinterchangeably, but fibrosis most often refers to the abnormal deposition of collagen that occurs in internal organsin chronic diseases


What are the basic mechanism of fibrosis?

. The basic mechanisms of fibrosis arethe same as those of scar formation in the skin duringtissue repair. Fibrosis is a pathologic process induced bypersistent injurious stimuli such as chronic infections andimmunologic reactions, and is typically associated withloss of tissue (Fig. 3-31). It may be responsible for substantialorgan dysfunction and even organ failure.


As discussed earlier, the major cytokine involved infibrosis is _______. 

TGF-β.The mechanisms that lead to the activationof TGF-β in fibrosis are not precisely known, but celldeath by necrosis or apoptosis and the production of reactiveoxygen species seem to be important triggers of theactivation, regardless of the tissue. Similarly, the cells thatproduce collagen under TGF-β stimulation may varydepending on the tissue. 


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



______________are the major collagen producers inliver cirrhosis.

stellate cells 


Fibrotic disorders include diverse chronic and debilitatingdiseases 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 discussedin the appropriate chapters throughout the book.Because of the tremendous functional impairment causedby fibrosis in these conditions, there is great interest in thedevelopment 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 formationof a scar can lead to two types of complications:_________

wound dehiscence and ulceration.


Dehiscence orrupture of a wound, although not common, occurs mostfrequently after __________. 

abdominal surgery and is due to increased abdominal pressure Vomiting, coughing, or ileus can generate mechanical stress on the abdominalwound.


Wounds can ulcerate because of ________ 

inadequatevascularization during healing.  For example, lowerextremity wounds in individuals with atheroscleroticperipheral vascular disease typically ulcerate (Chapter11). Nonhealing wounds also form in areas devoid ofsensation. These neuropathic ulcers are occasionallyseen in patients with diabetic peripheral neuropathy


Excessive formation of the components of the repairprocess can give rise to _________ 

hypertrophic scars and keloids.


What is a hypertophic scar?

The accumulation of excessive amounts of collagen maygive rise to a raised scar known as a hypertrophic scar;Hypertrophic scars generally develop after thermal ortraumatic injury that involves the deep layers of thedermis


What  is a keloid formation?

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


What is exuberant granulation?

Exuberant granulation is another deviation in woundhealing consisting of the formation of excessive amountsof granulation tissue, which protrudes above the levelof the surrounding skin and blocks reepithelialization(this process has been called, with more literary fervor,proud flesh). Excessive granulation must be removed bycautery or surgical excision to permit restoration continuity of the epithelium.  


Fortunately rarely, incisionalscars or traumatic injuries may be followed byexuberant proliferation of fibroblasts and other connectivetissue elements that may, in fact, recur after excision.Called _________, or aggressive fibromatoses, theseneoplasms lie in the interface between benign andmalignant (though low-grade) tumors.



Contraction in the size of a wound is an importantpart of the normal healing process. An exaggeration ofthis process gives rise to _______ 

contracture and results indeformities 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 burnsand can compromise the movement of joints.