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Inflammation and repair Flashcards

1
Q

Where do circulating cells and plasma proteins go during inflammation

A

they move out of the circulation (they are normally here and moving in the same direction of blood flow) and into the site of injury or infection

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2
Q

List the vascular changes that occur with acute inflammation

A
  1. histamine, prostaglandins and NO cause vasodilation allowing increased blood flow resulting in increased heat and redness
  2. histamine, bradykinin, leukotrienes and cytokines cause increased permeability of the vasculature, allowing protein rich fluid to leave vasculature and enter into extravascular tissues
  3. the loss of fluid out of the vessels and into the extravascular tissues results in more concentrated blood within the vessel (increased viscosity) and slower blood flow
  4. Neutrophils accumulate along the edge of the endothelium and soon migrate through the vessel wall and into the interstitial tissue
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3
Q

what is the hallmark of acute inflammation?

A

increased vascular permeability leading to protein rich fluid escaping into the extravascular tissue.

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4
Q

What is the function of the exudation in acute inflammation?

A

dilute and localize the stimulus

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5
Q

What does the loss of proteins from the plasma result in with acute inflammation

A
  • since the exudate is rich in the protein, it causes an increase in osmotic pressure outside the vessels. this results in fluid moving out of the vessel and towards the protein rich exudate and into the interstitial tissue.
  • this results in edema
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6
Q

Describe the mechanisms of vascular leakage in acute inflammation

A
  1. endothelial contraction: induced by histamine, bradykinin and leukotrienes. causes contraction of cytoskeletal proteins results in gaps between endothelial cells (cells go from being flat to being shorter and rounder)
    • reversible and only last 15-30min
  2. cytoskeletal reorganization: induced by cytokines (IL-1 and TNF). causes the underlying structure of the cytoskeleton to change so that the endothelial cells retract from one another and form intercellular gaps
    • delayed (~2 hrs) and lasts for 3-4 hours
  3. Direct endothelial damage: caused by burns, toxins and chemicals. causes the damaged endothelial cells to become necrotic and detach from one another
    • prolonged response that starts right after injury
  4. Leukocyte-dependent endothelial injury: activated leukocytes adhere to endothelium early in inflammation and release toxic free radical species and proteolytic enzymes causing endothelium injury and detachment
    • lasts several hours
  5. increased transcytosis: induced by VEGF. causes leakage from the blood vessels
  6. leakage from new blood vessels: happens during angiogensis. vessels remain leaky until the endothelial cells mature and form intercellular junctions
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7
Q 
compare exudates and transudates in respect to:
appearance
protein content
etiology/origin
nucleated cells
bacteria presence
A

Appearance: E: turbid/opaque, variable color
T: clear or lightly yellow
Protein content: E: much higher T: much lower
Etiology: E: inflammation
T: hemodynamic imbalance
Nucleated cells: E: much more T: much less
Bacteria: E: sometimes T: never
Exudate requires spaces between the endothelial cells but transudates do not

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8
Q

What type of vessel is primary site for inflammation to occur?

A

venules

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9
Q

what is ascites

A

abdominal transudate

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10
Q

What is the function of inflammation?

A

to activate and deliver leukocytes to the site of injury so that they can ingest offending agents, kill microbes and get rid of necrotic tissue and foreign substance.
Unfortunately, inflammation can also cause more damage and prolong inflammation because the leukocyte products can also injure normal host tissue

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11
Q

Name the steps involved in movement of leukocytes from circulation to inflamed areas

A
  1. margination within the lumen
  2. rolling of leukocytes within the lumen
  3. adhesion of leukocytes to endothelial cells
  4. Diapedesis
  5. Chemotaxis
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12
Q

Describe margination

A

because of the increased permeability allowing the protein rich fluid into the extravascular space and resulting in increased concentration of blood, the blood is more viscous and therefore moves slower.
This allows the neutrophils to accumulate along the vascular endothelium

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13
Q

Describe rolling

A
  • There are P and E-selectins on the endothelial surface, which have a low affinity for binding the neutrophil.
  • the selections bind to carbohydrate ligands that are on the leukocytes but the leukocytes may still detach because of the pressure of the blood moving them along. They will them attach again => this results in the rolling mechanism
  • histamine ad thrombin stimulate P-selectin proteins to go to the endothelial surface
  • TNF and IL-1 cause E-selectin proteins to go to the surface of the endothelial cells
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14
Q

Describe adhesion of the leukocyte to the endothelial cells

A
  • TNF and IL-1 induce the endothelial cells to express ligands for integrins on the leukocytes (mainly ICAM-1 (leukocyte molecule: integrin b1) and VCAM-1 (leukocyte molecule: integrin b2))
  • normally the leukocytes express integrins that are in low affinity state but once they are activated, they become high affinity and allow firm attachment to the ligands on the endothelial cells.
  • the leukocytes stop rolling, the cytoskeleton is reorganized and the endothelial surface is spread out

note: the type of inflammatory cell that is recited to the site of injury depends on the type of chemokine that is attached to the endothelium

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15
Q

Describe Diapedesis of leukocyte through the endothelium

A
  • chemokines act on leukocyte and stimulate them to migrate through the inter endothelial space and towards the chemical concentration gradient at the inflamed site
  • when the leukocyte reached the inter endothelial space, CD31 on the neutrophil binds to CD31 on the endothelial junction, resulting in an “exit signal”
  • this allows the neutrophil to squeeze through the junction.
  • once in extravascular connective tissue, leukocytes are able to adhere to the extracellular matrix by b1 integrins
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16
Q

What happens if you are leukocyte adhesion deficient? (LAD)

A

then the leukocytes won’t be able to be stopped when they are within the vessel and there fore they won’t be able to move through the endothelial junctions to the site of injury.
-there will still be stimulus telling the body that there needs to be the production of leukocytes (since non have reached the site of injury) so there will be an excess amount within the blood stream

animal will have a hard time dealing with infections

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17
Q

How does your body know what type of leukocyte is needed for the infection?

A
  • the type of leukocyte varies with age of inflammatory response and type of stimulus
  • acute inflammation: neutrophils mostly
    - first 4-6 hours of inflammation
  • at 24-48h mark, the neutrophils are replaced by monocytes/ macrophages
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18
Q

Why are neutrophils generally the first leukocyte to the site of inflammation?

A
  1. there are lots in the blood
  2. they respond rapidly to chemokines
  3. they attach more firmly to adhesion molecules that are on endothelial cells
  4. after entering the tissue, neutrophils don’t last very long until they undergo apoptosis. Monocytes last longer
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19
Q

Name 2 exceptions to when neutrophils are not the first leukocyte to the site of inflammation

A
  1. viral infections have lymphocytes at the site of inflammation first
  2. with hypersensitivity reactions, eosinophilic granules are the first cell to the site of inflammation
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20
Q

Describe Chemotaxis

A
  • it is the directed movement of cells towards a chemical gradient
  • stronger stimulus causes the cell to move towards it opposed to towards a different stimulus
  • there are both exogenous (bacterial products) and endogenous (complement or lipoxygenase pathway) that can act as a chemoattractant
  • there are normally more receptors for chemokines that are occupied on one side of the cell, which provides a chemotactic direction (cell is polarized)
  • the leukocyte moves by extending a pseudopodia that will pull the cell towards the chemoattractant
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21
Q

Describe leukocyte activation

A
  • induced by microbes, necrotic cells, antigen-antibody complexes and cytokines
  • activation increases the cytosolic calcium and activation of enzymes like protein kinase C and phospholipid A2
  • responses include:
    1. modulation of leukocyte adhesion molecules
    2. production of arachidonic acid metabolites from phospholipids because of activation of phospholipase A2
    3. degranulation and secretion of lysosomal enzymes and activation of oxidative burst
    4. secretion of cytokines that amplify and regulate inflammatory reactions
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22
Q

What are the 3 main stages of phagocytosis?

A
  1. recognition and binding of leukocyte to the particle that needs to be ingested
  2. particle engulfment by formation of the phagosome
  3. killing and degrading the ingested material
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23
Q

Describe the recognition and binding process of phagocytosis

A
  • phagocytosis is initiated when the receptors on the leukocyte recognize the foreign particle
  • when the microbe is opsonized, phagocytosis is enhanced. Opsonization is when the foreign particle is surrounded by an opsonin, such as IgG antibodies, complement protein C3b, mannose binding lectin or C reactive protein.
  • if not opsonized, the microorganism is recognized by PAMPs on its surface. TLRs on the leukocytes recognize the PAMPs on the microorganism
  • when leukocytes recognize these, there is a release of chemokines and cytokines, which initiate an acute inflammatory response
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24
Q

Describe the engulfment process of phagocytosis

A
  • binding of the particle with the leukocyte receptor initiates active phagocytosis
  • the leukocyte extends a pseudopod around the foreign particle, resulting in complete enclosure of the particle within the phagosome
  • the phagosome fuses with the membrane of a lysosome, releasing its lysosomal contents into the phagolysosome
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25
Q

Describe the process of killing of the particle when it comes to phagocytosis

A
  • microbial killing is mostly accomplished by oxygen dependent mechanisms when phagocytosis stimulates the production of reactive oxygen species
  • the H2O2-MPO-halide system is the most efficient method to killing by neutrophils
  • the MPO deficient leukocytes can kill bacteria by the formation of a superoxide and hydroxyl radicals but it is slower

oxygen independent killing:

  • BPI increases the permeability of the outer membrane of the microorganism
  • lysozyme causes hydrolyzation of bacterial wall
  • eosinophilic basic protein is cytotoxic to many parasites
  • defensins are cytotxic to microbes
  • lactoferrin supresses bacterial growth by binding and releasing iron
  • enzymes contribute to microbial killing
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26
Q

Describe how killed particles are degraded in the phagocytosis process

A
  • lysosomal acid proteases degrade the microbes within the phagolysosomes
  • following phagocytosis, neutrophils undergo apoptosis and are ingested by macrophages
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27
Q

What is a problem with inflammation?

what is this called?

A
  • it can cause damage to self cells and break down tissue by leukocytes releasing enzymes from the phagolysosome into the extracellular matrix
  • frustrated phagocytosis
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28
Q

Name and describe 2 of the most important lysosomal substances that can cause tissue injury during inflammation
How is it prevented?

A
  1. lysosomal enzymes: neutral proteases degrade extracellular components resulting in tissue destruction. This is handled by the tissue fluid and serum releasing antiproteases
  2. Reactive oxygen intermediates: activated leukocytes release oxygen derived free radical into the extracellular matrix. when low levels are released, there is an increased inflammation response. But when high amounts are released there is tissue damage from:
    • endothelial damage causes increased permeability to vessels (results in edema)
    • inactivation of antiproteases, resulting in more protease action (destructing extracellular matrix)
    • membrane injury of other cell types.
      • tissue fluids and host cells release antioxidants to protect the host from oxygen free radicals
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29
Q

List some attributes of chemical mediators of inflammation

A
  1. huge number of them
  2. they are short lived
  3. interactive
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30
Q

Why are chemical mediators short lived ?

A
  1. they decay quickly
  2. they are inactivated by enzymes
  3. they are scavenged (ex/ antioxidants)
  4. they are inhibited
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31
Q

What 3 plasma derived mediators in inflammation?

A
  1. complement
  2. kinins
  3. coagulation proteins
    - they are present in plasma in precursor forms and they need to be activated
32
Q

what is the complement system?

A
  • proteins that are produced in the liver and secreted into the plasma
  • functions in both innate and adaptive immunity to defend against microbials
  • the proteins are activated by and become proteolytic enzyme which go on to activate other complement proteins, causing a cascade and amplification effect
33
Q

What is the critical step in the activation of complement?

What are 3 ways of doing this?

A
  • activating C3
    1. Classical pathway: antibody and antigen combine and activate C1 which goes on to help activate C3 convertase, which will activate C3
    2. Alternative pathway: microbial surface of molecule comes in contact of C3 and activates it (no antibody involved)
    3. Lectin pathway: plamsa mannose binding lectin binds to the carbohydrates in the microbe and directly activates C1, which will then produce C3 convertase and activate C3
34
Q

Describe the process of complement

A
  • once C1 is activated by one of the 3 ways, it results in the formation of C3 convertase (which is an active enzyme). C3 convertase splits C3 into C3b and C3a.
  • C3a is released but C3b stays attached to the cell that complement is acting on
  • C3b binds to the previously generated fragments (from the classical and alternative pathway) to form C5 convertase. This then cleaves C5 to release C5a and keep C5b
  • C5b binds C6-C9 forming the MAC
35
Q

What are 4 biological functions of the complement system?

A
  1. Vascular phenomena: C3a and C5a stimulate histamine release from mast cells, which will increase vascular permeability and cause vasodilation -“anaphylatoxins”
  2. Chemotaxis: C5a is a chemotactic agent for neutrophils, monocytes, eosinophils and basophils
  3. Phagocytosis: C3b gets fixed to the bacterial cell wall and acts as an opsonin, which will cause increased phagocytosis by neutrophils and macrophages
  4. Cell lysis: MAC forms a channel in lipid membranes which allows fluid and ions to enter and cause cell lysis
36
Q

How is complement activation controlled? ( 3 ways)

A
  1. regulation of C3 and C5 convertase by regulatory proteins. these proteins enhance the speed of dissociation of convertase complex or proteolytically cleave C3b
  2. C1 activation is blocked by C1 inhibitor
  3. excessive complement activation is prevented by proteins that inhibit MAC formation
37
Q

What happens when the Kinin system is activated?

A
  • results in the release of bradykinin, which results in:
    • vasodilator
    • increases vascular permeability (because of the increased release of histamine)
    • produces pain
38
Q

Describe the Kinin system

A
  • activation of factor XII occurs when it is in contact with negatively charged surfaces (such as LPS on microbes), which results in the production of kinin.
  • also, activated factor XII converts plasma prekallikrein into kallikren, which cleaves kininogen to produce bradykinin
  • Kallikrein itself also activates factor XII, which allows an autocatalytic amplification
39
Q

What 4 mediator systems does activated factor XII activate?

A
  1. Kinin cascade - produce bradykinin
  2. Clotting cascade - resulting in the formation of thrombin and fibrin
  3. complement cascade - producing anaphylatoxins (C3a and C5a)
  4. fibrinolytic system - Kallikrein producing plasmin to break down fibrin
40
Q

How are cell derived mediators normally released?

A

-by intracellular granules that need to be secreted or are synthesized de novo in response to a stimulus

41
Q

What are some major sources of cell derived mediators?

A
  • platelets
  • neutrophils
  • monocytes/macrophages
  • mast cells
  • mesenchymal cells
42
Q

Describe histamines functions in being a cell derived mediator

A
  • histamine is within granules within mast cells**, blood basophils and platelets
  • it is one of the first mediators to be released during inflammation
  • histamine is released when:
    • physical injury (cold, trauma or heat)
    • immune reactions that involve antibodies binding to mast cells
    • anaphylatoxins
    • cytokines (IL-1, IL-8)

-causes arteriole dilation and increased permeability of venules causing endothelial gaps…. which results in redness and swelling

43
Q

Describe arachidonic acid metabolite function in terms of cell derived mediators

A
  • produced by platelets, endothelial cells and leukocytes during the remodelling of the plasma membranes
  • AA metabolites (“eicosanoids”) synthesize cyclooxygenases (COX) and lipoxygenases. Eicosanoids bind to many cell types and mediate almost every step in acute inflammation
44
Q

Describe cytokines and how they are involved in cell derived mediators
What are the two major cytokines that mediate inflammation?

A

-they are proteins that are produced by many cell types and they change the function of many cell types

  • > TNF and IL-1
  • they are produced by macrophages when they are activated by LPS, immune complexes or physical injury
45
Q

List and describe the most important effects of TNF and IL-1 on inflammation

A
  1. endothelium: they induce the production of endothelial adhesion molecules, cytokines, chemokines and eicosanoids and chemical mediators and they increase the thrombogenicity of the endothelium (procoagluation)
  2. induce the secretion of cytokines by leukocytes and TNF and they also prime the neutrophils
  3. induce fibroblastic proliferation, collagen synthesis and production of proteases
  4. induce systemic acute phase responses associated with infection or injury (fever, reduced appetite, increased sleep)
46
Q

Describe how chemokines are involved in cell derived mediators

A

-act as chemoattractants for specific types of leukocytes
ex/ IL-8 activated by macrophages and endothelial cells and causes the activation and chemotaxis of neutrophils
-MIP-1a attracts monocytes, eosinophils, basophils and lymphocytes
-eotaxin selectively recuits eosinophils

47
Q

What are 3 outcomes of acute inflammation?

A
  1. complete resolution
  2. Healing by fibrosis
  3. progression of tissue response to chronic inflammation
48
Q

Describe complete resolution when it comes to acute inflammation

A
  • happens when the injury is limited or when the damaged parenchymal cells can regenerate
  • involves neutralization or decay of chemical mediators, return of normal vascular permeability, no more leukocyte infiltration, apoptosis of neutrophils and removal of extra stuff from site
  • phagocytes and lymphatics play a major role
49
Q

Describe healing by fibrosis when it comes to acute inflammation

A
  • occurs after substantial tissue destruction (which needs to be removed and repaired), when the injury involved tissues that are incapable of regeneration or when there is abundant necrotic tissue or fibrin exudation
  • when it cannot be adequately cleared, granulation tissue grows into the area of exudate and converts it into a mass of fibrous tissue
50
Q

How does NO contribute to cell derived mediators?

A
  • it is a vasodilator that causes relaxation of vascular smooth muscle
  • NO free radicals are toxic to microbial and mammalian cells though
  • causes reduced platelet aggregation and adhesion
51
Q

Describe progression of the tissue to chronic inflammation

A

-may follow acute inflammation when it cannot be resolved because there is persistent injury or because there is interference with the normal healing process

52
Q

What is chronic inflammation?

A
  • inflammation of prolonged duration with active inflammation, tissue destruction and repair attempts all happening at the same time
  • may follow acute inflammation or may start out as chronic inflammation
53
Q

What are some causes of chronic inflammation?

A
  • persistant/resistant infection that the body can’t get rid of
  • granulomatous inflammation or pyogenic infections forming abcsesses
  • autoimmune disease and foreign material reactions
54
Q

What are morphological features of chronic inflammation?

A
  1. mononuclear infilltration - macrophages, lymphocytes and plasma cells
  2. tissue destruction because of persistent offending agent or by inflammation
  3. tissue repair via proliferation of small blood vessel (angiogensis) and fibrosis
55
Q

Describe macrophages and their role in chronic inflammation

A
  • dominant cell in chronic inflammation
  • originate as blood monocytes (short 1/2 life) but differentiate into macrophages (life span in tissue months to years) when the monocyte reaches the extracellular tissue
  • “weapons” include:
    • lysosomal oxygenase-dependent and independent toxic products
    • secretion of cytokines and chemokines causing more inflammatory cells to come
    • secretion of growth factors causing angiogenesis and fibrosis
56
Q

Describe lymphocytes and plasma cells and their role in chronic inflammation

A
  • lymphocytes are involved in both innate and acquired immune reactions
  • lymphocytes and macrophages interact in a bidirectional way: macrophage presents an antigen to the T cell and produces cytokines, which activate the t cell. the activated T cell produced cytokines which stimulate the macrophages
  • plasma cells develop from activated B lymphocytes and produce antibodies against the persistent antigen in the inflammatory site
57
Q

Describe granulomatous inflammation and its role in chronic inflammation

A
  • forms with chronic inflammation
  • dominated by epithelioid macrophages
  • doesnt have a capsule
  • it may or may not have a centre of caseous necrosis, it is surrounded by epithelioid macrophages (often with giant cells) and it also has lymphocytes, plasma cella and fibroblasts
58
Q

What is acute phase response in regards to inflammation?

A
  • it is an adaptive component of the innate defense.
  • it takes priority over homeostasis within the body when there is a severe disturbance
  • predominately mediate by IL-1, TNF and IL-6
  • some clinical signs include fever, anorexia, sleepiness, lack of appetite
59
Q

Describe how fever is involved in acute phase response of inflammation

A
  • most prominent clinical sign, especially when inflammation is associated with the infection
  • it is produced in response to pyrogens, which can be exogenous (LPS) or endogenous (IL-1 or TNF)
  • pyrogens cause the production of prostaglandins within the hypothalamus which will stimulate the production of neurotransmitters and reset the temperature set point to a higher level within the body
  • this may help mammals fight off the microbial infection or it may induce heat shock proteins
60
Q

Describe how acute phase proteins are involved in acute phase response of inflammation

A
  • they are produced by the liver, whose plasma concentrations are altered by at least 25% when the mammal is sick
  • positive acute phase proteins are increased because they are important in host protective anti-inflammatory or antimicrobial functions
  • negative acute phase proteins are decreased because they are associated with the maintenance of homeostasis
  • some include:
    • opsonins: increase phagocytosis
    • proteinase inhibitors: regulate complement, coagulation and fibrinolytic cascade and inactive proteinases released from leukocytes
      • metal binding proteins:transferrin, haptoglobin and ceruloplasmin - copper and iron are important for enzymes and metabolic mechanisms
    • coagulation and complement proteins: C3, C4, fibrinogen

-clinical importance is that is large animals you can measure fibrinogen concentrations to see if there are acute phase response

61
Q

Describe how leukocytosis is important in acute phase response in inflammation

A
  • when there is an increase in WBC to deal with the inflammation
  • there may be a left shift because there is an accelerated release of cells from the bone marrow reserve pool and there fore more neutrophils in the blood
  • with prolonged infections there may be increased amount of precursors in the bone marrow because the bone marrow is trying to put out as many cells into the blood stream that is can so it can keep up with the infection
  • common feature especially with bacterial infection
62
Q

What are the two processes of repairing tissue?

A
  1. regeneration: restoring the tissue to its original state with complete restitution of structure and function
  2. Scarring/fibrosis: when repair cannot occur and injured tissues are held together by fibrosis connective tissue
63
Q

Describe the stimulus that are needed for regeneration

A
  • need chemical messengers such as growth factors and cytokines which can stimulate or inhibit cell proliferation of normal or injured tissue
  • within hours the viable parenchymal cells undergo alterations that stimulate early regenerative change
  • 3 types of signalling are:
    1. autocrine signaling: cells respond to signalling molecules that they secrete forming an autocrine loop
    2. Paracrine signalling: one cell produces the ligand which acts on adjacent target cells that express appropriate receptors (CT repair)
    3. endocrine signalling: hormones synthesized by cells and act on target cells that are distant from the site of synthesis (n travel via blood)
64
Q

What are the requirements of regeneration?

Name and briefly describe them

A
  1. debridement: removing the necrotic tissue by sloughing or phagocytes from the inflammation
  2. preservation of tissue scaffold: needed for the parenchyma cells to grow on. Need to have the basement membrane or the extracellular matrix
  3. available blood supply: needed for nutrition. normally associated with the presence of the scaffolding
  4. survival of germinal cells: need to have cells capable of mitosis

if any of these are missing, regeneration will NOT occur

65
Q

What are the 3 groups of tissue proliferative activity?

Name and briefly describe

A
  1. Labile tissue: tissue that is continuously proliferating throughout life and is able to replace the cells that are lost. N derived from stem cells, have unlimited capacity to proliferate and can have options for differentiation (ex/ stratified squamous epithelium, mucosal epithelium or hematopoietic tissue)
  2. Stable tissues: have a lower level of replication. They can undergo rapid division in response to stimuli so may be able to reconstitute the tissue of origin. (ex/ parenchymal cells in liver, kidney and pancreas)
  3. permanent tissues: have only non dividing cells so none are able to undergo mitotic division (ex/ neurone and cardiac muscle)
66
Q

What are the morphological events of epithelial regeneration?

A
  • epithelial sliding along the basement membrane occurs within minutes or hours if initial loss of epithelial continuity
  • cellular proliferation occurs to repopulate the lost epithelial cells
  • maturation and normalization takes several weeks
67
Q

What are some examples of regeneration?

A
  1. superficial corneal ulceration: start with a superficial ulcer and you get edema in the cornea. Get epithelial sliding then proliferation and then maturation =regeneration
  2. atrophy of sm intestinal villi (corona virus): when columnar cells die, the surrounding cells flatten out to fill in gaps causing villi atrophy
  3. epithelial erosions (FMD, IBR): get a vesicle form, then it ruptures and then starts to regenerate if not invaded by bacteria
  4. compensatory hepatic hyperplasia: you liver regenerates (why we can donate some of liver and it will geo back but won’t be exactly the same)
68
Q

Describe repair by scar formation and fibrosis

A
  • this is what happens the majority of the time
  • can start as early as 48 hours after injury.
  • fibroblasts and vascular endothelial cells begin proliferating to form granulation tissue, which grossly looks pink, soft and granular but histologically there is the formation of new blood vessels and proliferation of fibroblasts
  • the new vessels are leaky so they allow the passage of proteins and RBC into the extravascular space. also edematous
69
Q

describe how angiogensis contributes to scar formation and fibrotic repair

A
  • it is the process of new blood vessel formation
  • can form from pre-existing vessels which occur in these steps:
  • NO causes vasodilation, increasing the permeability of vessels (from VEGF which is secreted by fibroblasts)
  • proteases degrade the vascular basement membrane
  • endothelial cells migrate towards the angiogenic stimulus
  • get proliferation of endothelial cells
  • maturation and remodelling of endothelium into capillary tubes
  • recruitment of periendothelial cells to support the endothelial tubes and form mature vessels
70
Q

describe the 3 processes that are involved in scar formation

A
  1. fibroblast migration and proliferation into the site of injury-> granulation tissue has many new vessels because VEGF promotes angiogenesis and vascular permeability. this allows plasma protein deposition in ECM.
    - migration to site of injury is triggered by growth factors that are released by fibroblasts
  2. ECM deposition and scar formation causing decreased proliferating endothelial cells and fibroblasts, increased deposition of ECM by fibroblasts (strengthens healing wounds), decreased vascular component of granulation tissue, fibroblasts maturing to fibrocytes
    - granulation tissue scaffolding is converted into a scar composed of fibroblasts
  3. tissue remodelling by balancing between the ECM synthesis and degradation
71
Q

What are the 3 stages of cutaneous wound healing

A
  1. inflammation
  2. granulation tissue formation and reepithlialization
  3. wound contraction, ECM deposition and remodeling
72
Q

What is healing by first intention?

A
  • healing of a clean, uninfected surgical incision
  • narrow incision space fills up with clotted blood (w fibrin and blood cells)
  • w/in 24h neutrophils are at margins of incision and move toward clot
  • 24-48h spurs of epithelial cells move from wound edges along the cut margins of dermis and meet at midline under the scab
  • 3d neutrophils replaced by macrophages and granulation tissue replaces incision space
  • 5d incision space filled with granulation tissue
  • 2w continued accumulation of collagen and proliferation of fibroblasts
  • 1m scar is made up of cellular connective tissue covered by intact epidermis
73
Q

What is healing by second intension?

A
  • when there is a larger wound so more loss of tissue and cells
  • stages are all fairly similar as 1st intension except there is more granulation tissue that has to be produced to allow the healing and there fore the scar formed is larger
  • also, it takes longer to do each step
74
Q

how does wound strength progress with time?

A
  • at the end of 1w the wound is about 10% the strength of unwounded skin.
  • 3m the wound strength is as strong as it is going to be, which is 70-80% of unwounded skin
75
Q

What are some complications of wound healing?

A
  • wound dehiscence: suture break open because there is too much tension on the incision or it is a highly mobile area. this results in deficient scar formation and formation of granulation tissue. it may also lead to ulceration
  • exuberant granulation tissue: when there is an excessive amount of granulation tissue and it protrudes above the level of surrounding skin so it blocks the ability of surrounding skin to heal –> proud flesh!
  • fibrous adhesion: adhesion between visceral and parietal layers of tissues (ex/ hardware disease)
  • hepatic cirrhosis: when there is massive necrosis or chronic inflammation or toxicity. often fatal because you do not have a functional liver anymore

Gen Path (10 decks)

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