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Basic Pathology Science Exam > Inflammation and repair > Flashcards

Inflammation and repair Flashcards

1
Q

Should neutrophils be sitting in tissue ready as sentinals?

A

No. They are circulating cells that are recruited by other cells to a site of infection or damage.

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2
Q

What is the prodominant cell type that drives acute respiartory destress syndrome? (ARDS)

A

Neutrophils

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3
Q

What are the cell types that are thought to drive pulmonary fibrosis?

A

Macrophages and fibroblasts

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4
Q

How do the spaces increase between endothelial cells following exposure to chemical mediators like histamine, leukatrienes and bradykinin?

A

Endothelial contraction. Also called the ‘immediate transient response’

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5
Q

What are the steps of leukocyte migration?

A

Margination
Rolling
Activation
Adhesion
Transmigration

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6
Q

What proteins are the proteins predominantly involved in leukocyte rolling?

A

Selectins

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7
Q

What are the proteins predominatly involved in firm adhesion the endothelial wall ready for transmigration?

A

Integrins, optimised by the presence of attractant chemokines

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8
Q

What protein orchestrates transmigration (aka diapedesis) out of the blood vessel for leukocytes?

A

PECAM-1 (aka CD31)
PECAM, confusingly, stands for platel endothelial cell adhesion molecule

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9
Q

What causes endothelial cells to express selectins in greater concentrations and allow leukocyte rolling and adhesion?

A

Macrophage/mast cell/and endothelial cells themselves to a degree produce innate pro-inflammatory cytokines TNF alpha, IL1-beta that predominantly mediate this.

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10
Q

How are the selectins labelled?

A

E-selectin (endothelium) and L-selectin (Leukocyte). Easy.
But also P-selecting - derived frp, Weibel-Palade bodies - which is expressed on endothelial cells later than E and L selecting.

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11
Q

Do selectins (E, L, P) bind to each other?

A

No, they bind to ligands on their counterpart cells. There is an L-selectin ligand on endothelial cells, and an E and P selectin ligand on leukocytes.

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12
Q

What are the main integrin ligands expressed by activated endothelium for binding to leukocyte integrins? What are the leukocyte integrins the bind to?

A

VCAM-1 is the ligand for the Beta-1 integrin VLA-4
Intracellular adhesion molecule-1 (ICAM-1) is the ligand for Beta 2-integrins LFA1 and MAC-1.

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13
Q

What happens to leukocyte integrins when the leukocyte is bound to chemoattractant pro-inflammatory chemokines?

A

They flip from low-affinty form to a high affinty form.

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14
Q

What family of molecules does PECAM-1 belong to?

A

Immunoglobulin (wild)

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15
Q

What pathway terminates in the production of leukotrienes?

A

Arachadonic acid pathway

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16
Q

Which leukotriene is classically considered the most potent chemoattractant?

A

Leukotriene B4

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17
Q

When chemoattractants bind to their recepotrs on leukocytes, what changes in the cytoskeleton to lead to the cell migrating down its concentration gradient?

A

Secondary signal transduction via G-coupled recepotrs lead to actin polymerisation in the direction of the receptor activation

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18
Q

What the extensions that come out of leukocytes called that pull it in thedirection of a chemoattractant?

A

Filopodia

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19
Q

What timeframe do neutrophils usually dominate acutely inflammed tissue for?

A

Between 6-24hrs.

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20
Q

Neutrophils dominate inflammaed tissue in the first 6-24hrs after an insult. What cell type predominates in the 24-48hr period?

A

Monotcytes.

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21
Q

During pseudomonas infection, what is unusually about the resultant inflammation and in particular leukocyte recruitment?

A

Continuous recruitment to the site of inflammation of neutrophils endures well passed the usual 6-24hrs period that occurs in other acute inflammatory scenarios.

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22
Q

With regards to cell recruitment to the site of an insult, what is unique about acute inflammation caused by viral illnesses?

A

Lymphocytes, no neutrophils, may be the first cells to the site of inflammation. This is due to the cytokines produced in response to the infective agent.

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23
Q

In acute inflammation caused by helminth infection - what is the predominant cell type during acute inflammation?

A

Unlike other types of inflammation, the predominent first responding leukocyte is eosinophils rather than neutrophils.

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24
Q

What are the unique features of neutrophils compared with macrophages?

A

Neuts
- secrete lysosomal enzymes more prominantly than macs
- NET (neutrophil extracellular traps) to trap microbes
- degranulate destrictive and vasoactive substances via cytoskeletal arrangement
- short lived

Macs are a more complex coordinating cell
- cytokine production heavy

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25
Q

What ion increases in cytosolic concentration during leukocyte activation?

A

Calcium

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26
Q

How does the mannose phagocytosis receptor delineate between human and invader glycoproteins and glycolipids?

A

N-acetylgalactosamine and sialic acid when in the terminal position of these substances is a human feature - not present on microbes. They interefere with mannose receptor binding.

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27
Q

What are scavenger receptors?

A

Originally described as they play a role in cholesterol metabolism (macs use them to collect VLDLs), but have also been found to be important microbe phagocytosis receptos

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28
Q

Mannose binding lectins and collectins can activate the complement cascade. What else do they do?

A

Phagocytes have MBL/Collecting receptors and can use them as opsonisation to guide the phagocytosis of microbes.

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29
Q

What is the significance of NADPH oxidase in phagocytes?

A

Also known as phagocyte oxidase, it oxidises reduced nicotinadmide-adenine dinucleide phsophate and in the process creates superoxide (O2 sans electron) for use in phagolysosomes to destroy engulfed microbes and other substances. AKA the respiratory burst.

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30
Q

What are the primary reactive oxygen species in neutrophil phagolysosomes?

A

NADPH generates free superoxide (O2 sans electron) which spontaneously becomes H2O2 (hydrogen peroxide). In the presence of myeloperoxidase and chloride ions, H2O2 becomes hypochlorite HOCl (highly destructive). H2O2 also becomes OH minus - very destructive.

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31
Q

Ceruloplasmin and transferrin are known for their copper and iron carrying capacity - what else are they important for?

A

They are both also potent antioxidents.

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32
Q

What disease is associated with dysfunction of the NADPH oxidase (phagocyte oxidase)?

A

Chronic granulomatous disease

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33
Q

Reactive O2 species are important for phagolysosome destructive capabilities. What other reactive species are important in the phagolysosome?

A

Nitrous oxide species. Specifically iNOS (inducible nitrous oxide). Mainly produced by macrophages - not as much in neutrophils.

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34
Q

What are the three subspecies of nitrous oxide?

A

eNOS - endothelial - constituitively expressed to maintain vascular tone
nNOS - neuronal - also important for vascular tone
iNOS - produced by phagocytes (predominantly macrophages) for microbial destroying.

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35
Q

In macrophages, inducible NO species are prodced in response to cytokines or microbial components. What happens to it?

A

It combines with superoxide in phagolysosomes to create peroxynitrite (ONOO sans electron) - very destructive.

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36
Q

Apart from reactive O2 and iNO species, what else is used in neutrophil phagolysosomes to damage microbes?

A

The abdundance of neutrophil primary and secondary granule enzymes (secondary - smaller - lysozyme, collagenase, gelatinase, lactoferrin, lasminogen activator, histaminase, alkaline phosphatase, primary - myeloperoxidase, lysozymes, defensins, acid hydrolases, elastase, cathepsin G, proteinase 3, collagenases).

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37
Q

What is meant by acid vs neutral proteases?

A

The primary granules within neutrophils contain proteases. Some of them work in an acidic environment such as the phagolysosome, and others work in the neutral pH cytoplasmic and extraceullar environments.

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38
Q

When neutral proteases from primary granules of neutrophils get into the extracellular space, what do they do?

A

They are responsible for much of th destruction that occurs in inflammed tissue
- degrade basement membranes
- cleave C3 and C5 leading to furhter recruitment of leukocytes
- kninogen cleavage and subsequen bradykinin production
- attack extracellular microbes

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39
Q

What is the role of alpha-1 antitrypsin?

A

It is the major inhibitor of te neutral protease extracellular neutrophil elastase and is critical to curtailing the destructive potential of neutrophils. This limits the amount of health tissue damage that can be done by activated and dying neutrophils.

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40
Q

What is alpha 2 macroglobulin?

A

Like alpha-1 antitrypsin, it is an anti-protease molecule that appears to protect health tissue from the effects of activated neutrophils.

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41
Q

What is Major Basic Protein?

A

A component of eosinophil granules that is highly toxic to helminths.

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42
Q

What makes up the sticky net of NETs? (neutrophil extracellular traps). What else in the NET?

A

Chromatin and DNA is the sticky meshwork. Dotted throughout are neutrophil granule components for destroying microbes.

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43
Q

What is the initiating step of NET formation by neturophils?

A

The ROS-dependent activation of arginine deaminase occurs. This leads to chromatin descondensation. Other neutrophil destructive enzymes then enter the nucleus to release the crhomatin.

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44
Q

What is a frustrated phagocyte?

A

These are phagocytes who have recognised an extracellular substance that should be phagocytosed but can’t be because it is either too large is in a position where it cannot be surrounded (e.g. immune complexes lodged in a glomerular basement membrane). Under these circumstances, the phagocyte releases large quantities of its destructive granular enzymes near the target rather than phagocytosing it.

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45
Q

Which helper T cell subtype appears to be critical to acute inflammation?

A

Th17 cells seems to play a key role. In pts with dysfunctional Th17 cells, ‘cold abscesses’ form in the skin, and they are more susceptible to bacterial and fungal infections in general.

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46
Q

What do TGF-beta, IL-10 and lipoxins all have in common?

A

They are all antiinflammatory cytokines and molecules that are produced in response to inflammation as a regulatory response to limit the extent of an inflammatory response.

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47
Q

What cells are the primary producers of histamine?

A

Mast cells
Basophils
Platelets

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48
Q

What do prostaglandins do when produced?

A

Vasodilation
Fever
Pain

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49
Q

Are leukotirenes just made by mast cells?

A

No! Made by Mast cells and all leukocytes (granulocytes and agranulocytes). Of a weird note - eos and masts have a unique progenitor

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50
Q

What does platelet activating factor do?

A

Vasodilation
Increased vascular permeability
Improved leukocyte adhesion
Chemotaxis
Degranulation

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51
Q

What are the ‘vasoactive amines’?

A

Histamine and serotonin

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52
Q

What are stimuli lead to mast cell degranulation?

A

Physical injury
Cold and heat
IgE binding to FcEpsilon rececptor
C3a and C5a binding to receptors
Substance P (neuropeptide)
IL-1 and IL-8

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53
Q

What action does histamine have on blood vessels?

A

Dilation of arterioles
Increases the permeability of venules

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54
Q

Where is serotonin for the purposes of inflammation sourced?

A

Platelets mainly
But also present in neuroendocrine cells (e.g. in the GI tract)
It’s used as a neurotransmitter in the enteric nervous system, but also as a vasoconstrictor

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55
Q

What are the largely pro-inflammatory molecules derived from the arachadonic acid cyclooxeganse pathway? What is the influence of each?

A

They are called the prostaglandins.

Prostacyclin - vasodilation
Thromboxane A2 - platelet aggregation, vasoconstriction
Prostoglandin E2 and D2 - vasocilation, increased permeability, WBB chemoattractant.

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56
Q

What arachadonic acid enzyme action is required for the production of prostacyclin, thromboaxane A2 and prostoglandins?

A

Cyclooxeganse (COX) 1 and 2.

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57
Q

Where does arachadonic acid come from? What enzyme is required to produce it?

A

It’s derived from the phospholipid bilayer. It is freed from phopholipid by phospholipase A2.

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58
Q

What influence do corticosteroids have on arachadonic acid production?

A

Corticosteroids inhibit phospholipase A2. Phopholipase A2 frees arachadonic acid from the phospholipid bilayer.

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59
Q

What’s the difference between COX-1 and COX2?

A

COX-1 leads to the production of thromboxane A2 (procoagulant) and prostaglandins that protect the stomach.
COX-2 does not lead to thromboxane A2 inhbition so doesn’t increase bleeding risk, but also doesn’t inhibit the stomach lining protective grostaglandins. COX-2 inhibitors do increase the risk of clotting (IHD, stroke etc).

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60
Q

What enzyme converts arachadonic acid into leukotrienes?

A

5-Lipoxygenase

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61
Q

Leukotriene A4 is the precursor to the active leukotriene’s B4, C4, D4, E4. What doe each of the active ones do?

A

B4 is a chemoattractant for leukocytes and participates in their adhesion.
C/D/E4 all increase vascular permeatbility, and cause bronchospasm.

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62
Q

COX1 and 2 are both involved in inflammation but are not expressed the same in different cell types. How does there distribution look?

A

COX-1 is constitutively expressed in most tissues
COX-2’s expression is confined to cells participating in inflammatory reactions.

63
Q

What do the numbers indicate in the naming of prostagladins? (e.g. PGE2, Thromboxane A2, etc)

A

The number of double bonds in the molecule.

64
Q

Thromboxane A2 precursors require cycloxegenase to synthesise them. What is needed to prodcue the TXA2?

A

Thromboxane synthase, which is really only present in platelets. Know that arachadonic acid pathway products (the eicosinoids) are not only dependent on the presence of COX 1 or 2, but also on the presence of their own specific enzymes that tend to be cell type specific.

65
Q

Where is PGI2 (COX dependent prostaglanin, aka prostacyclin) produced?

A

It is dependent on an enzyme called prostacyclin synthsae, which is abundant in endothelium. This makes sense as it’s role is primarily 1) as a vasodilator 2) as an inhibitor of platelet aggregation. In all, this keeps blood flowing consistently across the endothelium.

66
Q

Where are PGD2 and PGE2, COX dependent prostaglandins, primarily produced? What do they do?

A

Prostaglandins D2 and E2 are produced by Mast cells. When released these vasoactive substances cause vasodilation and increase the permeability of postcapillary venules leading to oedema. PGD2 is also a chemoattractant for neutrophils.

67
Q

What does the 5-lipoxygenase product 5-HETE do?

A

Chemoattractant for neutrophils.

67
Q

Other than leukotrienes, what other eicosanoids are produced through the 5-lipoxygenase arachadonic acid pathway?

A

5-hydroxyeicosatetraenoic acid (5-HETE)
Lipoxin A and B (LXA4/LXB4)

68
Q

In contrast to most of the prostaglandins, and all of the leukatrienes, what do the lipoxins (a non-leukatriene product of the 5-lipoxygenase path of the arachadonic acid pathway) do?

A

They are antiinflammatory by way of inhibiting neutrophil chemotaxis and endothelial adhesion.

69
Q

How does montelukast work?

A

Blocker of leukotriene C/D/E4 recptor CysLT type 1. This receptor on bronchial smooth muscle and epithelium causes marked bronchoconstriction.

70
Q

What is the effect of TNF on macrophages?

A

Activation! Increased microbicidal activity - in part by producing more nitric oxide for use in phagolysosomes.

71
Q

What is the effect of IL-1 on firboblasts and other mesenchymal cells?

A

Fibroblasts produce more collagen
Mesenchymal cells of all types proliferate

72
Q

What are the effects of TNF and IL-1 on T-helper cell maturation?

A

They push cells down a Th17 maturation pathway - the ‘extracellular pathogen’ response.

73
Q

What affect does TNF have on appetitie?

A

Suppression. Continuous elevations in malignancy associated with cachexia. Also induces insulin resistence in skeletal muscles leading to sarcopoenia.

74
Q

CXC, CX3C and CC chemokines differ because the ‘X’ indicates there is 1 or 3 amino acid residues between the first two otherwise conserved cysteine residues. C chemokines don’t even have the second cysteine. How does their function typically differ?

A

The CXC chemokines typically attract neutrophils (e.g. CXCL8, nee IL-8) ! Whereas, the CC chemokines bring the other leukocytes (monos, eos, basos, and lymphocytes) but are less potent overall.
C chemokines just recruit lymphotyes. CX3C chemokines (membrane and soluble forms) just appear to bind T cells and monocytes.

75
Q

What type of receptors bind chemokines?

A

G-coupled receptors

76
Q

What do chemokines become stuck to in the plasma membranes of endothelial cells to attract leukocytes to the site of inflammation?

A

Proteoglycans

77
Q

According to Robins and Cotran, which complement pathway can be directly activated by microbial surface molecules?

A

Alternative pathway. However know that at the time of discovery of the alternative pathway in the 1950s, that LPS an other microbe polysaccarides where known to activate complement via the classical pathway, and the existence of the lecting pathway wasn’t known.

78
Q

Which arm of the arachadonic acid pathway does C5a activate?

A

The lipoxygenase pathway - leading to the production of 5-HETE, leukotrienes and lipoxins.

79
Q

What are the two membrane bound complement regulators anchored by glycophosphatdylinositiol (GPI)?

A

Decay accelerating factor (DAF) - binds C3b and C4b inhibiting C3 convertase formation.
CD59 - inhibits MAC formation

80
Q

Apart from platelet aggregation, what does platelet activating factor PAF do?

A

Vasodilation
Venular permeability

81
Q

Where is the neuropeptides Substance P neurokinin A made and secreted from?

A

Sensory nerves and various leukocytes.

82
Q

What effect does vagal stimulation have on TNF plasma levels?

A

Decreases it. There is a link between the nervous system and inflammation that is likely mediated by neuropeptides (e.g. substance P and neurokinin A).

83
Q

What effect does substance P have on local tissue?

A

Increases vascular permeability

84
Q

What is serous inflammation?

A

Morphological term referring to inflammation with a paucity of cells, but instead a large proportion of serous fluid. E.g. a blister.

85
Q

What is fibrinous inflammation?

A

Morphological term. When vascular permeability is increasesd, larger proteins exit the vascular space and deposit in extravascular spaces. Dense eosinophilic deposits are seen (the proteins that have accumulated in the extravascular spaces). Typical or pleuritis, pericarditis etc.

86
Q

What is suppurative inflammation?

A

Neutrophil rich extravascular space with associated liquifactive tissue necrosis.

87
Q

What does an ulcer describe with regards to light microscopic morphology?

A

A local epithelial defect with caused by the sloughing of inflamed necrotic tissue.

88
Q

What are the 3 possible outcomes of acute inflammation?

A

Healing to normal tissue
Scar
Chronic inflammation

89
Q

Chronic inflammation is characterised by the presence of mononuclear cells (morphological term) - what are these cells?

A

Macrophages, lymphocytes, and plasma cells

90
Q

Mononuclear cells are typically present in areas of chronic inflammation. What else can be seen?

A

Dying cells (necrotic tissue)
Fibroblasts and fibrotic extracellular tissue.
Angiogenesis (immature blood vessels)

91
Q

What is the lifespan of blood monocyte? How does it compare to a tissue macrophage?

A

Monocyte - 1 day
Macrophage - many months

92
Q

What type of cell is a microglia?

A

Tissue macrophage.

93
Q

What are the two types of macrophage activation?

A

Classical (M1) and alternative (M2)

94
Q

What are the way’s the typically lead to classical macrophage activation?

A

Microbial binding to TLRs
Exposure to T cell derived cytokines - importantly INF-gamma.

95
Q

What do classically M1 activated macrophages do?

A

They produce more NO sand lysosomal enzyme to improve phagolysosomal killing. The also secrete more cytokines to attract more inflammatory cells and promote microbial killing further.

96
Q

What causes the alternative activation of macrophages (M2)?

A

Exposure to cytokines other than INF-gamma, notably IL-4 and IL-13.

97
Q

What do macrophages activated in the alternative way (M2 macrophages) do?

A

They are primarily antiinflammatory and promote tissue repair.

98
Q

What key cytokine to Th1 cells produce?

A

INF-gamma

99
Q

What key cytokines do Th2 cells produce?

A

IL-4, IL-5 and IL-13

100
Q

What are the three types of T helper cells described in Robbins?

A

Th1, Th2, Th17

101
Q

What is an immune granuloma?

A

Chronic inflammation structure aiming to contain organism or immune activiting substance. Central macrophages, giant cells (multinucleated), surrounded by activated macrophages, and a ring of Th1 helper T cells, as well as fibroblasts.

102
Q

What is a foreign body granuloma?

A

Chronic inflamatory structure that isn’t drive by T-cell activation. Macrophages surround the structure that is too large to engulf, epithelioid cells sometimes form between the foreing body and the other cells. Giant cels form. No circle of T cells around it.

103
Q

What form of IBD is associated with granulomas?

A

Chron disease

104
Q

Other than tuberculois, what other infections and non-infections can cause granumlatous inflammation?

A

Leposy (mycobacterium leprae) - non-caseating
Syphilis (teponema pallidum) - ‘gumma’ - necrotic centre.
Cat scratch disease (Bartonella henselae) - sellate granulomas, neutrophil involvement, giant cells uncommon
Sarcoidosis - non-caseating granulomas
Crohn disease - non-caseating granulomas.

105
Q

Which prostaglandin is most classically associated with fever?

A

PGE2

106
Q

CRP is a well known acute phase reactant. Do you know any othe liver made acute phase reactants?

A

Albumin (-ve)
Serum amyloid A
Fibrinogen
Hepcidin

107
Q

Most of the acute inflammatory cytokines (IL-1, TNF, and IL-6) stimulate the production of all of the liver made acute phase reactants, but some of these cytokines lead to the production of more of one acute phase reactant than the others. How do they match up?

A

IL-6 -> CRP, fibrinogen
IL-1 -> serum amyloid A
TNF-alpha -> serum amyloid A

108
Q

CRP and serum amyloid A can bind to bacteria and activate complement. What else do they bind to?

A

Chromatin of dead cells. Opsoninses them by activating complement and flags them for phagocytosis.

109
Q

Fibrinogen is an acute phase reactant. What happens to red cells when its concentration in plasma is high?

A

Leads to them sticking together - rouleux formation.

110
Q

The erythrocyte sedmintation rate times the sedimentation of red blood cells. What acute phase reactant is it indirectly measuring?

A

Fibrinogen concentration

111
Q

Chronic inflammation (particularly IL-1 and TNF heavy), leads to the production acute phase reactants from the liver - which of these ends up causing problems systemically?

A

Serum amyloid A (SAA) - deposits lead to secondary amyloidosis. Particularly renal disease.

112
Q

What platelet related growth factor is upregulated in the presence of inflammatory cytokines?

A

Thrombopoeitin

113
Q

Inflammatory states see leukocytosis on blood picture. What causes this?

A

Acute inflammatory cytokines cause increased release rate of white cells from the bone marrow.
Macrophages and marrow stromal cells then produce colony stimulating factors that increase the production of leukocytes.

114
Q

By convention, what do the terms repair and healing mean?

A

Repair refers to the normal fixing of parcnhymal and connective tissues, and healing refers to surface epithelia fixing.

115
Q

When tissue returns to its original form (cf with scar formation), what is the term for this?

A

Regeneration

116
Q

What does the term fibrosis mean?

A

Laying down of collagen by fibroblasts in place of previously damaged tissue

117
Q

What do we call it when fibrosis happens in a space occupied by inflammatory exudate?

A

Organisation (think organising pneumonia)

118
Q

What is meant by labil, stable and permanent tissues?

A

Labile - able to regenerate and constantly undergoing turnover. There a stem cells present.
Stable tissues - G0 non-replicating cells. Typical of most solid organs (liver, kidney, pancreas) but also fibroblasts and endothelial cells. Under the right conditions, they can go back into the cell cycle and replace damaged tissue.
Permanent tissues - terminally differentiated. Cannot regenerate. Typical of neurons and cardiomyocytes.

119
Q

Where do the growth factors stimulating cellular replication come from in injured tissues?

A

Primarily bound to the extracellular matrix and from resident macrophages.

120
Q

In the liver, what cytokine is responsible for priming hepatocytes so they will accept the growth factors required to take them out of senesence (G0) and devide to regenerate the tissue following an injury?

A

IL-6 produced be resident macrophages (Kupffer cells)

121
Q

If liver parenchyma is damaged by infection or inflammation - will it regenerate?

A

No, only after surgical ressection. The chronic inflammatory state impairs the remaining in tact tissue so it cannot regenerate. Instead, the liver will scar.

122
Q

What is a scar?

A

It is collagen. In the skin, it’s collagen at the surface of the skin.

123
Q

Following the elimination of a tissue damage causing entity (e.g. clearacne of an infection, removal of a toxin, etc) 4 cell types move in to take over tissue repair. What are they?

A

Epithelial cells - grow over the wound
Endothelial cells and pericytes - proliferate to form new blood vessels.
Fibroblasts - proliferate and migrate into the site of injury and lay down collagen fibres

124
Q

Granulation tissue and connective tissue deposition are important stages in healing - what comes first?

A

Granulation tissue is an admix of new fragile capillaries, loose ECM with macrophages and other inflammatory cells still in abundance.
Connective tissue deposition comes next with increasing presence of the fibroblasts and collagen production.

125
Q

Which macrophages (classically or alternatively activated, that is M1 or M2) are typically in greatest abundance in the healing wound after the clearance of any microbes?

A

M2 - alternatively activated macrophages. They produce many of the critical cytokines and chemokines needed to activate the endothelial cells, fibroblasta and epithelial cells to close the wound.

126
Q

What are the steps of angiogenesis?

A

1) Vasodilation - usually in response to VEGF or NO
2) Seperation of pericytes - from the abluminal surface and breakdown of the basement membrane to allow formation of the vessel sprout
3) Migration of endothelial cells toward the area of tissue injury
4) Proliferation of endothelial cells just behind the leading fron tip of migrating cells
5) Remodelling into capillary tubes
6) Recruitemnet of periendothelial cells to form the mature vessel
7) Suppression of enothelial proliferation and migration and deposition of the basement membrane.

127
Q

What is the main cytokine responsible for the migration and proliferation of endothelial cells for the purposes of angiogenesis?

A

VEGF-A.
FGF-2 also has an important role in endothelial cell replication.

128
Q

What is the role of fibroblast growth factor 2 (FGF-2) in angiogenesis?

A

Like VEGF-A, it stimulates the proliferation of endothelial cells. It also, however, promotes the migration of macrophages and fibroblasts to damaged areas, and stimulates the proliferation of epithelial cells to cover wounds.

129
Q

What is the role of angiopoeitin 1 and 2?

A

Stabilise newly forming blood vessels and lymphatics. Ang-1 prodcued by mesenchymal cells, Ang-2 produced by endothelial cells.

130
Q

Where do TGF-beta and platelet derived growth factor (PDGF) fit into angiogenesis?

A

They are invovled in the stabilisation of new vessels.
PDGF recruits smooth muscles cells for the vessel wall, and TFG-beta suppresses endothelial proliferation and migration (locking in the shape) and enhances the production of surrounding ECM.

131
Q

What signalling pathway appears to be critical to ensuring that new vessels (during angiogenesis) are spaced correctly to provide adequate nutrients and oxygen?

A

The Notch signalling pathway, stimulated by VEGF signalling initially, dictates the spread of new vessel formation during angiogenesis.

132
Q

What enzyme in the ECM plays an important role in carving a path through the ECM for new vessels during angiogenesis?

A

MMP - matrix metalloproteinases.

133
Q

What cytokines primarily stimulate the fibroblasts to lay down collagen following their arrival to the site of a wound?

A

TGF-beta is hands down the most important for this. However PDGF (platelet derived growth factor) and FGF-2 (fibroblast growth factor - 2) play a role. Mostly synthesised by M2 macrophages, but mast cells and lymphocytes are also capable of repair focussed cytokines.

134
Q

What unusual way is TGF-beta secretion increased at sites of injured tissue?

A

Levels of TGF-beta is regulated by activation of latent intracellular TGF-beta through integrin interactions with the altered extracellular matrix.

135
Q

How does TGF-beta orchestrate the laying down of new extracellular matrix?

A

It binds to receptors on fibroblasts and causes them to synthesize and secrete more collagen and fibronectin.
ALSO, it reduces the destruction of ECM by inhibiting MMPs (matrix metalloproteinases).

136
Q

What is TGF-beta’s effect on circulating lymphocytes?

A

It inhibits their proliferation.

137
Q

Are scars vascular or avascular?

A

Largely avascular. After the granulation tissue is layed down, then the connective tissue lay down process happens (all driven through the new blood vessels needed to bring nutrients and O2 to the site), the blood vessels regress and whats left is a largely avascular blob of collagen and fibroblasts.

138
Q

Over time, what happens to the fibroblasts in scar tissue?

A

They mature further into myofibroblasts, and then cause scar contraction.

139
Q

Why matrix metalloproteinases called METALLO-proteinases?

A

Becuase they relay on metal components for their function (e.g. Zinc).

140
Q

What is the origin of MMPs? (matrix metalloproteinases)

A

Made by fibroblasts, macrophages, neutrophils, synovial cells and some epithelial cells.

141
Q

What is interesting about he secreted state of MMPs? (matric metalloproteinases)

A

They are secreted as zymogens - inactive land mine proteins - in the ECM. The presence of an activating enzyme is needed to activate them and cause them to break down the ECM target.

142
Q

What are the proteins called that inhibit MMPs? (matrix metalloproteinases)

A

Tissue inhibitors of metalloproteinases (TIMPS) - produced by mesenchymal cells to temper MMP activity when they need to lay down scar.

143
Q

What is the primary reason corticosteroids inhibit wound healing?

A

They inhibit the formation of scar tissue by inhibiting the production of TGF-beta! Sometime useful to reduce the chance of scaring a tissue that will lose function if it scars (e.g. the cornea - steroid drops needed)

144
Q

In skin wound healing - what’s the primary difference between first and second intention healing?

A

In first intention healing, the epithelial layer heals first, tissue beneath heals second. In second intention healing, the wound heals from the subepithelial tissue first, then the epithelial tissue heals.

First intention healing is much faster and there is less inflammation involved.

Also wound contraction occurs in healing by secondary intention by the action of myofibroblasts, but doesn’t need to occur in first intention healing as there is only a very small space between the edges of the health tissue.

145
Q

What are the rsik factors for wound dehiscence?

A

Obesity, malnutrition, infection, vascular insufficiency, diabetes.

146
Q

What is a hypertrophic scar?

A

Excess collagen in a scar.

147
Q

What is a keloid scar?

A

A hypertrophic scar, but the collagen deposition has gone outside the bounderies of the wound and does not regress.

148
Q

What types of injuries are more likely to lead to hypertrophic scars?

A

Traumatic and thermal injuries involving deep layers of the dermis.

149
Q

What is ‘proud flesh’?

A

When granulation tissue extends beyond the bounds of normal tissue. It needs to be removed surgically to return the tissue to its normal architecture.

150
Q

What is a desmoid or fibromatoses?

A

Fibroblast tumour at the site of an incision. Somewhere at the interface between benign and malignant tumours.

151
Q

What type of skin healing (1st or 2nd intention) involves more inflammation, granulation tissue, scarring and contraction?

A

2nd intention

152
Q
A

Basic Pathology Science Exam (14 decks)

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