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PATH30001 Mechanisms of Human Disease > L3 07 Mar 2019 > Flashcards

L3 07 Mar 2019 Flashcards

Cells and Molecules in Healing

1
Q

labile tissues

A

constant proliferation for high cell turnover (e.g. haematopoietic cells, surface epithelia)

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2
Q

stable tissues

A

quiescent, but can be activated for proliferation (e.g. parenchyma of most solid organs, endothelial cells, fibroblasts, smooth muscle cells)

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3
Q

permanent tissues

A

no proliferation, irreversible injury and repair leads to scar formation (e.g. majority of neurons, cardiac muscle cells)

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4
Q

functions of biochemical factors released in response to cell injury, cell death or trauma

A
  • MOST IMPORTANT: induce resting cells to enter cell cycle
  • balance of stimulatory and inhibitory factors - regulation
  • shorten cell cycle - faster cell division inhibit apoptosis - decrease rate of cell losee
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5
Q

the two main types of healing

A

regeneration and connective tissue deposition (scar formation)

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6
Q

regeneration

A

proliferation of cells, survives injury, maintains function, and still has ability to proliferate and maintain stem cells

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7
Q

connective tissue deposition (scar formation)

A

deposition of new connective tissue (structural stability)

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8
Q

Repair is a balance of regeneration and connective tissue deposition. TRUE or FALSE

A

TRUE, they work together to achieve varying degrees of repair involving proliferation, differentiation, migration and communication of various cells and extensive interaction with the ECM

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9
Q

What is the purpose of remodelling scar tissue?

A

to return to homeostasis

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10
Q

methods to regulate/activate cell proliferation

A
  • cell-cell contact
  • cell-ECM interaction
  • paracrine or autocrine factors
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11
Q

PI3 pathway

A

growth factor attaches to receptor with intrinsic tyrosine kinase activity –> PI3 kinase attaches to receptor and PI3 pathway is activated with the Akt (PKB) ligand –> affects transcription factor –> proliferation

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12
Q

MAP-kinase pathway

A

growth factor attaches to receptor –> activation by phosphorylation via extracellular kinases –> activates MAP kinas cascade –> RAS compound attaches to RAF –> MEK –> ERK –> ERK breaks into nucleus and affects transcription factors –> multiple functional effects

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13
Q

cAMP pathway

A

GPCR attaches to intracellular proteins (including G-proteins) –> cAMP pathway –> cAMP –> multiple effects

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14
Q

JAK/STAT pathway

A

cytokines attach to receptors w/o intrinsic tyrosine kinase activity –> JAKs interact with receptor –> JAK/STAT pathway –> STATs directly bind to DNA –> multiple effects

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15
Q

EGF

A

epidermal growth factor: from activated macrophages mitogenic for keratinocytes & fibroblasts, stimulates keratinocyte migration; stimulates formation of granulation tissue important for first stages of healing

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16
Q

TGF-α

A

transforming growth factor-α: from activated macrophages and keratinocytes stimulates proliferation of hepatocytes and other epithelial cells

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17
Q

HGF

A

hepatocyte growth factor (scatter factor): from fibroblasts mitogenic for epithelial cells (not just hepatocytes) causes cell migration (therefore scatter factor) required for survival during embryogenesis

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18
Q

VEGF

A

vascular endothelial growth factor: from mesenchymal cells angiogenesis, VEGF-A for neoangiogenesis, bind to receptors on endothelial cells

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19
Q

PDGF

A

platelet derived growth factor: from platelets, macrophages, endothelial cells. smooth muscle cells, keratinocytes regulate inflammation, activation of fibroblast in first steps of healing

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20
Q

FGF

A

fibroblast growth factors (including acidic, FGF-1, and basic, FGF-2): activation of fibroblasts

21
Q

what is the significance of GFs that activate fibroblasts?

A

they have the ability to regulate formation of ECM and healing of tissues

22
Q

what are the two components of the ECM?

A

interstitial matrix and basement membrane

23
Q

interstitial matrix

A

in connective tissue, synthesised by mesenchymal cells, forms amorphous 3D gel contains: collagens, fibronectin, elastin, proteoglycans, hyaluronate

24
Q

basement membrane

A

highly organised, support and holds up epithelial cells, endothelial cells and smooth muscle cells contains: non-fibrillar type IV collagen and laminin

25
Q

what kind of thing creates the ECM

A

fibroblasts or mesenchymal cells

26
Q

structural fibers of the ECM

A

elastin, fibrillin, elastic fibres: provides elasticity

27
Q

functions of ECM in tissue repair

A
  • ECM regulates cell proliferation, locomotion, differentiation
  • provides: mechanical support, control of cell proliferation and scaffolding
28
Q

ECM maintains cell polarity. What is the importance of this?

A

Cell polarity is used in differentiation in cells (sometimes or always? idk?) and loss of polarity may (or will) trigger carcinogenesis

29
Q

adhesive proteins in ECM and cell-matrix interactions

A
  • Cell surface integrins interact with cytoskeleton at focal adhesion complexes
  • Can initiate production of intracellular messengers or can directly transduce signals to nucleus
  • Cell surface receptors for growth factors can activate signal transduction pathways that overlap with those mediated through integrins
  • Signals from ECM components and growth factors can be integrated by cells to produce a given response, including changes in proliferation, locomotion, and/or differentiation.
30
Q

proteoglycans

A
  • made up of core protein + polysaccharides (GAGs)
  • negative charge, large volume, hydrophilic
  • in all ECM, on cell surfaces and in biological fluids
  • regulates connective tissue structure and permeability
  • modulates cell growth and differentiation (esp. fibroblasts)
31
Q

examples of proteoglycans

A

heparan sulphate and chondroitin sulphate - molecules for skin hydration

32
Q

regulation of neoangiogenesis

A
  • other endothelial cells (VDGFs, PDGF, NO, prostaglandins (PGs))
  • ECM (once broken) - integrins and collagen debris
  • Inflammatory cells (PGs, angiopoietins (ang), COX, NO, inflammatory cytokines)
  • GF from activated cells
33
Q

fibroplasia

A

deposition of collagen by activated fibroblasts to regenerate structure of the tissue

34
Q

granulation tissue

A

has neoangiogenesis occuring, there is a new ECM and provides scaffolding for healing

35
Q

maturation of wounds

A
  • vascular granulation tissue leads to avascular scar, via growth factors
  • a new ECM is synthesised and old ECM (used during granulation tissue) is destroyed in favour of a more mature ECM - important because repair is about return to homeostasis
36
Q

Liver regeneration phases

A
  • priming phase: cytokines (IL-6 and Kupffer cells) act on hepatocytes to make them more receptive of GFs
  • growth factor phase: HGF and TGF-α act on primed hepatocytes, during this phase more than 70 genes are activated
  • termination phase: cells return to quiescence
37
Q

During liver regeneration all cells can be regenerated. TRUE or FALSE

A

FALSE. but is a high percent (much higher when compared to other organisms) 90%

38
Q

healing molecular mechanisms

A
  • wounding-proliferation-migration-synthesis-remodelling
  • ligand+receptor (cell membrane)-2nd messenger cascade (cytoplasm)-transcription factor activation (nucleus)-gene expression (nucleus)-healing
39
Q

What is the importance of the 2nd messenger cascades?

A

part of proliferation; signal transduction = MAP-kinase also includes PI3Km JAK/STAT and cAMP

40
Q

cellular environment in healing

A
  • non-cellular interstitium/matrix (ECM)
  • inflammatory cells: fibroblasts, endothelial cells, epithelial cells and stem cells
41
Q

why are cell interactions with ECM important for healing?

A

regulates cell proliferation, migration and differentiation

42
Q

steps of cutaneous wound healing

A
  • INFLAMMATION: wounding activates coagulation pathway, clot stops bleeding plus protects wounded area; macrophagesrelease proteolytic enzymes and begin to clear debris
  • PROLIFERATION: neutrophils replaced by macrophages, granulation tissue is synthesised by activated fibroblasts (ECM), neoangiogenesis, epithelial cells proliferate and migrate over granulation tissue
  • MATURATION: leukocytes, oedema and angiogenesis diminishes, scar formation
43
Q

haemostasis in inflammatory phase

A
  • platelet aggregation + release of fibrin
  • cytokines, chemokines, and hormones
  • vasoconstriction
  • platelet aggregation+vascular leaking=clot formation
  • platelet activation=degranulation
  • release of chemotactic and growth factors (PDGF, proteases, vasoactive agents, serotonin and proinflammatory cytokines e.g. histamine)
  • chemokines attract inflammatory cells
44
Q

acute inflammation in inflammatory phase

A
  • injured blood cells leak transudate = oedema
  • increased porosity of blood vessels= entry of inflammatory cells into wound site
  • inflammation prevents infetion - things are removed from wound area
  • leukocytes, GF, and enzymes create swelling, heat, pain, and redness
45
Q

proliferation phase and deposition of connective tissue (wound healing)

A
  • fibroblasts: migrate from surrounding edges, proliferate and some differentiate
  • synthesise and depose immature ECM (type III collagen, fibronectin) = granulation tissue = scaffold
  • secrete factors (FGFs and TGF-β) + ECM factors (integrins) + angiogenetic factors (VEGF) that regulate cell proliferation and neo-angiogenesis
  • start of wound contraction: myofibroblasts pull collagen fibres together. synthesis of type I collagen reinforces contraction
46
Q

during proliferation phase, acute inflammation is still occuring. TRUE or FALSE?

A

TRUE. acute inflammation still on: M2 macrophages (TGF-β stimulates fibroblasts + epithelial cells + endothelial cells)

47
Q

re-epithelialisation in proliferation phase

A
  • GT established - transformation (epithelial cells become less differentiated - more stem cell like)
  • proliferation
  • migration: newly formed cells migrate along newly synthesised basement membrane
  • epithelial migration stops with contact inhibition with other wound edge
  • epitheilal cells differentiate (keratinisation, squames)
48
Q

angiogenesis in proliferation phase

A
  • endothelial activation
  • separation of pericytes
  • M2 macrophages and endothelial cells secrete proteases (collagenases, MMPs) - break down existing vascular basement membrane
  • endothelial cells proliferate and detach from vascular wall, degrade and invade ECM, guided by FGFs
  • sprouting - extends in length until they encounter another cell: vascular loops then capillary tubes
  • maturation: endothelial proliferation and migration stops - new basement membrane and pericytes
49
Q

remodelling and contraction in maturation phase

A
  • remodelling: cells organise surrounding connective tissue and lead to formation of scar
  • fibroblasts replace type III collagen with type I = tensile strength
  • fibroblasts become less proliferate
  • myofibroblasts provides force for contraction
  • vascular regression - avascular scar
  • in skin: new continous basement membrane under regenerated epithelium

PATH30001 Mechanisms of Human Disease (14 decks)

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