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Foundations 2 > 9/14 > Flashcards

9/14 Flashcards

1
Q

Capillaries

A

Small blood vessels that form a network with tissues to carry blood from arteries to veins

Thin walls for efficient gas exchange

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2
Q

Characteristics of abnormal blood vessels

A

Higher number than normal tissue

Disorganized distribution and full of twists

Extremely permeable and leaky

Coverage of basement membrane and pericytrs around vessels is abnormal, pericytes sparse and loosely attached

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3
Q

Vasculogenesis

A

De novo blood vessel formation

Endothelial progenitor cells are recruited from the bone marrow

EPCs incorporate into blood vessel

EPCs proliferate and differentiate into endothelial cells

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4
Q

Angiogenesis

A

Blood vessels form from existing blood vessels

Endothelial cells in quiescent blood vessels are activated

ECs proliferate, migrate, and differentiate to form new blood vessel sprout

Two adjacent sprouts fuse, involves stalk EC and tip EC, non-functional vessels regress into two adjacent vessels again

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5
Q

Angiogenic switch activators/inhibitors

A 
Activators:
VEGF (vascular endothelial growth factor)
bFGF (basic fibroblast growth factor)
PDGF (platelet derived growth factor)
IL-8 (interleukin 8)
HGF (hepatocyte growth factor)
PIGF (placental growth factor)
Inhibitors:
Thrombospondin
Interferon
Angiostatin
Endostatin
Collagen IV fragments
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6
Q

2 Conditions that Turn on the Angiogenic Switch

A
  1. Inflammation- delivery of pro-angiogenic mediators by inflammatory cells
  2. Hypoxia- sensing low oxygen by HIF (hypoxia inducible factor) and stimulation of pro-angiogenic mediator production
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7
Q

Starvation Hypothesis

A

Anti-angiogenic drugs and anti-VEGF drugs will starve tumor and cause regression

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8
Q

Strategies for anti-angiogenesis therapy

A
  1. Reduce the activators: expression/production, bioavailability, signaling

Many pro-angiogenic GF receptors have tyrosine kinase activity like VEGF, use receptor tyrosine kinase inhibitors (RTKIs)

  1. Increase the inhibitors: production, exogenous addition
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9
Q

Common anti-angiogenic drugs

A
  1. Avastin/bevacizumab (single target): function blocking monoclonal antibody that binds VEGF, used for colorectal cancer
  2. Sunitinib/Sutent (multiple targets): inhibitor of receptor tyrosine kinases like VEGF and PDGF, for renal/pancreatic neuroendocrine/gastrointestinal cancers
  3. Sorafenib/Nexavar (multiple targets): inhibitor of receptor tyrosine kinases like VEGF and PDGF, for thyroid and renal cancer
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10
Q

Advantages of broad inhibitors for angiogenesis

A
  1. Broad inhibitors block multiple targets and cell types: includes endothelial cells (VEGF) and pericytes (PDGFR), withdrawal of anti-VEGF inhibitor leads to rapid regrowth of vasculature because pericytes are left when you only target VEGF
  2. Targeting VEGF and PDGF should increase effectiveness of anti-VEGF drugs: targeting pericytes allows higher sensitivity to VEGF-R inhibition and chemotherapy
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11
Q

Problems with anti-angiogenesis therapy

A
  1. High cost (100k/yr for Avastin)
  2. Modest overall survival for patients
  3. Side effects: wound healing complications and abnormal fetal development
  4. Resistance-
    Intrinsic: pre-existing non-responsiveness (tumors always resistant), absence of transient benefit
    Evasive/acquired: tumors respond for a limited time then develop resistance to treatment, usually comes from upregulation of alternative growth pathways
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12
Q

3 Steps of Wound Healing

A
  1. Inflammation
  2. Proliferation
  3. Remodeling (Scar formation)
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13
Q

Platelets Functions

A

Hemostasis

Activation of thrombin leads to formation of fibrin from fibrinogen

Fibrin clot functions: plugs damaged vessels to stop bleeding, forms provisional matrix

Also release contents of alpha granules (GFs and cytokines)

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14
Q

Functions of the Inflammatory Phase

A

Hemostasis

Clear wound of debris and foreign material

Destroy potential pathogens

Stimulates subsequent phases of healing

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15
Q

Signs of inflammation

A

Calor- heat

Rubor- redness (erythema)

Tumor- swelling (edema)

Dolor- pain

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16
Q

Recruitment of circulating inflammatory cells

A
  1. Rolling (selectins)
  2. Integrin activation (chemokines)
  3. Stable adhesion (integrin and adhesion molecules)
  4. Chemotaxis (chemokines)
17
Q

Pros and cons of inflammation on wound repair

A

Pros: prevent infections, clear debris and dead cells, growth factor production (promote reepithelialization)

Cons: protease and ROS production causes host/tissue damage (delayed healing), growth factor production (promote fibrosis)

18
Q

Clot reepithelialization

A
  1. Proliferation: GFs (like EGF, KGF, and TGF-alpha) stimulate proliferation of keratinocytes adjacent to the wound site
  2. Migration: cell-cell contacts and cell-basement membrane attachments loosen, matrix metalloproteinases dissolve clot ECM to help cell movement, GFs (like EGF, PDGF, and TGF-beta) stimulate cells at the leading edge to migrate across the wound to close the skin, cells elongate and have cytoskeleton rearrangement
  3. Differentiation: once wound covered with keratinocytes need some to differentiate to different layers of a functional epidermis
19
Q

Proliferative Phase for a wound

A
  1. Cell reepithelialization: see other card
  2. Angiogenesis: need new blood vessels to support growth via oxygen and nutrients, tissue hypoxia/ inflammation stimulates production of pro-angiogenic GFs (VEGF, PDGF, FGF-2), vessels regress as new dermal tissue matures
  3. Fibroblasts: GFs stimulate collagen production, fibroblasts replace the provisional matrix with hyaluronan collagen (types I and II) and other ECM proteins
20
Q

Remodeling (scar formation) for wound repair

A

New collagen aligned and cross-linked into fibrils hen fibers then bundles

Contraction of ECM by myofibroblasts, have alpha smooth muscle actin

Amount of scar tissue produced depends on matrix degradation/production ratio

Mediated partly by GFs like TGF-beta

Much more disorganized result than normal skin, smaller fibrils with heterogeneous diameters

21
Q

Regulation of matrix metalloproteinases

A

Tissue Inhibitor of Metalloproteinases (TIMPS)

22
Q

Transforming growth factor-beta (TGF-beta)

A

Activates fibroblasts, stimulate collagen deposition, induce myofibroblast phenotype

Shift ECM synthesis/degradation balance: reduce MMP expression, increase TIMPS expression

23
Q

3 Types of Abnormal Scarring

A
  1. Keloids: extensive scar tissue that extends past initial injury, hard to treat and high reoccurrence, genetic component (Blacks/Asians), type III collagen
  2. Hypertrophic scars: raised red scar, forms along original boundaries of wound in areas of high tension, type I collagen
  3. Contractures: tightening of skin that may affect underlying muscles/tendons, limits mobility around joints, normal elastic ECM replaced with elastic scar tissue
24
Q

Fibrosis

A

Exaggerated production of scar tissue

Can happen in any tissue or organ

Replacement of normal tissue with collagen results in loss of organ function

Lung fibrosis inhibits gas exchange and can lead to death, heart has pumping capacity reduced since scar tissue doesn’t contract, glial scarring prevents axon regeneration, vision loss in cornea

25
Q

Tissue regeneration

A

Lower vertebrae have blastema, mass of undifferentiated cells with capacity to regenerate an organ or appendage

Mammals have no blastema formation and rapid fibroproliferative response

Liver regeneration: replace functional mass but not original structure, compensatory hyperplasia and not true regeneration

Fetal skin regeneration: restoration of normal dermal matrix and skin appendages after injury

26
Q

Fetal wound healing

A

Less collagen accumulation and more organized, no inflammatory phase, remodeling phase has no scar formation

Transition around 3rd trimester between Regeneration (scarless healing, no inflammation) and Repair (fibrotic healing, inflammation)

Inflammation turns scarless wounds into fibrotic wounds

27
Q

Scar tissue features

A

Excess and disorganized collagen

Less strength

Loss of appendages (hair follicles)

Cosmetic and psychosocial problems

Loss of function

Impairs growth

28
Q

Difference between repair, regeneration, and fibrosis

A

Regeneration: Complete restoration of normal tissue architecture

Repair: imperfect healing with scar formation and restoration of some functional activity

Fibrosis: replacement of normal tissue with excessive scar tissue leading to loss of organ function

29
Q

Wound inflammation

A
  1. Microbes or injury activate resident inflammatory cells (mast cells and macrophages), platelets activated after injury (hemostasis)
  2. Activated cells produce and release pro-inflammatory mediators (amines, cytokines, chemokines, lipids)
  3. Pro-inflammatory mediators activate endothelial cells in blood vessels, leading to the recruitment of circulating inflammatory cells to the site of injury
  4. Activated inflammatory cells take up debris, foreign materials, dead cells, and potential pathogens through phagocytosis

Cells produce ROS and proteases to kill microbes and destroy ingested material

Cells also make cytokines, GFs, and other mediators to stimulate proliferation, migration, and activation of neighboring cells

Foundations 2 (18 decks)

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