9/14 Flashcards
Capillaries
Small blood vessels that form a network with tissues to carry blood from arteries to veins
Thin walls for efficient gas exchange
Characteristics of abnormal blood vessels
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
Vasculogenesis
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
Angiogenesis
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
Angiogenic switch activators/inhibitors
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
2 Conditions that Turn on the Angiogenic Switch
- Inflammation- delivery of pro-angiogenic mediators by inflammatory cells
- Hypoxia- sensing low oxygen by HIF (hypoxia inducible factor) and stimulation of pro-angiogenic mediator production
Starvation Hypothesis
Anti-angiogenic drugs and anti-VEGF drugs will starve tumor and cause regression
Strategies for anti-angiogenesis therapy
- Reduce the activators: expression/production, bioavailability, signaling
Many pro-angiogenic GF receptors have tyrosine kinase activity like VEGF, use receptor tyrosine kinase inhibitors (RTKIs)
- Increase the inhibitors: production, exogenous addition
Common anti-angiogenic drugs
- Avastin/bevacizumab (single target): function blocking monoclonal antibody that binds VEGF, used for colorectal cancer
- Sunitinib/Sutent (multiple targets): inhibitor of receptor tyrosine kinases like VEGF and PDGF, for renal/pancreatic neuroendocrine/gastrointestinal cancers
- Sorafenib/Nexavar (multiple targets): inhibitor of receptor tyrosine kinases like VEGF and PDGF, for thyroid and renal cancer
Advantages of broad inhibitors for angiogenesis
- 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
- Targeting VEGF and PDGF should increase effectiveness of anti-VEGF drugs: targeting pericytes allows higher sensitivity to VEGF-R inhibition and chemotherapy
Problems with anti-angiogenesis therapy
- High cost (100k/yr for Avastin)
- Modest overall survival for patients
- Side effects: wound healing complications and abnormal fetal development
- 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
3 Steps of Wound Healing
- Inflammation
- Proliferation
- Remodeling (Scar formation)
Platelets Functions
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)
Functions of the Inflammatory Phase
Hemostasis
Clear wound of debris and foreign material
Destroy potential pathogens
Stimulates subsequent phases of healing
Signs of inflammation
Calor- heat
Rubor- redness (erythema)
Tumor- swelling (edema)
Dolor- pain
Recruitment of circulating inflammatory cells
- Rolling (selectins)
- Integrin activation (chemokines)
- Stable adhesion (integrin and adhesion molecules)
- Chemotaxis (chemokines)
Pros and cons of inflammation on wound repair
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)
Clot reepithelialization
- Proliferation: GFs (like EGF, KGF, and TGF-alpha) stimulate proliferation of keratinocytes adjacent to the wound site
- 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
- Differentiation: once wound covered with keratinocytes need some to differentiate to different layers of a functional epidermis
Proliferative Phase for a wound
- Cell reepithelialization: see other card
- 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
- Fibroblasts: GFs stimulate collagen production, fibroblasts replace the provisional matrix with hyaluronan collagen (types I and II) and other ECM proteins
Remodeling (scar formation) for wound repair
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
Regulation of matrix metalloproteinases
Tissue Inhibitor of Metalloproteinases (TIMPS)
Transforming growth factor-beta (TGF-beta)
Activates fibroblasts, stimulate collagen deposition, induce myofibroblast phenotype
Shift ECM synthesis/degradation balance: reduce MMP expression, increase TIMPS expression
3 Types of Abnormal Scarring
- Keloids: extensive scar tissue that extends past initial injury, hard to treat and high reoccurrence, genetic component (Blacks/Asians), type III collagen
- Hypertrophic scars: raised red scar, forms along original boundaries of wound in areas of high tension, type I collagen
- Contractures: tightening of skin that may affect underlying muscles/tendons, limits mobility around joints, normal elastic ECM replaced with elastic scar tissue
Fibrosis
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
Tissue regeneration
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
Fetal wound healing
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
Scar tissue features
Excess and disorganized collagen
Less strength
Loss of appendages (hair follicles)
Cosmetic and psychosocial problems
Loss of function
Impairs growth
Difference between repair, regeneration, and fibrosis
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
Wound inflammation
- Microbes or injury activate resident inflammatory cells (mast cells and macrophages), platelets activated after injury (hemostasis)
- Activated cells produce and release pro-inflammatory mediators (amines, cytokines, chemokines, lipids)
- Pro-inflammatory mediators activate endothelial cells in blood vessels, leading to the recruitment of circulating inflammatory cells to the site of injury
- 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
