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93 Cards in this Set
- Front
- Back
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Define healing.
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repair involving a combination of regeneration and connective tissue deposition
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Why does scarring occur?
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occurs when tissues are intrinsically unable to regenerate, if the underlying connective tissue scaffolding is disrupted, or following extensive exudates
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Define regeneration.
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Cell or tissue growth that replaces lost structures. It generally involves proliferation of the same cell type, although stem cells may proliferate and differentiate to replace dead cells. Regeneration requires intact tissue scaffolding.
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What are 2 ways in which you can increase cell proliferation?
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1. shortening the cell cycle
2. recruiting quiescent cells into the cycle |
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What are the phases of the cell cycle?
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G1 (presynthetic)
S (DNA synthesis) G2 (pre-mitotic) M (mitosis) |
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What is G0?
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quiescent cells are in this pahse.
Most tissues are composed mainly of cells in G0 that can periodically enter the cell cycle |
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What are the 3 classes tissues can be divided into based on their proliferative capacity?
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1. Labile - continuously dividing
2. Stable - quiescent cells 3. Permanent - non-dividing cells |
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Describe labile cells.
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Cells proliferate throughout life, replacing those that are destroyed. Typically, mature cells derive from stem cells with unlimited capacity to regenerate and varying capacity to regenerate
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Describe quiescent(stable) cells.
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Cells are normally involved in low level replicatoin but are capable of rapid division in response to stimuli
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Describe permanent cells.
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These are cells that cannot undergo division in postnatal life - neurons, skeletal muscle, and cardiac muscle
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Describe stem cells.
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prolonged self renewal and asymmetric replication - with each cell division, one cell contains self-renewing property while the other differentiates to become a mature nondividing cell
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What are pleuripotent cells and where are they isolated from?
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these stems cells are capable of differentiating into any tissue type and are isolated from normal blastocytsts
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how are embryonic stem cells different from adult stem cells?
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Embryonic stem cells are pleuripotent. Adult stem cells have a more restricted differentiation capability and tend to be lineage specific
Nevertheless, adult stem cells with relatively broad differentiation potential occur in bone marrow and in tissue stem cells outside the bone marrow |
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What are hematopoietic stem cells?
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cells capable of regenerating all blood cell elements
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What are multipotential stromal cells?
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cells capable of differentiating for instance into bone, cartilage, fat or muscle.
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What are the hematopoietic stems cells of mesodermal linage capable of differentiating into?
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neurons (ectoderm), hepatocytes (endoderm) and other adult cell lineages -- this is transdifferentiation
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What is transdifferentiation?
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Conversion of one differentiated cell type into another differentiated cell type
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Do hematopoietic stem cells contribute significantly to normal tissue homeostasis or to replacement of injured tissues
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No, they do not contribute significantly.
their role may be in local production of growth factors to promote healing |
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Define plasticity.
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breadth of differentiation potential
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Where are multipotent adult progenitor cells found and describe the replication properties?
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found in bone marrow and toher tissues (brain, skin, and muscle)
these cells proliferate in culture without senescence and have broad developmental capacity |
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What is the role of tissue stem cells?
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Responsible for generating the mature cells of the organ in which they reside, thereby maintaining normal tissue homeostasis
Also have variable potential to differentiate more broadly and to repopulate tissues following injury |
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Describe the epithelium and its ability to regenerate.
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most epithelial surfaces are constantly maintained by stem cells with a discrete set of differentiation lineages. Terminally differentiated cells do not divide and are continuously sloghed at the external surface. After injury, stem cells repopulate the tissue
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Describe the liver and its ability to regenerate.
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liver stem cells reside in the canals of Hering - jxn of hepatocytes and bile duct system
liver stem cells give rise to oval bodies with a capacity to form hepatocytes or biliary epithelium they are typically only active if direct heptaocyte proliferation is not possible |
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Describe the brain and its ability to regenerate.
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neural stem cells exist and can even be integrated into neural circuits
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Describe the striated muscle and its ability to regenerate.
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skeletal and cardiac myocytes cannot proliferate
regeneration of injured skeletal muscle is accomplished by proliferation of satellite cells, a stem cell poll in adult muscle |
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What are the fxns of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha)?
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bind to the same EGF receptor - EGFR1 or ERB B1 - transmembrane molecule with intrinsic tyrosine kinase activity
They are mitogenic for epithelial cells, hepatocytes, and fibroblasts |
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What is the fxn of hepatocyte growth factor (HGF)?
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produced by fibroblasts, endothelial cells, and hepatocytes
it has mitogenic effects on most epithelial cells as well as promoting embryonic development |
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What is the fxn of vascular endothelial growth factor (VEGF)?
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promotes blood vessel formation in eary development (vasculogenesis) and plays a role in new blood vessel growth in adults (angiogenesis)
It is particularly important in angiogenesis associated with chronic inflammatory states and in healing wounds VEGF members act by binding to receptors with intrinsic tyrosine kinase activity VEGFR-2 is expressed by endothelial cells and is the receptor for vasculogenesis and angiogenesis VEGF-C and -D bind to VEGFR-3 to induce lymhatic endothelial proliferation (lymphangiogenesis) |
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What is the fxn of platelet derived growth factor (PDGF)?
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found in platelet alpha granules and made in endothelial cells, macrophages, and smooth muscle cells
causes migration and proliferation of fibroblasts, monocytes, and smooth muscle cells |
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What is the fxn of Fibroblast growth factor (FGF)?
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acidic and basic forms - bind to extracellular matrix heparan sulfate to form reservoirs of inactive forms
Basic FGF has the ability to induce all the steps necessary for angiogenesis and FGF members are centrally involved in wound repair, tissue development, and hematopoiesis. |
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What is the fxn of TGF-beta?
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growth inhibitor for most epithelial cells via receptor kinases that posphorylate Smad cytoplasmic transcription factors
Has potent anti-inflammatory effects promotes fibrosis by stimulating fibroblast chemotaxis, proliferation, and ECM synthesis and by inhibiting collagen degradation |
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What is the function of cytokines?
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mediators of immune and inflammatory responses and also have growth promoting activities
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Describe autocrine signaling.
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cells respond to signaling substances produced by themselves
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Descrive paracrine signaling.
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A cell produces substances that affect target cells in close proximity
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Describe endocrine signaling.
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cells synthesize hormones that circulate in the blood to act on distant targets
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How do receptors with intrinsic kinase activity induce intracellular signaling?
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Intrinsic kinase activity is usually activated following ligand binding. The active kinases then posphorylate downstream effector molecules leading to their activation
Examples: Ras signlaing - binds to Raf which phosphorylates MAPs PI-3-kinase - activates series of kinases leading to cell survival Phosphlipase C-gamma - leads to calcium release from ER and DAG formation with protein kinase C activation |
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How do receptors without intrinsic kinase activity induce intracellular signaling?
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Receptors associate with and and activate cytosolic protein kinases
Example: Janus kinases (JAKs) link activated receptors with downstrream STATs that shuttle into the nucleus and activate gene transcription |
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How do G protein-linked receptors induce intracellular signaling?
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receptors are 7-transmembrane spans (ex - chemokine, epi, and glucagon receptors)
ligand binding activates a signal transducing the G protein complex, generating intracellular 2nd messengers including calcium and cAMP |
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How do steroid hormone receptors induce intracellular signaling?
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ligands for these receptors are lipophilic; they directly diffuse through plasma membranes; receptors are typically intranuclear transcription factors that are activated by ligand binding
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What is the end result of most signal transduction?
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altered gene transcription driving by changes in transcription activity.
The rapid responses demanded by cell signaling do not permit synthesis of new transcription factors but rather rely on post-translational modifications that allow transcription factor migration into nucleus |
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What are CDKs?
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cyclin dependent kinases
they are constitutively expressed protein kinases that become active only after forming complexes with specific cyclins |
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What are cyclins?
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regulatory proteins whose concentrations rise and fall during the cell cycle
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How do cyclin-CDK complexes regulate the cell cycle?
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by phosphorylating various target proteins
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What is p53?
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a tumor supressor gene that is activated in response to DNA damage and inhibits further progression through the cell cycle by increasing expression of a CDK inhibitor
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In mammals, why is their inadequacy of true regeneration of of tissues?
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due to a rapid fibroproliferative response and scar formation after wounding
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Describe the components of the ECM.
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consists of fibrous structural proteins - collagen and elastin - and adhesive glycoproteins embedded in a gel of proteoglycans and hyaluronan
These macromolecules assemble into an intersitial matrix, present in the spaces b/w cells, or into a basement membrane. |
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Describe collagen and what is its fxn?
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provides tensile strength
Composed of a triple helix braid of 3 polypeptide chains each having a primary glycine-X-Y repeating sequence Procollagens are synthesized as alpha chains, followed by enzymatic hydroxylation of prolines and lysines. 3 chains then align to form a triple helix and the product is secreted. The globular C- and N- terminal fragments are proteolytically cleaved and lysine oxidase oxidizes lysines and hydroxylysines to permit interchain cross-linking and stabilize the fibrils |
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Where do you find each of the following types of collagen:
I? II? IV? Which ones are fibrillar collagens and which ones form sheets? |
I - skin and bone
II - cartilage IV -forms sheets and is found in basement membranes Fibrillar collagen and most abundant - I, II, III, V, XI Sheets - IV |
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Describe elastin and what is its fxn?
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provides ECM with elasticity (stretch and recoil)
elastic fibers consist of elastin central core with an associated scaffolding network of fibrillin |
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What are the 4 main families cell adhesion proteins can be broken down into?
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1. Immunoglobulin family
2. Cadherins 3. Integrins 4. Selectins |
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What are cadherins and what is their role in cells?
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Cell adhesion proteins that mediate calcium-dependent interactions with cadherins on adjacent cells and interact with the cytoskeletonvia catenins
Cadherins bind beta-catenins that link to alpha-catenins that connect to actin These connections play major roles in cell motility and cell differentiation; they also account for the contact inhibition of cell proliferation when cells touch |
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What are integrins and what is their role in cells?
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participate in cell-cell adhesion as well as adhesion to the ECM by binding to fibronectin and laminin
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What is fibronectin and what is their role in cells?
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binds to many molecules
alternate splicing produces either tissue fibronectin or plasma fibronectin Tissue fibronectin - forming fibrillar aggregates at sites of wound healing Plasma fibronectin - forming provisional blood clots in wounds preceding ECM deposition |
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What are laminin and what is their role in cells?
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most abundant glycoprotein in the basement membrane
has binding domains for EXM and cell surface receptors |
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What are focal adhesion complexes?
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ligand binding to integrins causes clustering and formation of focal adhesion complexes that function as activated receptors to trigger signal transduction pathways
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What is SPARC and what is its function?
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secreted protein acidic and rish in cystein
aka osteonectin contributes to tissue remodeling after injury and is an engiogenesis inhibitor |
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What is the fxn of thrombospondins?
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ibhibit angiogenesis
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What is the fxn of osteopontin?
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regulates calcification and also mediates leukocyte migration
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What is the fxn of tenacins?
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involved in morphogenesis and cell adhesion
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What is glycoaminoglycans?
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long repeating polymers of modified disaccharides
ECM components have a core protein linked to one or more glycosaminoglycans |
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What is hyaluronan?
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molecule with many disaccharide repeats that serves as a ligand for cell surface receptors and other core proteins
binds large amounts of water giving ECM its turgor and ability to resist compression |
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What is the name of preteoglycans that are integral membrane proteins?
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syndecans
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What is the difference between regeneration and healing?
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Regeneration involves restitution of tissue identical to that lost by injury
Healing is a fibroproliferative response that "patches" rather restore a tissue |
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What do we produce scars?
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repair for tissues incapable of regeneration -- get ECM deposition producing a scar
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What is fibrosis?
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ECM deposition in a setting where inflammation is chronic and tissue damage and repair occur concurrently
Generically, fibrosis applies to any abnormal deposition of connective tissue |
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Describe the sequence of healing.
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1. inflammatory response to eliminate initial stimulus, remove injured stimulus, and intitiate ECM deposition
2. Proliferation and migration of parenchymal and connective tissue cells 3. formation of new blood vessels and granulation tissue 4. Synthesis of ECM proteins 5. Tissue remodeling 6. Wound contraction and acquisition of wound strength |
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Histologically, describe granulation tissue.
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proliferating fibroblasts with numerous new blood vessels in a loose matrix
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What is the difference between angiogenesis and vasculogenesis?
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during embryonic development -vessels arise by vasculogenesis - primitive vascular network assembled from EC precursor angioblasts
Adult tissues - vessel formation is angiogenesis - branching of preexisting vessels and by recruitment of endothelial cell precursors from bones marrow |
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In embryonic development, what generates both hematopoietic stem cells and angioblasts?
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hemangioblasts
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What can angioblasts proliferate and form?
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differentiate into endothelial cells, pericytes, and vascular smooth muscle cells
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Describe the steps of angiogenesis.
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1. NO dilates preexisting vessels
2. VEGF induces increased permeability 3. Metalloproteinases degrade the basement membranes 4. Plasminogen activator disrupts endothelial cell-cell contact 5. endothelial cells proliferate and migrate toward the angiogenic stimulus 6. Endothelial cell maturation occurs, including growth inhibition and remodeling into capillary tubes 7. Periendothelial cells are recruited |
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What are the 2 most important growth factors in angiogenesis?
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VEGF and angiopoietins
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What is the most important receptor for angiogenesis?
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VEGFR-2 tyrosine kinase receptor -- it is largely restricted to endothelial cells and endothelial cell precursors
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What is the importance of VEGF/VEGFR-2 interactions?
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1. mobilize endothelial cell precursor cells from bone marrow and enhance their proliferation and differentiation at sites of angiogenesis
2. stimulate proliferation and motility of existing endothelial cells, promoting capillary sprouting |
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What is the fxn of angiopoietin 1?
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interacts with endothelial cell receptor Tie2 to recruit periendothelial cells
interaction also mediates vessel maturation from simple tubes into more elaborate vascular structures and helps maintain endothelial cell quiescence Angiopoietin-2:Tie-2 interactions are opposite |
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What is the fxn of PDGF?
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recruits smooth muscle cells
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What is the fxn of TGF-beta?
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stabilizes newly formed vessels by enhancing ECM production
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What proteins are involved in the directed migration of endothelial cells in angiogenesis? What is the fxn of each?
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integrins - critical for forming and maintaining newly formed vessels
matricellular proteins proteases - remodel tissue during endothelial cell invasion; they release matrix bound VEGF and FGF-2 to stimulate angiogenesis as well as inhibitors of angiogenesis (endostatin) |
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What are the 3 general steps involved in scar formation?
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1. fibroblast migration and proliferation
2. ECM deposition and scar formation 3. Tissue remodeling |
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What repair progresses in the healing/scarring process, what happens to the number of endothelial cells and fibroblasts
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numbers of proliferating endothelial cells and fibroblasts decrease; fibroblasts become more synthetic and deposit more collagen and other ECM components
Eventually the granulation tissue scafolding is converted into a scar composed of fibroblasts and collagen |
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What are matrix metalloproteinases? What is required for their activity
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MMPs - family of more than 20 enzymes that degrade ECM; they are secreted as proenzymes and activated extracellularly
Need zinc to be active |
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What are interstitial collagenases?
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cleave fibrillar collagen types I, II, and III
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What are gelatinases?
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degrade amorphous collagen as well as fibronectin
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What are stromelysins?
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act on a variety of ECM components, including proteoglycans, laminin, fibronectin, and amorphous collagen
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What are ADAMs?
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disintegrin and metalloproteinase-domain
membrane bound MMPs that release extraceullar domains of cell surface proteins |
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What inhibits MMPs?
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tissue inhibitors of metalloproteinases (TIMPs)
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What is the next effect of TIMPs and MMPs?
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net effect of ECM synthesis versus degradation results in debridement of injured sites and remodeling of the connective tissues framework
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Describe the generalized steps involved in wound healing.
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1. induction of inflammation by the initial injury
2. granulation tissue formation and reepithelialization 3. ECM deposition and remodeling with wound contraction |
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What is the difference between healing by first intention and second intention?
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first intention - wounds with opposed edges where the scar consists of connective tissues devoid of inflammation covered by intact epidermis
2nd intention - wounds with separated edges - abundance of granulation tissue - substantial scar deposition and overlying epidermis is thin - characterized by wound contracture in which the defect is markedly smaller than its original size - this is largely through the contractile activity of myofibroblasts |
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What are some factors that influence wound healing?
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local factors that delay healing - infections, mechanical forces, and foreign bodies
system factors - nutritional status of host, metabolic status, circulatory status or vascular adequacy, and hormones |
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What is deficient scar formation?
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inadequate granulation tissue or collagen deposition and remodeling that can lead to either wound dehiscence or ulceration
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What is excessive repair?
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excessive granulation can protrude adove the surrounding skin and block reepithelization (exuberant granulation or proud flesh)
excessive collagen accumulations form a raise hypertrophic scar and progression beyond the original area of injury without subsequent regression is known as a keloid |
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What does it mean when you have formation of contractures in a complications of wound healing?
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exaggerated process of wound contraction
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