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wound repair

question

what are the 3 participants in tissue creation? who are the main participants?
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cells, matrix, and cytokines. cells are the main participants
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what are the characteristics of cells in the process of wound repair?
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cells are the workers, sythesizing extracellular matrix and affecting its creation, they are regulated by cytokines, they also synthesize and release cytokines, cells also degrade cytokines
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what are the characteristics of the matrix in the process of wound repair?
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the matrix can be degraded and form agents that affect cells
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what are the characteristics of cytokines in the process of wound repair?
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these are proteins which control cell communication, and affect cells significantly
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what happens if wound healing doesn’t take place?
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non-healing ulcerative wounds result
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what is the sequence of the wound healing process?
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blood vessel injury -> thrombus formation -> inflammation reaction -> cellular invasion -> tissue repair
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what is critical to the process of wound healing?
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timing, (it is “orchestrated”)
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what lasts longer than the open wound?
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biochemical processes last longer than the open wound, the wound may close in a few days but wound healing is a long process (can last several years esp with collagen reformation)
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what are the over-lapping phages of wound healing?
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inflammation -> granulation stage -> acute inflammation -> collagen accumuation and remodeling
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is inflammation hemostatic? what does it involve?
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yes and it involves blood coagulation, which is essential b/c when blood clots it forms platelets (which secrete a number of important cytokines which regulated the process of healing)
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what are the 4 steps involved in the inflammation/hemostatic stage of wound healing?
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platelet aggregation, cytokine secretion from platelets, platelet clot formation, and fibrin clot formation
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after platelets aggregate, what are the cytokines secreted from platelets? what do they affect?
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PGDF, EGF, TGFb, IL1, LTB4 that directly attract neutrophils chemostatically, who can then start the inflammation process
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after the formation of the platelet clots, how does the fibrin clot form? what is the fibrin clot?
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the fibrin clot is a hemodynatic seal that prevents blood loss and contributes to the inflammation state.
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what does factor XIII do? how important is this process? does factor XIII crosslink fibrin with other adhesive proteins?
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factor XIII crosslinks fibrin, an important process for wound healing -> a deficiency in factor XIII and closed wounds open back up. factor XIII does crosslink fibrin with other adhesive proteins such as fibronectin
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what is fibronectin? what does it do? what happens if fibronectin doesn’t do it’s job?
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an important adhesive protein that plays an essential role in wound healing. fibronectin cross links with fibrin which helps direct cells in a certain direction during the healing process. if this doesn’t occur the wound healing process is chaotic and weak
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what else acts like fibronectin?
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thrombospondin
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what do alpha-macroglobin and alpha-anti plasmin inhibit?
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proteolysis, essentially allow crosslinking to be continue -> endow thrombus with protection against excessive degradation
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what are the two levels of the coagulation and hemostasis phase?
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platelet action and thrombus formation, (the chemostatic phase)
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what are the cytokines secreted by platelets? what do they do?
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platelet derived growth factor (PGDF), epithermal growth factor (EGF), interleukin-1 (IL-1), transformin growth factor beta (TGH-beta), leukotriene D-4 (LTD-4). these all directly affect neutrophils by attracting them through a chemostatic process that starts inflammation
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what is the thrombus composed of? what does this component get degraded into?
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the thrombus is composed of fibrin, which is degraded into fibrinopeptide A + B, which are released upon conversion of fibrinogen to fibrin (by thrombin). these are chemoattractants for neutrophils
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what does FDB stand for?
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fibrin degradation products, which are formed with fibrin is degraded proteolytically, (mostly by plasmin), which is chemotactic for neutrophils
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what very important phase starts wound healing?
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the chemostatic phase
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what is an important substrate for starting the inflammation stage?
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arachidonic acid
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how is thrombin instrumental in the release/production of arachidonic acid?
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thrombin activates phopholipase A2 which cleaves fatty acid from the #2 position of glycerol, (a phospholipid). these fatty acids are usually unsaturated, and in membrane lipids, the fatty acid is arachidonic acid
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what happens to arachidonic acid once cleaved from glycerol by phopholipase A2?
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either lipoxygenase makes it into leukotrienes (such as LTD-4 which activates neutrophils) or cyclooxygenase converts it into prostaglandins which cause pain and are components of inflammation, (specifically PGE2).
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where does pain mostly come from?
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bradykinin, from the kinin system
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how do you get the heat, redness, pain and swelling that is involved in inflammation?
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the coagulation system needs to induce inflammation
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what is necessary for wound healing and must be resolved in 2 days?
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acute inflammation
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is the thrombus, (fibrin clot), wet or dry? what viable cells does it contain?
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wet, platelets, chemoattracted neutrophils, macrophages to engulf and phagocytize debris
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what cells move very early in the wound healing process?
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epidermal cells to form a new epidermis on the surface of viable tissue, (not the scab)
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what are 2 important cytokines secreted by platelets?
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transformin growth factor beta/TFG-beta, (forms 1,2,3), and platelet derived growth factor/PDGF, (AB, BB, AA)
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what cytokines are secreted by neutrophils?
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TFG and PGDF
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what cytokines are involved in formation of new blood vessels? how do the epithelim and fibrblasts communicate?
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vascular endothelial growth factor, (VEGF), and fibroblast growth factor, (FGF). the epithelium sends cytokines to fibroblasts, in response fibroblasts send a different cytokine which acts on epithelial cells, (time and conc. dependent)
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what is the function of inflammation mediated by?
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neutrophils
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what is the primary function on neutrophils? how are they attracted to microbes?
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to fight infection. they are attracted to microbes by N-formyl peptides, particularly N-formyl methionine, which is usually present on most bacterial species
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what is an initial janitorial function provided by neutrophils?
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neutrophils remove insoluble matrix present in the inflammatory response
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what is an initial janitorial function provided by macrophages?
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macrophages engulf remnants of dead bacteria and dead tissue to clean the wound
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what are janitorial functions of neutrophils and macrophages regulated by?
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cytokines, (small proteins – 20,000 kda which are short lived and degraded quickly)
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what is the characteristic property of cytokines?
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they have receptors on cells, and after binding, there is a cascade of signal conduction intracellular which mediates the response
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what does PGDF help do?
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platelet derived growth factor helps cytokines have different effects on the same cell depending on the conditions
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why does plasma not promote cell growth in petri dishes, but serum does?
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serum still contains platelet derived growth factor(PGDF), which has been anti-coagulated in plasma.
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do only platelets make PGDF?
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cells other than platelets also synthesize PGDF, the name is a historical reference
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what are the 2 genes that PDGF has? what most it do in order to be active?
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PGDF is a cytokine that has 2 genes: A and B which synthesize PGDFA or PGDFB and in order to be active, and PGDF must dimerize
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what are PGDFA and PGDF B? how are they connected?
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parts of the PGDF dimer, held together by disulfide bonds, (covalent bonding)
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what does the dimerized PDGF do when it bind to its receptor?
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dimerizes the receptor
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what are the parts of PDGF’s receptor, and what parts of dimerized PDGF bind to?
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the dimerized receptor has alpha and beta parts. PGDF A binds to the to alpha-receptor and PGDF B binds to the beta receptor
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how does the structure of PDGF lead to its differing effect on cells?
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PGDF A-A, PGDF A-B, and PGDF B,B all have different effects on cells, (PGDF B-B is mostly responsible for atherosclerotic changes, and PGDF A-A has a lesser effect on atherosclerosis)
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what is the structure of the PGDF extracellular receotor?
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it has 5 Ig domains, 4 of which participate in the dimer formation part of the process and the 5th domain has not been resolved
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what is the structure of the intracellular part of the PGDF receptor?
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it has 8 tyrosine residues which can be phosphorylated by protein kinase, which is a part of the intracellular receptor -> therefore it is called autophosphorylation. (also common in the insulin receptor)
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are the 8 tyrosine residues of the intracellular part of the PGDF receptor are phosphorylated 1 at a time?
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yes
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what happens if tyrosine 785 is phosphorylated?
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a binding site is created for the SH2 domain
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what does the SH2 domain do once it binds to the site created by phosphorylation of tyrosine 785?
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SH2 gives the mitogen activated protein kinase (MAPK) the ability to bind to phosphotyrosine 785 and triggers a signal transduction cascade causing translocation of the kinase to nucleus to start mitosis of the cell -> cell proliferation
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what happens if tyrosine 490 is phosphorylated?
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a binding site is created for the SH2 domain
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what does the SH2 domain do once it binds to the site created by phosphorylation of tyrosine 490?
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SH2 allows phosphoinositol triphosphate to bind to phosphotyrosine 490 which leads to movement of the cell through a series of events
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how can PDGF A-B induce different responses in the same cell?
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the response to PDGF A-B depends on which tyrosine has been phosphorylated and thus what signal transduction cascade will be started
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what are cellular sources of PDGF?
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platelets, monocytes, smooth muscle cells and macrophages.
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what does PDGF do in terms of fibroblasts and smooth muscle cells?
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chemotaxis, proliferation and contraction of fibroblasts and smooth muscle cells, (in the granulation phase of wound healing)
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what does PDGF do in terms of neutrophils?
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chemotaxis and activation of neutrophils
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why is PDGF important to the process of acute inflammation?
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it triggers neutrophils, whose invasion of the site begins acute inflammation
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if PGDF is released by aggregated platelets, will the thrombus and scab will be affected?
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yes
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what is PDGF a trigger of?
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acute inflammation
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what does TGF-beta stand for? what are its cellular sources?
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transforming growth factor beta. platelets, monocytes, fibroblasts, and smooth muscle cells
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what are the functions of TGF-beta?
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it has the broadest range of functions in wound repair, including inhibitory effects on some cytokine-stimulated cells
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why can TGF-beta’s actions be considered at times inconsequential? what does this depend on
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its actions can be can be either stimulatory, inhibitory or an even process. this depends on concentration in some cases
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what does TGF-beta have an inhibitory effect on?
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some cytokine-stimulated cells such as endothelial cells during blood vessel formation
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does TGF-alpha have similar functions to TGF-beta? what cell produces it?
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no, (the name is historical), it is involved in re-epithelialization/proliferation. it is produced by macrophages.
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what does EGF stand for? what cell produces it? what is its function?
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EGF stands for epidermal growth factor, it is produced by platelets and it effects reepithelialization
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when does reepithelialization take place in wound healing, either as dircted by TGF-alpha or EGF?
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epithelial formation starts very early in the wound healing process when the cells line the boundary between viable undamaged tissue and the clot and scab that covers it.
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what does IL-1 do? what cells produce it?
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interleukin-1 causes stimulation of immune response and induces inflammation. it is produced by platelets, lymphocytes, monocytes, and fibroblasts
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what does TNF-alpha do?
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tumor necrosis factor alpha is responsible for inflammation and is produced by monocytes/macrophages
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what does FGF do? what cells produce it? when does its action appear in the overall process of wound healing?
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fibroblast growth factor induces proliferation of fibroblasts and epidermal cells, it also promotes angiogenesis. it is produced by fibroblasts, macrophages and endothelial cells. its action takes place later in wound healing
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what is IGF? what cell produce it? when does its action take place?
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insulin growth factor. it is produced by fibroblasts, smooth muscle cells, and macrophages. it effects proliferation of various cells. its action is seen later in the wound healing process
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what does VEGF do? what cells make it? can it be considered autocrin?
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vascular endothelial growth factor is made by endothelial cells and macrophages. it induces angiogenesis and increases permeability of blood vessels, (swelling part of inflammation-> blood plasma leaking out). in terms of its endothelial action, it is considered autocrine.
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what is KAF? what cells produce it? what does it do? what is it similar to?
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keratinocyte growth factor. it is produced by epithelium/fibroblasts and induces proliferation of keratinocytes and reepithelialization, (like EGF)
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what happens before the inflammatory phase has been completed, (at its end)?
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the re-synthesis of the extracellular matrix has already been started, debris has been removed and cell pattern has been changed
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during the formation of granulation tissue, is the clot dry?
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yes, and it contains no cells
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what leaks from the fibroblasts and endothelial cells that leads to fibrin and other proteins being cleaves?
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proteolytic enzymez such as urokinase plasminogen activators/tissue plasminogen activators which convert plasminogen to plasmin. plasmin then cleaves fibrin as well as other proteins in the scab
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what other enzymes come from fibroblasts and epithelial cells that degrade collagen?
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matrix-metalloproteinases, of which there are 20 and only 1,2, and 3 are important.
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how does epithelial tissue grow differently in the granulation tissue phase, (as opposed to the inflammation phase)? why is this important?
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epithelial tissue detaches from the original viable tissue and grows up and over the granulation tissue and under the scab, (which is important b/c it protects the wound from pathogens). outside the scab is present and underneath the epithelial tissue is already forming
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why is the granulation tissue formation step important? where does the “granular” name come from?
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it fills the place where the tissue has been removed, (in any injury you remove some tissue). the name comes from the granular appearane, which is the result of the new blood vessel presence
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what is angiogenesis? why is it needed? does it remain?
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angiogenesis provides RBCs which provide O2 for the highly active ETCs creating ATP for process. most of the new blood vessels will eventually be removed via apoptosis
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what is the “work horse” of granulation tissue? what do they do?
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fibroblasts which synthesize collagen, elastin, glycosaminoglycans, and adhesive proteins.
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how do fibroblasts deposit collagen? what is collagen crosslinked with? what if this doesn’t happen?
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fibroblasts synthesize collagen and deposit it in long lines of fibrin fibers that cross-link with fibronectin. if this doesn’t happen, collagen synthesis will occur but it will not be organized, and the synthesized tissue will be weak
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what % strength if healed tissue to undamaged? what about during wound healing?
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healed tissue is only 75% as strong as undamaged. during wound healing, tissue is only 20% as strong
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what kind of smooth muscle moves into granulation tissue to synthesize extracellular matrix?
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contractile proteins which are important in wound contraction
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what function does synthesis of extracellular matriperform?
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it causes the granulation matrix to full up the space left by the injury
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what are the adhesive functions of fibrinogen?
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aggregation of platelets, adhesion of platelets to surfaces, and clumping of bacteria
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what are non-adhesive functions of fibrinogen?
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substrate for fibrin polymer, cross-linked fibrin promotes fibroblast migration
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what do adhesion molecules do?
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bind cells to extracellular matrix and complement of extracellular matrix between themselves
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how does the structure of adhesion molecules inform their function?
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adhesion molecules form tri, bi or monovalent molecules with binding sites on monomeric subunits. so for ex. a dimer with 2 binding sites for cells can bridge them together
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what is the structure of fibrinogen?
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fibrinogen is a bivalent molecule whose structure is made of 2 halves
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what is the structure of collagen?
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collagen is a polyvalent adhesion molecule with many binding sites, and thus collagen forms polymers with multiple binding sites along the molecule
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why is fibrinogen essential for wound healing?
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its crosslinking promotes fibroblast migration who then synthesize collagen and deposit it in long lines of fibrin fibers that crosslink with fibronectin
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is fibrinogen indispensable for aggregation of platelets?
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yes
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how is fibrinogen a bacteriostatic protein?
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it clumps bacteria, which forms mult-bacterial complexes that can precipitate
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what is fibronectin?
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a bivalent chemotactic protein that allows fibroblast and smooth muscle cell, (cells that further expands the tissue), movement towards fibronectin
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does fibronectin regulate cell growth and gene expression?
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yes
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what are the adhesive functions of fibronectin?
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platelet adhesion, binding to bacteria, neutrophils and fibroblasts
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what are the adhesive functions of thrombospondin? other functions? how many subunits does it have?
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thrombospondin binds to cells and extracellular matrix. it also regulates cell growth. it has 3 monomeric subunits, (trivalent)
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what does laminin do in terms of adhesion? other functions?
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laminin mediates binding of the matrix to adhesive cells. it also effects cell migration, reepithelialization and angiogenesis
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what does vitronectin do in terms of adhesion? other functions?
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vitronectin binds to epithelial cells. it also effects reepithelialization
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what does collagen do in terms of adhesion? other functions?
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collagen is the main adhesive component of the extracelluar matrix. it is also involves in connective tissue formation, and is a source of cytokines
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what is the structure of collagen? what is its shape in granulation tissue?
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it is a long polymeric protein. it is synthesized rapidly and creates a scaffold on which other components of the extracellular matrix can be deposited
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how does collagen formation lead to scarring?
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in large wounds, synthesis of collagen is too fast and is associated with the formation of scars.
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is there cytokine involvement with scar formation?
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TGF-beta-1 operates in high conc. in fetal wounds, but in excess it can actually lead to extensive scarring. this is because when cells synthesize TGF-1, it can activate fibroblasts to stimulate more collagen
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what are excessive growths of collagen called?
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keloids
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what is the adhesive function of elastin? other function?
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elastin is an important adhesive component of the extracellular matrix. it is also the major protein of elastic fibers and a source of cytokines
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what is a main difference between elastin and collagen?
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elasin can be stretched, collagen just bends
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are elastins essential for integrity of new tissue formation?
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yes
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what is the adhesive function of proteoglycans? other function?
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proteoglycans bind other substrate adhesion moleceules. they also are important in connective tissue formation and are a source of cytokines
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what do proteoglycans interact with?
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proteoglycans interact with collagen and elastin to form the essence of the extracellular matrix
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what are collagen, elastin and proteoglycans all sources of?
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cytokines
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are collagen, elastin and proteoglycans cells?
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no they are macromolecules
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what do degradation products of collagen, elastin and proteoglycans function as?
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they function as function as cytokines that bind to receptors and trigger signal transduction cascades
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can both cells and degradation products of macromolecules can secrete cytokines?
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yes
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why is angiogenesis required for new tissue formation?
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an oxygen supply is needed
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how can cancer possibly be treated in terms of angiogenesis?
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cancer promotes angiogenesis, so if we can stop angiogenesis we can possibly starve cancer to death by removing its ability to receive oxygen
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what are cytokines with angiogenic properties that also promote endothelial cell proliferation and motility?
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acidic FGF 1, basic FGF 2, and VEGF
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what are cytokines with just angiogenic properties?
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angiogenin, TGF-alpha, TGF-beta, (inhibits proliferation of endothelial cells), wound fluid (promotes endothelial cell motility), prostaglandins, adipocyte lipids (promotes endothelial cell motility)
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where do new blood vessels come from?
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they bud from existing blood vessels
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what does formation of extracellular matrix accomplish? is the scab still present in this phase?
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this step fills the empty tissue after the wound is closed over with new epithelium. the scab still present in this phase
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what do matrix-metallo proteinases (MMP) do?
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these enzymes that attack collagen, which is important because newly formed ECM is collagen rich
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what does collagenase digest?
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fibrillar collagens I, II, and III
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what does gelatinase digest?
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other collagen types
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what does stromelysin digest?
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proteoglycans, fibronectin, elastin
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what does plasmin do?
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this fibrinolytic enzyme activates zymogens of MMPs and other proteins
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what makes collagenase, gelatinase, stromelysin, and plasmin?
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many cells but esp. fibroblasts and keratinocytes
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why does collagen need to be degraded in the final steps of wound healing?
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collagen is initially formed and organized along fibrin-fibrinogen fibers in a loose, weak network that must be degraded and re-sythesized to make thicker fibers to add to tissue strenght
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after wound closure, what is the main process?
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restructuring
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are skin substitutes useful or beneficial in wound healing?
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yes, esp with burns that have large scale skin damage
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what are used in skin substitutes?
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various ECM components, such as elastins supplemented with cytokines.
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have live sheets of cells been used in patients successfully?
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yes with partially successful results
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whya re skin subsitutes only used in extreme cases?
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expense
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what is a cytokine that has been FDA approved for clincal wound healing? how useful is it?
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PDGF. it has some positive effects, but none that are universal or dramatic b/c of all the cytokines, concentration differences and timing involved in natural healing.
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is there anything PDGF has shown particular help with?
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ulcerative wounds
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does recombinant human growth hormone have beneficial effects?
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this has some beneficial effect, but cannot start the cascade that normal human growth hormone can use
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what is fibrin glue? how does it work?
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bovine fibrinogen and thrombin that can be mixed together and used in surgery, will stop bleeding in seconds. these provide a scaffold for subsequent granulation tissue
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what circumstances can make wound healing worse?
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in stressful states, IL-1 and 8 are decreased
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what has been found about churchgoers and wound healing capabilities?
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churchgoers had IL-6 decreased, C-reactive, and fibrinogen decreased which are all assciated with the stress response