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63 Cards in this Set
- Front
- Back
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Q: During tissue repair, what is one of the first steps taken?
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-since almost all injurious processes involve the inflammatory process, one of the first repair steps is to begin clearing the parts of the inflammatory process that are needed for repair, macrophages do this job very well
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Q: What are the two processes that are needed for repair to occur?
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-regeneration of parenchymal cells of the injured tissue and some replacement by connective tissue (AKA scarring, fibrosis and fibroplasia (fibroblasts are the major cell involved)
-regeneration of the parenchymal cells involves tightly controlled cell growth and proliferation (fibroplasias = scarring) |
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Q: What are the steps involved in cell proliferation?
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-must go through the cell cycle (G1 -> S -> G2 -> M phases) or (pre-synthetic -> synthetic -> pre-mitotic -> mitotic)
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Q: What are the three groups of tissues in the body based on their proliferative activity?
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-continuously dividing tissues (labile tissues), quiescent (stable) tissues, and nondividing (permanent) tissues
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Q: Are there some cells dividing continuously?
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-some cells are continuously dividing to replace ones that are being destroyed or sloughed (including squamous cells of the epidermis, the columnar epithelium of the GI tract and bone marrow cells), in most of these tissues, regeneration is derived from a population of stem cells, which have an unlimited capacity to proliferate and whose progeny may undergo various streams of differentiation
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Q: What are quiescent cells and what is there role in tissue-proliferation?
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-Quiescent cells normally demonstrate a low level of replication. They can undergo proliferation in response to stimuli and can therefore reconstitute the tissue of origin. They usually are in the Go phase.
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Q: What are some examples of quiescent cells?
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In this category are the glandular organs of the body. These would include the liver, kidney, vascular endothelial cells and smooth muscle cells.
-In most organs for regeneration to occur there must be a basement membrane. This forms a supporting scaffold for the replicating cells. If the tissue has been severely injured, the basement membrane may be so disrupted that cells proliferate in a haphazard fashion and produce disorganized masses. Neoplastic cells can proliferate without basement membranes. Fibroblasts are a type of quiescent cell that proliferate during tissue repair and are a very important cell in restoring tissues. |
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Q: Can non-dividing cells undergo tissue-proliferation and repair?
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-Non-dividing cells have left the cell cycle and cannot undergo mitotic division. Most nerve cells, striated muscle cells and cardiac myocytes are in this group. If neurons are lost they cannot regenerate. They are replaced by CNS supportive cells, the glial cells. When cardiac myocytes undergo necrosis from anoxia they usually cannot regenerate and the area of myocardial infarction is replaced by scarring (fibrosis).
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Q: What role do growth factors have on cell growth, proliferation and repair?
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-an extracellular growth factor (a ligand) interacts with its cell surface receptor. Ligand binding causes a change in the cytosolic portion of the receptor, which activates various proteins of pathways called cascades. This is called transduction and usually ends in the nucleus where a transcription factor is activated. Genes, for cell growth, are then activated and express growth-inducing proteins.
-growth factors also have effects on cell locomoation, contractility, differentiatona dn angiogenesis |
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Q: What are the different functions that growth factors have on binding to the target cells?
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-they stimulate the transcription of many genes that were silent in the resting cells and several of these genes regulate the entry of the cells into the cell cycle and their passage through the various stages of the cell cycle
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Q: What are the different modes of signaling that ligands can bind to their receptors?
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-There are three general schemes of intercellular signaling based on the distance over which the signal acts. They include autocrine, paracrine and endocrine.
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Q: Describe autocrine signaling.
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-Autocrine signaling (self-signaling) is cell response to the signaling substance, which this same cell secreted. forms an autocrine loop
-For example, tumor cells secrete growth factors that can stimulate their own growth. plays a role in liver regeneration and proliferation of lymphocytes |
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Q: Describe paracrine signaling.
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-Paracrine signaling is when a cell produces substances, which affect cells within close proximity. Paracrine signaling is common in wound healing where macrophages stimulate adjacent fibroblasts to produce collagen.
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Q: What is juxtacrine signaling?
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-a form of paracrine signaling, occurs when the signaling molecule is anchored in the cell membrane and binds a receptor in the plasma membrane of another cell, promotes cell to cell adhesion
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Q: Describe endocrine signaling.
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-Endocrine signaling occurs when hormones secreted by endocrine organs and carried in the blood, act on distant cells.
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Q: What role does cAMP have on cell repair?
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-Cyclic AMP is called a second messenger because it is second in line to be activated. First, the growth factor was activated and next cAMP is activated followed by a series of intermediate steps to finally stimulate target gene expression.
-activation of G-protein activates cAMP, cAMP activates a more restricted set of targets (PKA and cAMP-gated ion channels) |
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Q: How about IP3?
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-IP3 is also activated by activation of G protein, IP3 releases Ca2+ from the ER, Ca2+ signals target cytoskeletal proteins, Cl- and K+ activated ion pumps, enzymes (calpain) and Ca2+ binding proteins such as calmodulin
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Q: What role do cyclins have on controlling the cell cycle?
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-Cyclins are proteins, which help control the cell cycle. Cyclins perform their functions by forming complexes with a group of constitutively expressed proteins called cyclin-dependent kinases (CDK’s).
-activated CDKs drve the cell cycle by phosphorylating proteins that are critical for cell cycle transitions |
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Q: What are some examples of cyclins and what their functions are?
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-For example, the cyclin B/CDK1 function controls the transition from G2 to M.
-A major control of the transition from G1 to S is the retinoblastoma protein (Rb). Normally, Rb binds to and sequesters members of E2F, which are transcription factors. In this bound state they cannot travel to the nucleus and activate cell cycle genes. As G1 progresses specific CDK’s become activated which phosphorylate Rb. E2F is released from Rb and travels to the nucleus, genes for entry into S phase are activated and the cell progresses into S phase. Rb is mutated in a variety of cancers and will be discussed further in the future. |
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Q: What regulates CDK function?
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-tightly regulated by CDK inhibitors, some growth factors shut off production of these inhibitors
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Q: What role do checkpoints play in regulating the cell cycle?
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-Checkpoints are another way the cell cycle is regulated. Checkpoints are activated by problems with DNA replication and DNA damage to ensure they do not complete replication. When activated, checkpoints send signals to the cell cycle machinery that arrest the cell cycle. Checkpoints allow time for DNA repair and decrease mutations. A common tumor suppressor gene, p53, is activated by DNA damage. This inhibits the cell cycle by increasing expression of the CDK inhibitor, p21. In many neoplasms, p53 has been lost or mutated.
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Q: What are the different checkpoints in the cell cycle?
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-the G1/S checkpoint checks the integrity of DNA before replication, whereas the G2/M checkpoint checks DNA after replication and monitors whether the cell can safely enter mitosis
-checkpoint activation delays the cell cycle and triggers DNA repair mechanisms |
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Q: What role does the ECM play in cell repair?
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-Cells grow, move and differentiate in intimate contact with the ECM (extracellular matrix) and the matrix can directly influence the form and function of cells. So, the ECM is very important in tissue repair and wound healing.
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Q: Describe ECM.
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-secreted locally and assembles into a network in the spaces surrounding cells
-its functions include sequestering water that provides turgor to soft tissues and minerals that give rigidity to skeletal tissue, also function as a reservoir for growth factors controlling cell proliferation, important for cell-to-cell interactions and provides a substratum for cells to adhere, migrate and proliferate |
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Q: What are the consituents of the ECM?
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-fibrous structural proteins (collagen and elastin), diverse group of adhesive glycoproteins and proteoglycans and hyaluronic acid
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Q: What is the most important ECM protein?
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-Collagen is the most common ECM protein. There are about 14 different types of collagen. Collagen type IV is very important in basement membranes. Vitamin C is required for collagen synthesis. This appears to explain the poor wound healing observed in vitamin C deficiency (scurvy). Fibroblasts are the main cells, which produce collagen and many other proteins and components of the ECM.
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Q: What happens to ECM and parenchymal cells after tissue destruction?
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-Tissue destruction usually involves both parenchymal cells and the ECM. Replacement of the stromal framework usually occurs with collagen. This is called fibrosis or scarring
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Q: What are the four components of fibrosis/scarring?
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-1. formation of new blood vessels (angiogenesis)
-2. migration and proliferation of fibroblasts -3. deposition of ECM -4. maturation and organization of the fibrous tissue, also known as remodeling |
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Q: When injury beings, when do fibroblasts and vascular endothelial cells migrate to the are for cell repair?
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-repair begins early in inflammation, fibroblasts and vascular endothelial cells begin migrating into the area by 3 to 5 days. In many wounds the blood clot provides a provisional ECM for cell migration. The fibroblasts and endothelial cells form a specialized type of tissue called granulation tissue.
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Q: Describe granulation tissue.
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-It derives its name from sprouting capillaries protruding from the wound surface as minute red granules (has a pink, soft, granular appearance on the surface of wounds). At its peak, granulation tissue has more capillaries per unit volume than any other type of tissue. Seeing granulation tissue in a wound usually is a good sign that healing is proceeding normally and no infection is present.
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Q: What are the histological features of granulation tissue?
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-the formation of new small blood vessels (angiogenesis) and the proliferation of fibroblasts
-the new vessels are leaky allowing the passage of proteins and red cells into the extravascular space (so granulation tissue is edematous) |
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Q: What role do macrophages in the granulation tissue have?
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-Also found in granulation tissue are macrophages which clear debris, lymphocytes because wound healing is a type of chronic inflammation, fibrin and foreign material. Macrophages can phagocytize the foreign material as well as elaborate growth factors involved in fibroblast migration and proliferation. Macrophages are very important in wound repair and healing
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Q: What is the eventual fate of the granulation tissue?
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-Ultimately the granulation tissue scaffolding is converted into a scar composed of dense collagen, fragments of elastic tissue and other ECM components. Only a few blood vessels remain. Enzymes called matrix metalloproteinases degrade collagen and other ECM proteins. They are essential in the debridement of disrupted, dead tissue and its remodeling. They are called metalloproteinases because they depend on Zinc (a metal) ions for their activity.
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Q: When does angiogenesis begin?
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-Angiogenesis occurs when preexisting blood vessels send out capillary buds to form new blood vessels. This is also called neovascularization. This is essential to tissue remodeling. The precursor to endothelial cells are the angioblasts.
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Q: What stimulates angiogenesis?
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-VEGF, vascular endothelial growth factor, promotes angiogenesis.
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Q: Describe healing by first intention.
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-Healing of a clean, uninfected surgical incision, which is approximated by sutures, is called healing by first intention. The narrow incisional space fills with clotted blood, which serves as a matrix. Within 24 hours neutrophils move into the clot. Within 24 to 48 hours epithelial cells from the epidermal edges move toward each other and fuse beneath the surface scab. By day 3 the neutrophils have largely been replaced by macrophages. Granulation tissue is developing in the incision space. By day 5 the incision space is filled with granulation tissue and collagen fibrils are beginning to bridge the incision space. In the 2nd week there is continued accumulation of collagen and proliferation of fibroblasts. Regression begins with the neovasculature. By the end of the first month the scar is composed of cellular connective tissue devoid of inflammation and covered by an intact epidermis. The dermal appendages such as hair follicle and sweat glands, which were destroyed by the incision, are permanently lost.
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Q: What type of wounds undergo healing by fist intention?
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-wounds with opposed edges, this incision causes death of a limited number of epithelial and connective tissue cells as well as disruption of epithelial basement membrane continuity
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Q: Describe healing by second intention.
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-Healing by second intention occurs when skin wounds involve more extensive tissue disruption as in this example or with blunt force trauma or abscess formation. The wound involves a large defect, which must be filled in. The same sequence of events as in healing by first intention occurs but the inflammatory reaction is more intense and there are much larger amounts of granulation tissue. When the wound edges finally meet they begin a process called wound contracture. Fibroblasts with smooth muscle features (called myofibroblasts) are present and they contract to draw the original wound edges closer together. The wound defect eventually is filled with low vascularity scar tissue.
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Q: In healing by second intention, can parenchymal cells completely restore the original architecture?
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-regeneration of precnhymal cells cannot completely restore the original architecture and hence abundant granulation tissue grows in form the margin to complete the repair
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Q: How does healing by second intention differ from primary intention?
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-large tissue defects generate a larger fibrin clot, consequently the inflammatory reaction is more intense
-much larger amounts of granulation tissue are formed -wound contraction is present -substantial scar formation and thinning of the epidermis |
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Q: Describe wound contraction.
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-occurs in large surface wounds, the initial steps of wound contraction involve the formation of a network of actin-containing fibrobalsts at the edge of the wound. Permanent wound contraction requires the action of myofibroblasts (altered fibroblasts that have the ultrastructural characteristics of smooth muscle cells), contraction of these cells at the wound site DEC the gap between the dermal edges of the wound
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Q: Which type of healing heals faster and better?
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-Wounds heal faster and better with first intention. This is why stitches are used in so many minor wounds that you’ll be seeing in the ER and on Family Med. In an average surgical skin incision, the stitches are removed at the end of the first week. Wound strength is only 10% of the original “unwounded” skin. Wound strength increases rapidly over the next 4 to 12 weeks. It slows around the 3rd post-op month and eventually reaches a plateau of about 70 to 80% of the tensile strength of the original skin. Many people think healed wounds are stronger than normal skin. This is not so! But let’s say you have a particular area of “breakdown” in the peritoneum where a bowel loop is pushing through the wall. This is called a hernia. Here, the repaired wound is definitely stronger than the old wall area and that’s why it most likely will stay repaired for life.
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Q: What are some local and systemic factors that influence wound healing?
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-Nutritional factors such as vitamin C deficiency can retard healing. People in nursing homes can become protein deficient and this retards wound healing and contributes to causing pressure ulcers (also known as bedsores).
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Q: Describe bedsores.
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-These ulcers are usually caused by repetitive or continuous pressure. The above example is like a bad bedsore. So, relief of pressure is one factor in helping them heal.
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Q: With diabetics, how is there healing process efficiency and speed?
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-Diabetics can develop wounds, which slowly heal or don’t heal at all. These can occur on the feet and lower legs and are called diabetic ulcers. These usually have a neuro-vascular component. Maintaining appropriate blood glucose levels can help.
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Q: Does vascular disease complicate wound healing?
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-Vascular disease also contributes to poor wound healing and chronic ulcers. Venous stasis ulcers develop on the lower legs from poor venous drainage. Usually the area is edematous so various types of wraps and pressure are applied to try and control the edema. Arterial ulcers also occur on the legs and the underlying cause is artery disease. Surgery may help correct these types of ulcers.
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Q: What effect does chronic infection have on wound healing?
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-Chronic infection is a very important cause/factor in delaying wound healing. This is one reason why wounds are debrided. The old, necrotic tissue is cut away because it is a great culture media for bacteria. Usually oral or parenteral antibiotics needed rather than topical ones.
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Q: What effect do medications and mechanical factors have on wound healing?
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-Medications such as steroids slow wound healing, apparently by interfering with collagen synthesis and also by interfering with the inflammatory response.
-Mechanical factors such as early motion of wounds can delay healing. |
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Q: What effect does foreign material have on wound healing?
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-foreign material such as bone, glass and steel fragments will continue the inflammatory process and delay healing.
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Q: What happens with inadequate formation of granulation tissue?
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-There are some other problems, which can lead to improper wound healing. Inadequate formation of granulation tissue can lead to wound dehiscence, which is the pulling apart of the wound edges. Many of the factors discussed in the previous paragraph can contribute to dehiscence.
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Q: What are keloids?
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Excessive formation of the components of the repair process, such as excess collagen can lead to a raised, tumorous scar known as a keloid or hypertrophic scar.
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Q: Describe burn victim healing.
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In serious burns the resultant scar and healing can lead to contractures. The scarring becomes so tight that it interferes with the movement of one or more joints.
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Q: Give a summary of the steps that involve wound healing.
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-injury -> hemostasis (platelets, fibrin, fibronectin, transglutaminases)
-hemostasis -> inflammation (neutrophils, macrophages, lymphocytes, plasma proteins) -inflammation -> demolition (macrophages, collagenases) -demolition -> proliferation (granulation tissue (angiogenesis, extracellular matrix synthesis, wound contraction)) -proliferation -> maturation (collagen crosslinking, remodeling, capillary resorption) |
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Q: What is the function of macrophages/monocytes?
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-regulates inflammatory response, regulates coagulation/fibrinolytic pathway, regulates immune response
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Q: What are the primary inflammatory mediators for macrophages?
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-cytokines (IL-1, TNF-alpha, IL-6), lysosomal enzymes (acid hydrolases, serine proteases, metalloproteases (collagenase)), cationic proteins, prostaglandings/leukotrienes, plasminogen activator
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Q: Give an outline for the repair reponses after injury and inflammation.
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-injury leads to cellular and vascular reponse, can have persistent tissue damage or removal of the stimulus (acute injury)
-with persistent injury get fibrosis (examples include chronic inflammatory disease such as cirrhosis, chronic pancreatitis, and pulmonary fibrosis) -if the stimulus is removed can have parenchymal cell death associated with deep wounds or superficial wounds |
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Q: What happens with the different types of wounds form the outline listed above?
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-deep wounds-get scar formation (organization of exudate), examples include deep excisional wounds and myocardium infarction
-superficial wounds-get regeneration (restitution of normal structure), examples include liver regeneration after parial hepatectomy, superficial skin wounds and resorption of exudate in lobar pneumonia |
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Q: Describe VEGF.
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-vascular endothelial growth factor, potent inducer of blood vessel formation in early development (vasculogenesis) and has a central role in the growth of new vessels, promotes angiogenesis in tumors, chronic inflammation and healing of wounds
-single through three tyrosine kinase receptors |
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Q: Describe EGF.
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-epidermal growth factor, is mitogenic for a variety of epithelial cells, hepatocytes and fibroblasts, widely distributed in tissue secretions and fluids, such as sweat, salive, urine and intestinal contents
-produced by keratinocytes, marcophages, and other inflammatory cells that migrate into the area |
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Q: Describe TGF.
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-transforming growth factor, comes from macrophages, T cells, keratinocytes and many tissues, functions similarly to EGF, sitmulates replication of hepatocytes and certain epithelial cells
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Q: What are the different phases of wound healing?
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-inflammation (0.1-3 days), granulation tissue (0.3-10 days), wound contraction (3-30 days), then collagen accumulation and remodeling (30-100 days)
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Q: What factors are associated with best outcomes in reconstitution?
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-aggressive wound debridement with clearance of nonviable tissue
-use of antibiotics to organism in wound -rigid fixation of fractures -well-vascularized soft-tissue coverage with local flaps or free-tissue transfers |
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Q: What factors effect wound healing?
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-medications, blood supply, nutrition, size/shape of wound, diabetes, infection, foreign material, degree of immobilization, medications
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