chapter 4 notes
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Date Created: 01/28/15
Tissue repair restoration of tissue structure and function after an injury 71 0 Regeneration or replacement by connective brous tissue Cell Proliferation and Tissue Regeneration 71 0 Body organs and tissues are composed of two types of tissues 1 Parenchymal functioning cells of an organ or body part 2 Stromal contain supporting connective Ussues Cell Proliferation versus Differentiation 71 0 Cell proliferation process of increasing cell numbers by mitotic division 0 A balance of cell proliferation and death determines the size of cell population by apoptosis 0 Proliferation of injured parenchymal cells vascular endothelial cells and broblasts are driver by proteins called growth factors 0 Cell differentiation process whereby a cell becomes more specialized in terms of structure and function 0 All cell types come from a single cell the fertilized ovum 0 As embryonic cells increase in number they differentiate creating all different tissues and organs 0 Each progressive step it loses ability to develop different cell characteristics and stimuli that induce mitosis become limited 0 The more specialized cells cannot divide relying on progenitor or parent cells Progenitor cells are differentiated so that the daughter cells are limited to the same cell line but they have no reached the point of differentiation that preludes the potential for active proliferation Epithelial stem cells can differentiate into different cell types The Cell Cycle 727475 1 Synthesis and mitosis a 2 major phases b synthesis S phase takes 1012 hours i DNA synthesis occurs gives two separate sets of chromosomes one for each daughter cell c Mitosis M phase takes less than an hour i Phase of nuclear division and cytokinesis ii Formation of mitotic spindle and cell division with formation of two daughter cells 2 Gaps l and 2 a G1 i Postmitotic phase where deoxyribonucleic acid DNA synthesis ceases while ribonucleic acid RNA synthesis and protein synthesis and cell growth take place increase in organelle and cytoskeletal elements b G2 i Premitotic phase DNA synthesis ceases while RNA synthesis and protein synthesis continues enzymes and proteins are synthesized and moved to their proper sites 3 Gap 0 a After mitosis cell can leave cell cycle and remain in inactivity or reenter cell cycle at another time b Labile cells blood cells do not enter GO continue cycHng c Stable cells hepatocytes enter GO after mitosis but can reenter cell cycle when stimulated by the loss of other cells d Permanent cells neurons leave cell cycle and are no longer capable of cell renewal 4 Checkpoints and Cyclins a Checkpoints where cycle can be arrested if previous events have not been completed b GlSDmonitors whether DNA in chromosomes is damaged by radiation or chemicals c GZMDprevents entry into mitosis if DNA replication is not complete d Cyclins are proteins controlling entry and progression of cells through cell cycle i Activate proteins called CDKs ii CyclinCDK complexes are regulated by CDK inhibitors which are important in regulating cell cycle checkpoints during mistakes in DNA are repaired o lnterphase 61 S phase 62 o Gap l 61 Postmitotic phase where deoxyribonucleic acid DNA synthesis ceases while ribonucleic acid RNA synthesis and protein synthesis and cell growth take place 0 S phase DNA synthesis occurs gives two separate sets of chromosomes one for each daughter cell o 62 Premitotic phase DNA synthesis ceases while RNA synthesis and protein synthesis conUnues o M phase Phase of nuclear division and cytokinesis 0 GO When nutrient or growth factors are unavailable or cells become terminally differentiated cells can go to resting state called GO They can reenter cell cycle in response to extracellular nutrients growth factors hormones blood loss injury that trigger cell renewal Neurons and highly differentiated cells stay in GO 0 DNA damage checkpoints ensure daughter cell receives full complement of genetic information Cyclins are a family of proteins that control the entry and progression of cells through the cell cycle synthesized then degraded O Bind and activate cyclindependent kinases CDK CDK s phosphorylate target proteins expressed O inache o GZMDcyclin B and CDKl directs events leading to mitosis including DNA replication and assembly of mitotic spindle most important checkpoint o CDK inhibitors regulate cell cycle checkpoints during DNA replication mistakes are repaired 0 Cell cycle is reactivated by removing CDK inhibitors for nonproliferating cells and quiescent cells Potential implications for tissue repair Proliferative Capacity of Tissues 73 0 Capacity for regeneration o Continuously dividing or labile tissues Cells continue to replicate and divide throughout life replacing cells that are continually being destroyed Surface epithelial cells oral cavity vagina cervix Can regenerate after injury as long as stem cells are reserved Bleeding stimulates proliferation of replacement cells by bloodforming progenitor cells of the bone marrow 0 Stable tissues Cells normally stop dividing when growth ceases Remain quiescent in the GO stage Capable of regeneration when stimulated Capable of reconstituting the tissue of an organ Liver and kidney wound healing 0 Permanent tissues Stem Cells 73 Do not proliferate Terminally differentiated Do not undergo mitotic division in postnatal life Nerve cells neurons cardiac muscle cells Do not normally regenerate once destroyed replaced with brous scar tissue that lacks functional characteristics of the destroyed Ussue o lncompletely differentiated throughout life 0 As mature cells die the tissue is replenished by the differentiation of cells generated from stem cells Remain quiescent until needed for cell replenishment 0 When needed they divide producing other stem cells and cells that can carry out the functions of the differentiated cell 0 One daughter cell retains stem cell characteristics other daughter cell becomes progenitor cell leading to terminal differentiation 0 3 properties of stem cells 0 self renewal can undergo numerous mitotic divisions and remain undifferentiated o asymmetric replication after each cell division some progeny of the stem cell enter a differentiation pathway while others remain undifferentiated retaining their selfrenewal capachy a single stem cell can give rise to many cells needed for normal tissue repair or blood cell production 0 differential potential or potency totipotent stem cells are produced by fertilized ovum can differentiate into embryonic and extraembryonic cells pluripotent stem cells can differentiate into three germ layers of the embryo multipotent stem cells give rise to a family of cells like red blood cells and leukocytes unipotent stem cells produce one cell type but retain property of selfrenewal o 2 different categories of stem cells 76 o embryonic stem cells pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo can generate multiple cell lines 0 adult stem cells or tissue stem cells stem cells with the capacity to generate multiple lineages and are present in bone marrow and other tissues of adult individuals bone marrow stem cells have shown to have very broad differentiation capabilities 0 whether adult stem cells have a differentiation capacity similar to that of embryonic stem cells remains the subject of current debate and research regenerative medicine 0 the regeneration and restoration of damaged organs using embryonic and adult stem cells 0 therapeutic cloning In uence of Growth Factors 76 0 small proteins that increase cell size and cell division 0 growth factors can trigger cell proliferation assist in regulating the in ammatory process serve as chemoattractants for neutrophils stimulate angiogenesis generate ECM some stimulate proliferation of some cells and some inhibit cycling of others can have opposite effects on the same cell depending on its changing concentration during the healing process growth factors are produced by leukocytes recruited to the site of injury or activated at the site of the in ammatory process produced by parenchymal cells or stromal cells in response to injury or loss named for their tissue of origin 0 plateletderived growth factor PDGF broblast growth factor FGF or their biologic activity 0 transforming growth factor TGF or cells on which they act 0 vascular endothelial growth factor VEGF 0 TABLE 41 Signaling pathways are similar to those of other cellular receptors that recognize extracellular ligands o Signaling may occur in the cell producing the growth factor autocrine signaling o In cells in the immediate vicinity of the cell releasing the growth factor paracrine signaling 0 ln distant target cells through growth factors that are released into the blood stream endocrine signaling 0 The binding of a growth factor to its receptor triggers a series of events by which extracellular signals are transmitted into the cell leading to the stimulation or inhibition of gene expression 0 These genes typically have several functions Relieve blocks on cell cycle progression Cell proliferation Prevent apoptosis Enhance synthesis of cellular proteins for mitosis 0 Interest in growth factors inhibiting malignant cell proliferation Extracellular Matrix and CellMatrix Interactions 77 o 2 basic forms of ECM o the basement membrane surrounds epithelial endothelial and smooth muscle cells 0 interstitial matrix present in the spaces between cells in connective tissues and between the o ECM epithelium and supporting cells of blood vessels Secreted locally and assembles into a network of spaces surrounding tissue cells 3 basic components 0 brous structural proteins collagen elastin bers 0 waterhydrated gels proteoglycans and hyaluronic acid 0 permit resilience and lubrication adhesive glycoproteins bronectin laminin 0 connect matrix elements to one another and to cells integrins are a family of transmembrane glycoproteins that are main cellular receptors for ECM components like bronectin and laminin o bind to many ECM components 0 initiate signaling cascades that affect cell proliferation and differentiation broblasts reside in close proximity to collagen elastic and reticular bers and complex carbs in the ground substance ECM provides turgor to soft tissue and rigidity to bone supplies the substratum for cell adhesion it is involved in the regulation of growth movement and differentiation of the cells surrounding it and it provides for the storage and presentation of regulatory molecules that control the repair process Also provides scaffolding for tissue renewal Injury does not always result in restoration of normal structure unless ECM is intact o the integrity of the basement membrane is critical to regeneration of the tissue 0 if it is disrupted cells proliferate in a haphazard way resulting in disorganized and nonfunctional tissues transitions in the composition of the ECM are important in the process of wound healing transitional process ECM components are degraded by proteases enzymes that are secreted locally by a variety of cells 0 tightly controlled due to their potential to produce havoc so they are produced in an inactive form that must be activated by certain chemicals likely present at the site of injury and rapidly inactivated by tissue inhibitors collagenases are very speci c cleaving particular proteins at a small number of sites 0 allows for structural integrity of the ECM to be retained while healing occurs 0 research has focused on unregulated action of the proteases in disorders such as cartilage matrix breakdown in arthritis and neuroin ammation in multiple sclerosis Healing by Connective Tissue Repair 78 o extensive regeneration can occur only if the residual tissue is structurally and functionally intact if it is damaged by infection or in ammation then regeneration is incomplete and accomplished by replacement with scar tissue 0 when regeneration cannot occur healing by replacement with a connective brous tissue occurs a process that terminates in scar formation o brosis is extensive deposition of collagen that occurs in organs that are incapable of regeneration brous tissue grows into the area of damage converting it to a mass of brous tissue lorganization adhesions can trap loops of bowel and cause obstruction o Phases of Repair by Connective Tissue o Begins within 24 hours of injury 0 3 phases 1 hemostasis angiogenesis and ingrowth of granulation tissue a by 35 days granulation tissue is apparent which then progressively accumulates connective tissue resulting in a scar i involves angiogenesis the growth of new capillaries 1 involves endothelial cells migrating to the site of injury formation of capillary buds and proliferation of endothelial cells followed by fusion and remodeling of the endothelial cells into capillary tubes VEGF and FGF2 induce angiogenesis a VEGF stimulates both proliferation and mortility of endothelial cells while FGF2 stimulates proliferation of endothelial cells New blood vessels are leaky during angiogenesis because incompletely formed interendothelial cell junctions and because VEGF increases vascular permeability a This explains appearance of granulation tissue and swelling after acute in ammation ends ii granulation tissue is red moist connective tissue that lls injured area while necrotic debris is removed iii composed of newly formed capillaries proliferating broblasts and residual in ammatory cells 2 emigration of broblasts and deposition of ECM 79 a scar formation on granulation tissue framework of new vessels and loose ECM b two phases emigration and deposition ofECM i emigration is regulated by FGF2 and TGFB c as healing progresses proliferating broblasts and formation of new vessels decrease while synthesis and deposition of collagen increase i collagen synthesis develops strength in healing wound site d the scar composed of largely inactive spindleshaped broblasts dense collagen bers fragments of elastic tissue and ECM components e vascular degeneration eventually transforms the vascular granulation tissue into a pale largely avascular scar 3 maturation and remodeling of the brous tissue 79 a shifts in modi cation and remodeling of the ECM help transition from granulation tissue to scar tissue b the outcome of repair process is balance between ECM synthesis and degradation c rate of collagen synthesis diminishes until equilibrium with collagen degradation is reached d metalloproteinases require zinc help degrade collagen and other ECM proteins i synthesis and secretion of these are regulated by growth factors cytokines ii released as inactive precursors that require activation by enzymes like proteases iii suppressed by corticosteroids Cutaneous Wound Healing 79 o Involves both epithelial cell regeneration and connective tissue scar formation 0 Healing by Primary and Secondary lntention 79 o A sutured surgical incision is primary intention while larger wounds where greater loss of tissue and contamination is secondary intention 0 Secondary intention lasts longer and has larger amounts of scar tissue 0 A wound that might otherwise have healed by primary intention may become infected and heal by secondary intention Phases of Cutaneous Wound Healing 808283 1 In ammatory Phase a Begins at time of injury and prepares the wound for healing b Formation of blood clot hemostatic and migration of phagocytic white blood cells into the wound site cellular phase c First cells to arrive are neutrophils that ingest and remove bacteria and cellular debris gone by day 3 or 4 d Within 24 48 hours macrophages join them and they do phagocytosis and release growth factors that stimulate epithelial cell growth angiogenesis and attraction of broblasts e A wound cannot heal without macrophages but it can heal without neutrophils 2 Proliferative Phase a Usually begins in 23 days and focuses on building of new tissue to ll the wound space b Key cell in this phase if the broblast a connective tissue cell that synthesizes and secretes collagen proteoglycans and glycoproteins needed for wound healing and also growth factors that induce angiogenesis and endothelial cell proliferation and migration c 2448 hours after injury broblasts and endothelial cells begin proliferating to form granulation tissue for scar tissue development that bleeds easily i secondary intention have more necrotic debris and exudate to be removed takes more granulation tissue d the nal component is epithelialization where epithelial cells at the wound edges proliferate to form a new surface layer that is similar to that which was destroyed by injury i 2448 hours in primary intention ii when a signi cant portion of the wound has been covered with epithelial tissue the scab lifts off iii proud esh excessive granulation tissue can extend above edges of wound preventing reepithelialization e continued accumulation of collagen and broblasts 3 Remodeling Phase and Wound contraction 81 a Begins 3 weeks after injury and can continue for 6 months or longer Continued remodeling of scar tissue by simultaneous synthesis of collagen by broblasts and lysis by collagenase enzymes The scar becomes reoriented to increase the tensile strength of the wound making it less visible Carefully sutured wounds have 70 of the strength of unwounded skin because of placement of sutures ln secondary intention an injury undergoes wound contraction during proliferation and remodeling phase so that the scar is considerably smaller than the original wound i This can limit movement and cause deformities ii Scar tissue that is stretched fails to return to its original length f Keloid formation is an abnormality in healing i Benign tumorlike masses caused by excess production of scar tissue ii Develop in predisposed individuals and more common in African Americans and dark skinned people iii They lead to cosmetic defects like deformity and limiting joint mobility Factors that Affect Wound Healing 81 o Malnutrition impaired blood ow and oxygen delivery impaired in ammatory and immune responses infection wound separation and foreign bodies and age effects cause impaired wound healing o Nutritional status 0 Protein de ciencies prolong in ammatory phase and impair broblast proliferation collagen and protein matrix synthesis angiogenesis and wound remodeling Carbohydrates have a proteinsparing effect Fats are needed for synthesis of new cells Vitamin C is needed for collagen synthesis Vitamin C de ciency Administration of vitamin C and restore the 0000 healing process to normal 0 Vitamin A stimulates and supports epithelialization capillary formation and collagen synthesis Also counteracts corticosteroids o B vitamins help enzymatic reactions that contribute to woundhealing process 0 Vitamin K indirectly helps by preventing bleeding disorders that contribute to hematoma formation and infection 0 Sodium potassium calcium copper zinc and phosphorus Zinc is a cofactor in a variety of enzyme systems responsible for cell proliferation In animal studies it also aids in reepithelialization 0 Blood ow and oxygen delivery 83 o Arterial disease and venous pathology cause impaired wound healing o A decrease in blood volume may cause a reduction in blood ow to injured tissues 0 Molecular oxygen is required for collagen synthesis and killing of bacteria by phagocytic white blood cells Even a temporary lack of oxygen can result in the formation of lessstable collagen lschemic tissue wounds become infected more easily than wellvascularized Oxygen is required for neutrophils and macrophages to destroy microorganisms that invade the area They can accomplish phagocytosis in a anoxic environment but cannot digest bacteria All cells in wound environment are tted with specialized enzymes to convert oxygen to reactive oxygen species ROS 0 These ROS are cellular messengers stimulate cytokine action angiogenesis cell motility and extracellular matrix formation the central area of a wound has lower oxygen level topical oxygen therapy hyperbaric oxygen therapy increase oxygen delivery to tissues o Impaired In ammatory and Immune Responses 84 0 In ammation is essential to the rst phase of wound healing while immune mechanisms prevent infections that would impair wound healing o Phagocytic function diabetes mellitus and corticosteroid drugs impair in ammation and immune function 0 Extrinsic phagocytic disorders impair attraction of phagocytic cells to the wound cite prevent engulfment of bacteria and foreign agents by phagocytic cells opsonization or cause suppression of the total number of phagocytic cells immunosuppressive agents 0 Intrinsic phagocytic disorders are the result of enzymatic de ciencies in the metabolic pathway for destroying the ingested bacteria by the phagocytic cell Include chronic granulomatous disease 0 Infection wound separation and foreign bodies 84 o All wounds are contaminated at time of injury badly contaminated wounds can overwhelm host defenses which can result in wound infection 0 Increased local pressure or torsion can cause wounds to pull apart or dehisce o Sutures are foreign bodies too but are needed for closure of surgical wounds but still an impediment to healing Wound healing in the elderly 84 0 Most wounds heal although it may be delayed 0 Reduced rate of proliferation 0 Sun exposure 0 More vulnerable to chronic wounds chie y pressure diabetic ischemic ulcers
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