Exam III: Inflammation Part III Flashcards

Question

Stem Cells

Answer 1

Characterized by: self-renewal properties and capacity to generate differentiated cell lineages Need to be maintained during the life of the organism Achieved by two mechanisms: 1. Obligatory asymmetric replication: with each stem cell division, one of the daughter cells retains its self-renewing capacity while the other enters a differentiation pathway 2. Stochastic differentiation: stem cell population maintained by the balance between stem cell divisions that generate either two self-renewing stem cells or two cells that will differentiate

Answer 2

``` Bone marrow Skin Gut Liver Brain Muscle Cornea ```

Answer 3

Contains hematopoietic stem cells (HSCs) Contains stromal cells aka multipotent stromal cells, mesenchymal stem cells or MSCs Hematopoietic Stem Cells: generate all of the blood cell lineages, reconstitute the bone marrow after depletion caused by disease or irradiation

Answer 4

Widely used for the treatment of hematologic diseases Collected directly from: Bone marrow Umbilical cord blood Peripheral blood of individuals receiving cytokines: granulocyte-macrophage colony-stimulating factor, which mobilize HSCs; make the person have a fever and sick because the body is trying to produce all the cells to donate to someone else

Answer 5

Multipotent Potentially important therapeutic applications: generate chondrocytes, osteoblasts, adipocytes, myoblasts, and endothelial cell precursors Depends on the tissue to which they migrate Migrate to injured tissues Generate stromal cells or other cell lineages Do not participate in normal tissue homeostasis

Answer 6

Contains stem cells/progenitor cells in the canals of Hering: junction between the biliary ductular system and parenchymal hepatocytes Give rise to a population of precursor cells: oval cells, which are bipotential progenitors capable of differentiating into hepatocytes and biliary cells

Answer 7

Cells of the liver Function as a secondary or reserve compartment, which are activated only when hepatocyte proliferation is blocked Proliferation and differentiation during fulminant (sudden onset) hepatic failure, liver tumorigenesis, and chronic hepatitis and advanced liver cirrhosis

Answer 8

Neurogenesis from neural stem cells (NSCs) Occurs in the brain of adult rodents and humans AKA neural precursor cells Capable of generating neurons, astrocytes, and oligodendrocytes Identified in two areas of adult brains: Subventricular zone (SVZ) Dentate gyrus of the hippocampus

Answer 9

Even this process is not one of true regeneration Resection of tissue does not cause new growth of liver Triggers a process of compensatory hyperplasia in the remaining parts of the organ Other organs capable of compensatory growth Kidney, pancreas, adrenal glands, thyroid, and the lungs of very young animals Display it in less dramatic form than the liver

Answer 10

New nephrons cannot be generated in the adult kidney Growth of the contralateral kidney after unilateral nephrectomy Involves nephron hypertrophy Replication of proximal tubule cells In kidney, you take out one kidney, and the other side you will get nephron hypertrophy to increase function and handle the body enough Process like there were two but in one tissue

Answer 11

Limited capacity to regenerate exocrine components and islets Regeneration of pancreatic beta cells Beta-cell replication Transdifferentiation of ductal cells Differentiation of putative stem cells

Answer 12

Remarkable capacity to regenerate demonstrated by its growth after partial hepatectomy Tumor resection or for living-donor hepatic transplantation Resection of approximately 60% of the liver in living donors Doubling of the liver remnant in about one month Portions of the liver that remain after partial hepatectomy constitute an intact "mini-liver" rapidly expands and reaches the mass of the original liver Restoration of liver mass achieved without regrowth of resected lobes Growth occurs by enlargement of the lobes that remain after the operation= compensatory growth or compensatory hyperplasia End point of liver regeneration after partial hepatectomy Restitution of functional mass rather than the reconstitution of the original

Answer 13

Hepatocytes are quiescent cells G0 phase, but several hours to enter the cell cycle after a partial hepatectomy Progress through G1 and reach the S phase of DNA replication Wave of hepatocyte replication is synchronized followed by synchronous replication of nonparenchymal cells Kupffer cells, endothelial cells, and stellate cells Replication of non-paraenchymal cells to make ECM

Answer 14

Two major restriction points for hepatocyte replication: 1. G0/G1 transition that bring quiescent hepatocytes into the cell cycle 2. G1/S transition needed for passage through the late G1 restriction point Gene expression in the regenerating liver proceeds in phases Starts with the immediate early gene response Transient response that corresponds to the G0/G1 transition

Answer 15

Become competent to enter the cell cycle through a priming phase mediated by the cytokines TNF and IL-6, and components of the complement system Priming signals activate several signal transduction pathways as a necessary prelude to cell proliferation Under the stimulation of HGF, TGFα, and HB-EGF, primed hepatocytes enter the cell cycle and undergo DNA replication Norepinephrine, serotonin, insulin, thyroid and growth hormone: act as adjuvants for liver regeneration and facilitates the entry of hepatocytes into the cell cycle

Answer 16

Individual hepatocytes: replicate once or twice during regeneration and then return to quiescence in a strictly regulated sequence of events Intrahepatic stem or progenitor cells do not play a role in the compensatory growth that occurs after partial hepatectomy No evidence for hepatocyte generation from bone marrow-derived cells during this process

Answer 17

Tissue Repair and Regeneration depends on: 1 Activity of soluble factors 2. Interactions between cells and the components of the extracellular matrix Regulates the growth, proliferation, movement, and differentiation of the cells

Answer 18

1. Mechanical support- cell anchorage and migration, scaffolding, and maintenance of cell polarity (all lined up in a certain way) 2. Control of cell growth: ECM components can regulate cell proliferation by signaling through cellular receptors of the integrin family 3. Maintenance of cell differentiation: type of ECM proteins affect the degree of differentiation of the cells in the tissue 4. Scaffolding for tissue renewal: maintenance of normal tissue structure Requires a basement membrane or stromal scaffold Integrity of the basement membrane or the stroma of the parenchymal cells Critical for the organized regeneration of tissues

Answer 19

5. Establishment of tissue microenvironments: basement membrane boundary between epithelium and underlying connective tissue that forms part of the filtration apparatus in the kidney 6. Storage and presentation of regulatory molecules Growth factors FGF and HGF are secreted and stored in the ECM in some tissues Allows rapid deployment of growth factors after local injury or during regeneration

Answer 20

Composed of three groups of macromolecules 1. Fibrous structural proteins: collagens and elastins that provide tensile strength and recoil 2. Adhesive glycoproteins: connect the matrix elements to one another and to cells 3. Proteoglycans and hyaluronan: provide resilience and lubrication (especially to joints)

Answer 21

1. Interstitial matrix: found in spaces between epithelial, endothelial, and smooth muscle cells, as well as in connective tissue Consists mostly of fibrillar and nonfibrillar collagen, elastin, fibronectin, proteoglycans, and hyaluronan 2. Basement membranes: closely associated with cell surfaces Consist of nonfibrillar collagen (mostly type IV), laminin, heparin sulfate, and proteoglycans

Answer 22

Human epidermis has a high turnover rate: about 4 weeks Stem cells are located in three different areas of the epidermis 1. Hair follicle bulge: constitutes a niche for stem cells that produce all of the cell lineages of the hair follicle 2. Interfollicular areas of the surface epidermis: stem cells are scattered individually in the epidermis and are not contained in niches Divide infrequently, generate transit amplifying cells, and denerate the differentiated epidermis 3. Sebaceous glands

Answer 23

Small intestine 1. Crypts: monoclonal structures derived from single stem cells Stem cells regenerate the crypt in 3 to 5 days 2. Villus: differentiated compartment that contains cells from multiple crypts

Answer 24

Skeletal muscle myocytes do not divide, even after injury Growth and regeneration of injured skeletal muscle Occur by replication of satellite cells Located beneath the myocyte basal lamina Constitute a reserve pool of stem cells Generate differentiated myocytes after injury

Answer 25

Transparency of the cornea: integrity of the outermost corneal epithelium maintained by limbal stem cells (LSCs) Located at the junction between the epithelium of the cornea and the conjunctiva

Answer 26

Severe or persistent tissue injury: damage to parenchymal and stromal cells Leads to a situation in which repair cannot be accomplished by parenchymal regeneration alone Repair: occurs by replacement of nonregenerated parenchymal cells with connective tissue

Answer 27

Four components of repair process 1. Angiogenesis 2. Migration and proliferation of fibroblasts 3. Deposition of ECM 4. Remodeling (maturation and reorganization of the fibrous tissue)

Answer 28

Tissue repair begins within 24 hours of injury Stimulate the emigration of fibroblasts Induction of fibroblasts and endothelial By 3-5 days of tissue repair a specialized type of tissue appears Characteristic of healing “granulation tissue” Name from pink soft appearance of tissue seen beneath scab Characterized by fibroblast proliferation and new, thin walled delicate capillaries Outcome is formation of dense fibrosis (scarring)

Answer 29

Blood vessels are assembled by two processes: Vasculogenesis: assembly of primitive vascular network - from angioblast; in fetus only Angiogenesis or neovascularization: pre-existing blood vessels send out capillary sprouts

Answer 30

Critical process in the healing at sites of injury Development of collateral circulations at sites of ischemia is stimulated following MI or atherosclerosis Allows tumors to grow: inhibit blood flow to “starve” tumor growth

Answer 31

1. Vasodilation: response to nitric oxide VEGF-induced increased permeability of the preexisting vessel 2. Proteolytic degradation of the basement membrane of the parent vessel; use matrix metalloproteinases (MMPs) Disruption of cell-to-cell contact between endothelial cells by plasminogen activator 3. Migration of endothelial cells toward the angiogenic stimulus 4. Proliferation of endothelial cells just behind the leading front of migrating cells 5. Maturation of endothelial cells: includes inhibition of growth and remodeling into capillary tubes 6. Recruitment: periendothelial cells, pericytes and vascular smooth muscle cells to form the mature vessel

Answer 32

FGF (fibroblast growth factor) Mainly FGF-2 Stimulates proliferation of endothelial cells Promotes migration of macrophages and fibroblasts to the damaged area Stimulates epithelial cell migration to cover epidermal wounds

Answer 33

VEGF (vascular endothelial growth factor) Mainly VEGF-A Stimulates both migration and proliferation of endothelial cells Initiating the process of capillary sprouting in angiogenesis Promotes vasodilation by stimulating the production of NO Contributes to the formation of the vascular lumen *helps with sprouting of new vessels

Answer 34

Divided into three phases 1. Inflammation: initial injury causes platelet adhesion and aggregation and formation of a clot in the surface of the wound 2. Proliferation: formation of granulation tissue, proliferation and migration of connective tissue cells, and re-epithelialization of the wound surface; 3-5 days 3. Maturation: involves ECM deposition, tissue remodeling, and wound contraction * Phases overlap; separation is somewhat arbitrary

Answer 35

Simplest type of cutaneous wound repair: healing of a clean, uninfected surgical incision Approximated by surgical sutures Referred to as healing by primary union or by first intention

Answer 36

Death of a limited number of epithelial and connective tissue cells Disruption of epithelial basement membrane continuity Re-epithelialization to close the wound Occurs with formation of a relatively thin scar

Answer 37

Excisional wounds Repair process is more complicated Create large defects on the skin surface Extensive loss of cells and tissue

Answer 38

More intense inflammatory reaction Formation of abundant granulation tissue Extensive collagen deposition Leading to the formation of a substantial scar that generally contracts Healing by secondary union or by second intention Pull a wound together, but have granulation tissue deposition and collagen deposition If you don’t have a suture close the wound: a lot of granulation tissue and collagen = secondary union by second intention Secondary: big scab, wound contraction and end up with puckering of the skin

Answer 39

Wounding causes the rapid activation of coagulation pathways Formation of a blood clot on the wound surface Entrapped red cells, fibrin, fibronectin, and complement components Clot serves to stop bleeding and as a scaffold for migrating cells Attracted by growth factors, cytokines and chemokines released into the area Release of VEGF: increased vessel permeability and edema

Answer 40

Dehydration occurs at the external surface of the clot Forms a scab that covers the wound Within 24 hours, neutrophils appear at the margins of the incision Use the scaffold provided by the fibrin clot to infiltrate in Release proteolytic enzymes that clean out debris and invading bacteria In a cutaneous lesion, neutrophils appear within 24 hours… 6-24 hours for acute inflammation

Answer 41

Fibroblasts and vascular endothelial cells Proliferate in the first 24 to 72 hours of the repair process Form a specialized type of tissue Granulation tissue: HALLMARK OF TISSUE REPAIR

Answer 42

Granulation tissue: pink, soft, granular appearance on the surface of wounds Histologic feature: presence of new small blood vessels (angiogenesis) and proliferation of fibroblasts *Usually see edema because new vessels will be leaky

Answer 43

New vessels are leaky, which allow the passage of plasma proteins and fluid into the extravascular space New granulation tissue is often edematous Progressively invades the incision space

Answer 44

Amount of granulation tissue that is formed depends on: Size of the tissue deficit created by the wound Intensity of inflammation Much more prominent in healing by secondary union By 5 to 7 days, granulation tissue fills the wound area and neovascularization is maximal

Answer 45

Neutrophils are largely replaced by macrophages by 48 to 96 hours Macrophages are key cellular constituents of tissue repair Clearing extracellular debris, fibrin, and other foreign material at the site of repair Promoting angiogenesis and ECM deposition

Answer 46

1. Debridement/Removal of injured tissue and debris via phagocytosis, collagenase, and elastase 2. Antimicrobial activity using nitric acid and ROS 3. Chemotaxis and proliferation of fibroblasts and keratinocytes via PDGF, TGF beta, TNF, IL-1, and KGF-7 4. Angiogenesis via VEGF, FGF-2, and PDGF 5. Deposition and remodeling of ECM: TGF beta, PDGF, TNF, OPN, IL-2, collagenase, and MMPs

Answer 47

Migration of fibroblasts to the site of injury driven by chemokines TNF, PDGF, TGF-β, and FGF Proliferation is triggered by multiple growth factors PDGF, EGF, TGF-β, FGF, and the cytokines IL-1 and TNF Macrophages are the main source for these factors Need fibroblasts and go to site of injury via chemokines that attract them

Answer 48

Collagen fibers are present at the margins of the incision, which are vertically oriented and do not bridge the incision 24 to 48 hours, spurs of epithelial cells move from the wound edge along the cut margins of the dermis, depositing basement membrane components as they move. Fuse in the midline beneath the surface scab producing a thin, continuous epithelial layer that closes the wound (re-epithelializing)

Answer 49

Full epithelialization of the wound surface Much slower in healing by secondary union because the gap to be bridged is much greater Subsequent epithelial cell proliferation thickens the epidermal layer In primary intention: quick fix Secondary intention: takes a lot longer to re-epithelialize

Answer 50

Macrophages stimulate fibroblasts to produce FGF-7 (keratinocyte growth factor) and IL-6, which enhance keratinocyte migration and proliferation Signaling through the chemokine receptor CXCR 3 also promotes skin re-epithelialization Helps to proliferate the surface of the skin and get rid of scab: IL-6 and FGF-7 Start to see underneath dermis that the collagen fibers become more dense

Answer 51

Concurrently with epithelialization collagen fibrils become more abundant and begin to bridge the incision Provisional matrix containing fibrin, plasma fibronectin, and type III collagen is formed Replaced by a matrix composed primarily of type I collagen Type III collagen replaced by type I because it is much stronger

Answer 52

TGF-β is the most important fibrogenic agent Produced by most of the cells in granulation tissue Causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM by metalloproteinases Need more fibroblasts, fibronectin and collagen production to produce the scar

Answer 53

Leukocytic infiltrate, edema, and increased vascularity disappears during the second week and blanching begins Blanching: increased accumulation of collagen within the wound area and regression of vascular channels Encouraging scar to form and not allowing anything else to break down During the 2nd week, the swelling, redness, etc is gone without an infection present and the scar is present after the scab falls off

Answer 54

Original granulation tissue scaffolding is converted into a pale, avascular scar By the end of the first month Scar is made up of acellular connective tissue devoid of inflammatory infiltrate, covered by intact epidermis

Answer 55

Generally occurs in large surface wounds Contraction helps to close the wound by decreasing the gap between its dermal edges and by reducing the wound surface area Important feature in healing by secondary union Replacement of granulation tissue with a scar Involves changes in the composition of the ECM

Answer 56

Fibrillar collagens (mostly type I collagen) Form a major portion of the connective tissue in repair sites Essential for the development of strength in healing wounds Net collagen accumulation depends not only on increased collagen synthesis but also on decreased degradation

Answer 57

Length of time for a skin wound to achieve its maximal strength Sutures are removed from an incisional surgical wound End of the first week, wound strength is approximately 10% that of unwounded skin Wound strength increases rapidly over the next 4 weeks Slows down at approximately the third month after the original incision Reaches a plateau at about 70% to 80% of the tensile strength of unwounded skin

Answer 58

Lower tensile strength: healed wound area may persist for life Recovery of tensile strength Results from the excess of collagen synthesis over collagen degradation during the first 2 months of healing Structural modifications of collagen fibers (cross-linking, increased fiber size) after collagen synthesis ceases

Answer 59

Adequacy of wound repair may be impaired by systemic and local host factors Systemic factors include: 1. Nutrition: protein deficiency: Esp vitamin C deficiency, inhibit collagen synthesis and retard healing 2. Metabolic status: diabetes mellitus is associated with delayed healing, a consequence of the microangiopathy

Answer 60

Circulatory status: Modulate wound healing Inadequate blood supply, usually caused by arteriosclerosis or venous abnormalities (e.g., varicose veins) that retard venous drainage, also impairs healing Hormones: Glucocorticoids: well-documented anti-inflammatory effects and influence various components of inflammation Agents also inhibit collagen synthesis

Answer 61

Infection: sesults in persistent tissue injury and inflammation Mechanical factors: Early motion of wounds, can delay healing Compressing blood vessels and separating the edges of the wound

Answer 62

Foreign bodies: unnecessary sutures or fragments of steel, glass, or even bone, constitute impediments to healing Size, location, and type of wound: Richly vascularized areas, such as the face, heal faster than those in poorly vascularized ones, such as the foot Small incisional injuries heal faster and with less scar formation than large excisional wounds or wounds caused by blunt trauma

Answer 63

Local Factors: blood supply, denervation, local infection, foreign body, hematoma, mechanical stress, necrotic tissue, protection (dressings), surgical techniques, type of tissue Systemic Factors: age, anemia, drugs, genetic disorders, hormones, diabetes, malignant disease, malnutrition, obesity, systemic infection, temperature, trauma, hypoxia, uremia, vitamin deficiency, trace metal deficiency (zinc and coppe

Answer 64

Arise from abnormalities; three categories 1. Deficient scar formation 2. Excessive formation of the repair components/ scar formation 3. Formation of contractures

Answer 65

Lead to two types of complications 1. Wound dehiscence: rupture of a wound is most common after abdominal surgery due to increased abdominal pressure caused by vomiting, coughing, or ileus 2. Ulceration: inadequate vascularization during healing Areas devoid of sensation

Answer 66

Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids Accumulation of excessive amounts of collagen may give rise to a raised scar Hypertrophic scar: develop after thermal or traumatic injury and involves the deep layers of the dermis Keloid: individual predisposition and more common in African Americans; dense collagen bundles that can arise from a specific dermatome from surgerical incision

Answer 67

Deviation in wound healing Formation of excessive amounts of granulation tissue Protrudes above the level of the surrounding skin Blocks re-epithelialization Must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium

Answer 68

Important part of the normal healing process Exaggeration of this process gives rise to contractures and results in deformities of the wound and the surrounding tissues Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax Contractures are commonly seen after serious burns and can compromise the movement of joints

Answer 69

Denote the excessive deposition of collagen and other ECM components in a tissue Deposition of collagen in chronic diseases

Answer 70

Chronic Inflammation (persistent stimulus) causes: 1. Activation of macrophages and lymphocytes, which activate growth factors (PDGF, FGF, and TGF beta) 2. Cytokines (TNF, IL-1, IL-4, and IL-13) 3. Decreased metalloproteinase activity GF cause proliferation of fibroblasts, endothelial cells, and specialized fibrogenic cells Cytokines cause increased collagen synthesis Decreased metalloproteinase activity causes decreased collagen degradation *END RESULT = FIBROSIS

Answer 71

``` Injury and vascular response Persistent tissue damage= fibrosis caused by chronic inflammatory diseases Stimulus removed (acute injury): regeneration and repair ``` Regeneration (restitution of normal structure) if parenchymal cell death with intact tissue framework, superficial wounds, and acute inflammatory process Repair (scar formation) if parenchymal cell death with damaged tissue framework or deep wounds

Exam III: Inflammation Part III Flashcards

(95 cards)