Ch. 3 - Inflammation and Repair Flashcards

Question

What is Leukocyte margination?

Answer 1

Normal blood flow confines RBCs to the central axial column This displaces leukocytes toward the wall of the vessel When blood flow slows in the event of inflammation, hemodynamic conditions change This change causes more white cells to assume a peripheral position along the endothelial surface It is important that WBCs travel along the walls of the vessel so they are in position to exit the vessel when responding to inflammation signals

Answer 2

Leukocytes roll along the walls of blood vessels to slow their momentum in order to be able to exit the blood vessel The initial rolling interactions are mediated by SELECTINS - L-selectin (leukocyte) - E-selectin (endothelium) - P-selectin (platelets) Expression selectins and their ligands is regulated by cytokines produces in response to infection and injury TNF and IL-1 act on the endothelial cells of POSTCAPILLARY VENULES adjacent to infection and induce coordinate expression of numerous adhesion molecules Within 1-2 hours the endothelial cells begin to express E-selectin and the ligands for L-Selectin The interaction of Selectins between the endothelium and leukocyte cause rolling to occur

Answer 3

Firm adhesion is mediated by a family of Heterodimeric Leukocyte Surface Proteins called INTEGRINS TNF and IL-1 induce endothelial epxression of ligands for integrins, mainly vascular cell adhesion molecule (VCAM-1)

Answer 4

Member of Immunoglobulin (Ig) superfamily It is an adhesion molecule present in the intercellular junctions between endothelial cells and is involved in the migration of leukocytes

Answer 5

Several adhesion molecuels present in the intercellular junctions between endothelial cells are involved in the migration of leukocytes Including CD31 (or PECAM-1; platelet endothelial cell adhesion molecule) After traversing endothelium, leukocytes pierce the basement membrane, probably by secreting COLLAGENASES, and enter the extravascular tissue The cells then migrate toward the chemotactic gradient created bychemokines and other chemoattractants

Answer 6

Leukocytes move in the tissues toward a site of injury via a process called chemotaxis Chemotaxis is defined as locomotion along a chemical gradient

Answer 7

Molecuels responsible for chemotaxis Bacterial products - Peptides that possess an N-formylmethionine terminal amino acid - Some lipids Cytokines - Particulary of the chemokine family (e.g., IL-8) Components of Complement System - Particularly C5a ``` Arachidonic acid (AA) metabolites - Mainly Leukotriene B4 (LTB4) ```

Answer 8

Chemoattractants bind to specific GPCRs on surface fo leukocyte Transduction signals result in activation of secondary messengers that increase cytosolic Ca2+, thus activating small GTPases of the Rac/Rho/CD24 family and other kinases These signals induce polymerization of actin at the leading edge of the cell Leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension (toward source of chemoattractants)

Answer 9

In most forms of acute inflammation, neutrophils predominate during the first 6-24 hours and replaced by macrophages in 24-48 hours After entering the tissues, neutrophils are short-lived They undergo apoptosis and disappear within 24-48 hours Macrophages not only survive longer, but may also proliferate in the tissues Thus they become the dominant population in prolonged inflammatory reactions

Answer 10

They are more numerous in the blood than other leukocytes They respond more rapidly to chemokines They may attach more firmly to adhesion molecules

Answer 11

1. Recognition of the offending agent by TLRs (toll-like receptors) and other receptors 2. Receptors deliver signals that activate leukocytes to phagocytose and destroy the offending agents

Answer 12

Mannose Receptors, Scavenger Receptors, and Receptors for various opsonins bind and ingest microbes

Answer 13

Macrophage receptor. It is a lectin that binds TERMINAL MANNOSE AND FUCOSE residues of glycoproteins and glycolipids Typically part of microbial cell walls

Answer 14

Bind a variety of microbes in addition to modified LDL particles Macrophage Integrins, notably Mac-1 (CD11b/CD18) may also bind microbes for phagocytosis

Answer 15

Opsonization is when microbes are targeted by phagocytes when bound with opsonin proteins Opsonization greatly enhances phagocytosis The major opsonins are IgG antibodies IgG is the breakdown product of C3 of the complement system as well as plasma lectins (notably mannose-binding lectin) Phagocytes express high-affinity receptors for opsonins

Answer 16

Once a particle is bound to the phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle. Phagosome then fuses with a Lysosomal granule, resulting in discharge of the granules contents into the phagolysosome Phagocytosis is dependent on polymerization of actin filaments Similar process to chemotaxis

Answer 17

Leukocytes use ROS, reactive nitrogen species (derive from NO), and lysosomal enzymes to destroy phagocytosed debris Most phagocytosed material are brought to the lysosome, segregating potentially harmful substances from the cells cytoplasm and nucleus Avoids damage to the phagocyte

Answer 18

ROS are prouced in the lysosomes of neutrophils An enzymatic reaction creates H2O2 (hydrogen peroxide) in the phagolysosome H2O2 cannot kill microbes Azurophilic granules of neutrophils contain MYLOPEROXIDASE (MPO) - Converts H2O2 into HClO (ClO-; hypochlorite; aka bleach) H2O2-MPO-halide system is most efficient bactericidal system of neutrophils

Answer 19

iNOS = Inducibe NO Species - kill microbes Production of iNOS is induced in phagocytes when they are activated by the cytokines (e.g., IFN-gamma) or microbial products In macrophages: - NO reacts with superoxide (O2-) to generate the highly reactive free radical PEROXYNITRITE (ONOO-) Similar to ROS, iNOS attack and damage the lipids, proteins, and nucleic acids of microbes and host cells

Answer 20

Lysosomes contain proteases that, when released, start breaking down various parts of both bacterial and host cells

Answer 21

Neutrophil Extracellular Traps They are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of microbes by trapping them in fibrils Basically a literal net

Answer 22

Extracellular traps consist of a viscous meshwork of NUCLEAR CHROMATIN that binds and concentrates granule proteins such as antimicrobial peptides and enzymes In the process of NET formation, the nuclei of the neutrophils are lost, leading to death of the cells

Answer 23

Once leukocytes become activated, their effector mechanisms do not distinguish between offender and host. The microbical substances that leukocytes produce within the phagolysosome (ROS, NO, lysosomal enzymes) are also released into the extracellular space, This causes dmage to normal cells and vascular endothelium The leukocyte response may amplify effects of the initial injurious agent

Answer 24

Inflammation declines after the offending agents are removed - Mediators of inflammation are no longer present Neutrophils also have short half lives in tissues - Die by apoptosis within hours after leaving the blood Inflammation process itself triggers a variety of stop signals that actively terminate the reaction

Answer 25

Mast cells - Normally present in the connective tissue adjacent to blood vessels Blood Basophils Platelets

Answer 26

Histamine causes vasodilations of arterioles Histamine causes increased permeability in Post-capillary Venules Histamine causes contraction of some smooth muscles

Answer 27

Every tissue Lipid modulators prostaglandins and leukotrienes are PRODUCED FROM ARACHIDONIC ACID (AA) AA is present in membrane phospholipids Mechanical, chemical, and physical stimuli or other mediators (C5a) release AA from membrane phospholipids through the action of cellular phospholipases Mainly phospholipase A 2

Answer 28

Prostacyclin is a VASODILATOR and a potent INHIBITOR of PLATELET AGGREGATION It also potentiates the permeability-increasing and chemotactic effects of other mediators

Answer 29

Prostaglandin D2 i made by mast cells along with PGE2 PGD2 causes VASODILATION and INCREASES PERMEABILITY of postcapillary venules Potentiates edema

Answer 30

Prostaglandin E2 is a HYPERALGESIC Means that is makes the skin hypersensitive to painful stimuli such as intradermal injections It is involved in cytokine-induced FEVER during infections pgEEEE2 FEEEEver

Answer 31

Platelets contain the enzyme Thromboxane Synthase Thus, Thromboxane A2 (TxA2) is the major product in these cells TxA2 is a potent Platelet-Aggregatig Agent and VASOCONSTRICTOR It is very unstable and rapdily converts to its inactive form TxB2

Answer 32

Cyclooxygenase Inhibitors - Aspirin - NSAIDs (ibuprofen) They inhibit both COX-1 and COX-2 Thus they inhibit Prostaglandin synthesis

Answer 33

Leukotrienes are produced by Leukocytes and Mast Cells by the action of Lipoxygenase They are involved in vascular and smooth muscle reactions and leukocyte recruitment

Answer 34

Leukotriene B4 is a potent chemotactic agent and activator of neutrophils Causes aggregation and adhesion of the cells to venular endothelium Causes generation of ROS Causes release of Lysosomal Enzymes

Answer 35

Leukotrienes C4, D4, and E4 are cysteinyl-containing leukotrienes They cause intense - Vasoconstriction - Bronchospasms - Increase permeability Leukotrienes are more potent than is Histamine in increasing vascular permeability and causing Bronchospasms

Answer 36

Lipoxygenase inhibitors: - 5-lipoxygenase is not affected by NSAIDs Pharmacological agents Zileuton or Montelukast inhibit leukotriene synthesis Useful for treating asthma

Answer 37

TNF (tissue necrosis factor) and IL-1 (interleukin-1) are CYTOKINES that serve critical roles in Leukocyte Recruitment Promote adhesion of leukocytes to endothelium and their migration These cytokines are produced by macrophages and Dendritic Cells TNF Augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates microbicidal activity of macrophages - Induces production of NO IL-1 activates fibroblasts to syntehsize collagen and stimulates proliferation of synovial and other mesechymal cells IL-1 stimulates TH17 responses, which induce acute inflammation IL-1 and TNF (plus IL-6) induce systemic acute-phase responses associated with infection or injury, INCLUDING FEVER TNF suppresses appetite, contributing to cachexia (muscle wasting)

Answer 38

Implicated in the syndrome of sepsis, along with IL-1 and TNF Come from macrophages

Answer 39

IL-17 specifically comes from T cells Serves in recruitment of neutrophils and monocytes/macrophages

Answer 40

IFN-gamma comes from T cells and NK (natural Killer) cells Helps in the activation of macrophages (increasing its ability to kill microbes and tumor cells)

Answer 41

Complement proteins come from the liver They circulate in the plasma in their inactive form

Answer 42

Triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen GM makes CLASSIC cars

Answer 43

Triggered by: - Microbial surface molecules (e.g., endotoxin, or LPS) - Complex polysaccharides - Cobra venom - Other substances in the absence of antibody

Answer 44

Plasma Mannose-Binding LECTIN binds to carbohydrates on microbes Directly activating C1

Answer 45

All 3 pathaways cause the formation of C3 Convertase C3 convertase splits C3 into C3a and C3b C3a is relased, while C3b binds to the cell which complement is being activated More C3b binds to previously generated fragments to form C5 Convertase C5 convertase splits C5 into C5a and C5b C5a is released while C5b attaches to cell surface C5b binds to late components (C6-C9) culimating in the formation of the Membrane Attack Complex (MAC, composed of multiple C9 molecules)

Answer 46

Inflammation Opsonization and Phagocytosis Cell Lysis

Answer 47

C3a, C5a, and C4a are cleavage products of the corresponding complement components They stimulate histamine release from mast cells Histamine causes increased vacular permeability and causes vasodilation C5a is also chemotactic (attractant) for neutrophils, monocytes/macrophages, eosinophils, and basophils C5a also activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes, causing further release of inflammatory mediators (leukotrienes)

Answer 48

C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins Opsonins promote phgocytosis by neutrophils and macrophages

Answer 49

The deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis) Important for killing microbes with thin cell walls

Answer 50

C1 inhibitor (C1 INH) blocks the activation of C1, the first protein in the CLASSICAL PATHWAY Inherited deficiency of this inhibitor is the cause of hereditary angioedema

Answer 51

Decay Accelerating Factor prevents formation of C3 convertases CD59 inhibits formation of the MAC Acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells Disease called Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 52

Serous Inflammation Fibrinous Inflammation Purulent (suppurative) inflammation/abcess Ulcer

Answer 53

Serous inflammation is marked by exudation of Cell-Poor Fluid into spaces created by cell injury or into body cavities lined by peritoneum, pleura or pericardium EFFUSION

Answer 54

Fibrinous exudate develops when vascular permeability allows LARGE molecules such as FIBRIN to pass out of the blood OR there is local procoagulant stimulus (malignant cells) Fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as meninges, pericardium, and pleura

Answer 55

Purulent inflammation is characterized by production of pus - Exudate consisting of neutrophils, liquefied debris of necrotic cells, and edema fluid Most often caused by infection with bacteria taht cause liquefactive necrosis

Answer 56

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue

Answer 57

Resolution Fibrosis Chronic Inflammation

Answer 58

Resolution invovles: - Clearance of injurous stimuli - Clerance of mediators and acute inflammatory cells - Replacement of injured cells - Normal function

Answer 59

Two paths can occur Either the acute inflammation causes the formation of an abcess (pus formation) and then heals to become fibrotic OR Acute inflammation heals and directly becomes fibrotic Fibrosis - Scar formation LOSS OF FUNCTION

Answer 60

Either it is directly stimulated through: - Viral infection - Chronic Infections - Persistent Injury - Autoimmune Disease OR It progresses from an acute inflammation that began as: - Infarction - Bacterial infections - Toxins - Trauma

Answer 61

Persistent Infections - Microorganisms that are difficult to eradicate - Myobacteria - Viruses - Fungi - Parasites Hypersensitivity Diseases - Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system Prolonged exposure to potentially toxic agents - Exogenous - Or endogenous

Answer 62

Acute inflammation is manifested by vascular changes, edema, and predominantly neutrophilic, CHRONIC INFLAMMATION is characterized by: - Infiltration of Mononuclear Cells (macrophages, lymphocytes, and plasma cells) - Tissue destruction, induced by persistent offending agent or by the inflammatory cells - Attempts at healing by connective tissue replacement of damaged tissue - Acomplished by angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis -SCARRING

Answer 63

Liver = Kupffer cells Spleen and lymph nodes = Sinus Histiocytes Central nervous System = Microglial Cells Lungs = Alveolar Macrophages/dust cells Skin = Langerhans Cells Monocytess = Blood

Answer 64

M1 / Classical Pathawy M2 / Alternative Pathway

Answer 65

May be induced by Microbial Products (endotoxin) Microbial products engage TLRs and other sensors T-cell derived signals, importantly the cytokine IFN-gamma, in immune responses; or by foreign substances (crystals and particulate matter)

Answer 66

Induced by cytokines other than IFN-gamma, such as IL-4 and IL-13, produced by T-lymphocytes and other cells

Answer 67

Classically activated Macrophages (aka M1 Macrophages) produce NO and ROS and up-regulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory reactions

Answer 68

Alternatively Activated Macrophages (aka M2 Macrophages) are not actively microbicidal and the cytokines may actaully inhibit the classical activation pathway Instead the principal function of M2 macrophages is in the TISSUE REPAIR They Secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.

Answer 69

Classically Activated macrophages (M1) are capable of injuring normal tissues Alternatively Activated Macrophages DO NOT injure tissues

Answer 70

Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophils have granules that contain major basic protein - highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells

Answer 71

Mast cells are also present in chronic inflammatory reactions. Because they secrete a plethora of cytokines, they may promote inflammatory reactions in different situations

Answer 72

Although neutrophils are characteristic of acute inflammation, many forms of chronic, lasting months, continue o show large numbers of neutrophils, induced by persistent microbes or by mediators produced by activated macrophages and T lymphocytes This pattern of inflammation has been called acute or chronic

Answer 73

Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation Macrophages: - Display antigens to T cells - Express membrane molecules (costimulators) - Produced Cytokines (IL-12 and others) that stimulate T cell responses - IL-12 increases IFN-gamma production Activated T cells, in turn, produce cytokines which recruit and activate macrophages, promoting more antigen presentation and cytokine secretion The result is a cycle of cellular reactions that fuel and sustain chronic inflammation

Answer 74

Granulomatous Inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis

Answer 75

Foreign Body Granuloma Immune Granuloma

Answer 76

A type of granuloma incited by relatively inert foreign bodies, in the absence of T-cell-mediated immune responses. Typically, foreign body granulomas form around materials such as Talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to prevent phagocytosis by a macrophage and do not incite any specific inflammatory or immune response

Answer 77

Type of granuloma caused by a variety of agents that are capable of inducing a persistent T-cell-mediated immune response This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self antigen

Answer 78

In H/E staining, activated macrophages in granulomas have pink granular cytoplasm with distinct cell boundaries and are called epitheloid cells (due to similarity to epithelial cells) Aggregates of epitheloid macrophages are surrounded by a collar of lymphocytes Older granulomas may have a rim of fibroblasts and connective tissue Frequently but not invariably, multinucleated giant cells 40 to 50 micrometers in diameter, are found in granulomas; these are called Langhans giant cells They consist of a large mass of cytoplasm and many nuceli, they derive from the fusion of multiple activated macrophages In granulomas associated with certain infectious organisms (myobacterium tuberculosis) a combination of hypoxia and free radical-mediated injury leads to a central zone of necrosis Grossly this has a granular, cheesy appearance, and is therefore called Caseous Necrosis (seen in tuberculosis)

Answer 79

- Tuberculosis - Leprosy - Syphilis - Cat-scratch Disease - Sarcoidosis - Crohn's Disease (inflammatory bowel disease)

Answer 80

Mycobacterium Tuberculosis Caseating granuloma (tubercle): focus of activated macrophages (epitheloid cells), rimmed by fibroblasts, lymphocytes, histiocytes, ocasional Lnaghans giant cells Central necrosis with shape-less granular debris. Acid-fast bacilli

Answer 81

Mycobacterium leprae Acid-fast bacilli in macrophages Noncaseating Granulomas

Answer 82

Treponema Pallidum Gumma: type of granuloma. Microscopic grossly visible lesion, enclosing wall of histiocytes, plasma cell infiltrate CEntral cells are necrotic without loss of cellular outline

Answer 83

Gram-negative bacillus Rounded or stellate granuloma containing central granular debris and recognizable neutrophils Giant cells uncommon

Answer 84

Unknown cause Noncaseating granulomas with abundant activated macrophages

Answer 85

Caused by immune rection against intestinal bacteria, possibly self antigens Occasional noncaseating granulomas in the wall of the intestine with dense chronic inflammatory infiltrate

Answer 86

Inflammation, even if localized, is associated with cytokine-induced systemic reactions that are collectively called the ACUTE-PHASE RESPONSE Cytokines TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction Other cytokines, notably Type I Interferons, also contribute to the reaction

Answer 87

Fever = elevation of body temp by 1-4 degrees C. More prominent of the manifestations of acute phase response Especially when inflammation is associated with infection Increase in body temp caused by prostaglandins that are produced in the vascular and perivascular cells of the HYPOTHALAMUS Prostaglandins, especially PGE2 (Eeee2; feeever) in the Hypothalamus stimulates the production of neurotransmitters that reset the temperature set point at a higher level NSAIDs, including aspiring, reduce fever by inhibiting prostaglandin synthesis

Answer 88

Exogenous Pyrogens - Bacterial products, such as LPS, stimulate leukocytes to release cytokines such as IL-1 and TNF (Endogenous Pyrogens) Endogenous pyrogens increase the enzymes (cyclooxygenases) that convert Arachadonic Acid (AA) into prostaglandins Acute Phase Proteins have beneficial effects during acute inflammation, but prolonged production of these proteins (especially SAA) in states of chronic inflammation causes secondary amyloidosis

Answer 89

Acute phase proteins are plasma proteins mostly synthesized in the LIVER, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli Three of the best known of those proteins are - C-reactive Protein (CRP) - Fibrinogen - Serum Amyloid A (SAA) protein

Answer 90

Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement They also bind chromatin, possibly aiding in clearing necrotic cell nuclei Serum amyloid is associated with secondary amyloidosis Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease

Answer 91

Fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual red cells This is the basis for measuring the erythrocyte sedimentation rate as a simple test for an inflammatory response caused by any stimulus

Answer 92

Another Peptide whose production increases in the acute phase response is the Iron-regulated peptide hepcidin Chronically elevated plsama concentrations of hepcidin reduce the availability of iron and are responsible for anemia associated with chronic inflammation

Answer 93

Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections The leukocyte count usually climbs to 15,000 or 20,000 cells/ml But sometimes it may reach extraordinarily high levels of 40k to 100k cells/ml These extreme elevations are referred to as leukemoid reactions, because they are similar to the white cell counts observed in leukemia and have to be distinguished from leukemia The leukocytosis occurs iniitally because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood referred to as a Left Shift

Answer 94

Other manifestations of the Acute phase Response include: - Increased pulse and blood pressure - Decreased sweating (because of redirection of blood flow from cutaneous to deep vascular beds; minimize heat loss through the skin - Rigors (shivering) - Chills (search for warmth) - Anorexia - Sleepiness - Malaise (feeling sick)

Answer 95

High blood Levels of cytokines (TNF and IL-1) cause various widespread clinical manifestations such as - DISSEMINATED INTRAVASCULAR COAGULATION - HYPOTENSIVE SHOCK - METABOLIC DISTURBANCES (including insulin resistance and hyperglycemia) This clinical triad is known as SEPTIC SHOCK

Answer 96

Regeneration Connective Tissue Deposition

Answer 97

Some tissues are able to replace damaged components and essentially return to a normal state This process if called regeneration Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate Ex: Rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver In other cases, tissue stem cells may contribute to the restoration of damaged tissue

Answer 98

AKA scar formation If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of CONNECTIVE (FIBROUS) TISSUE A process that may result in scar formation Although the fibrous scar is not normal, it provides enough structural stability that the injured tissue is usually able to function

Answer 99

Labile = continuously dividing tissues Cells of these tissues are continuously being lost and replaced by maturation from tissue stem cells and by proliferation of mature cells Labile cells include: - Hematopoietic Cells in bone marrow - Majority of surface epithelia (skin, oral cavity, vagina, and cervix, ducts draining exocrine organs, Gi tract, uterus, fallopian tubes, transitional epithelia of the urinary tract) These tissues readily regenerate after injury as long as the pool of stem cells is preserved

Answer 100

Cells fo this tissue are quiescent (in G0 stage) and have only minimal proliferative activity in their normal state However, these cells are capable of dividing in response to injury or loss of tissue mass Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney , pancreas They also include endothelia, fibroblasts, and smooth muscle Proliferation of these cells is particularly important in wound healing With the exception of liver, stable tissues have a limited capacity to regenerate after injury

Answer 101

The cells of permanent tissues are considered terminally differentiated and nomproliferative in postnatal life The majority of neurons and cardiac muscle cells belong to this category Skeletal muscle is usually classified as a permanent tissue But satelite cells attached to the endomysial sheath provide some regenerative capacity for muscle In permanent tissues, repair is typically dominated by scar formation

Answer 102

macrophages play a central role in repair by CLEARING offending agents and dead tissue They provide GROWTH FACTORS for theprolfieration of various cells They secrete CYTOKINES that stimulate fibroblasts proliferation and connective tissue synthesis and deposition The macrophages that are involved in repair are mostly of the alternatively activated (M2) type

Answer 103

Vascular Endothelial Growth Factors (VEGFs) mainly VEGF-A, simtulates both migration and proliferation of endothelial cells Thus initiating the process of capillary sprouting in angiogenesis NOTCH SIGNALING - Through cross-talk with VEGF, the Notch Signaling pathway regulates the sprouting and branching of new vessels and thus ensures that new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood ECM PROTEINS - Participate in the process of vessel sprouting in the angiogenesis, largely through interactions with integrin receptors in endothelial cells and by providing the scaffold for vessels growth ENZYMES IN THE ECM - Notably the matrix metalloproteinase (MMPs) degrade the ECM to permit remodeling and extension of the vascular tube

Answer 104

Transforming Growth Factor - Beta Is the most important cytokine for the synthesis and deposition of connective tissue proteins It is prouced by most of the cells in granulation tissue, including alternatively activated macrophages (M2) TGF-Beta stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of metalloproteinase TGF-Beta is involved in not only scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation TGF-Beta is also an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes

Answer 105

After deposition, the connective tissue in the scar continues to be modified and remodeled The DEGRADATION OF COLLAGEN and other ECM components is accomplished by a family of MATRIX METALLOPROTEINASES (MMPs) so called because they are dependent on metal ions (e.g., zinc) for their activity

Answer 106

Infection Diabetes Nutritional Status Glucocorticoids Mechanical Factors Poor perfusion Foreign Bodies Type and Extent of Tissue Injury Location of Injury

Answer 107

When an injury invovles only the EPITHELIAL LAYER, the principal mechanism of repair is Epithelial Regeneration Also called Primary Union Also called Healing by First Intention

Answer 108

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring

Answer 109

First intention healing occurs for an injury that involves only the epithelial layer The principal mechanism of repair is epithelial regeneration (First Intention Healing) Wound causes the rapid activation of coagulation pathways, which results in the formation of a blood clot on the wound surface As dehydration occurs at the external surface of the clot a scab covering the wound is formed Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot They release proteolytic enzymes that begin to clear the debris Basal cells at the cut edge of the epidermis begin to show increased mitotic activity - Within 24-48 hours, epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane components as they progress. The cells meet in the midline beneath the surface of the scab, yielding a thin but continuous epithelial layer that closes the wound Macrophages are key cellular constituents of tissue repair, clearing extracellular debris, fibrin, and other foreign material, and promoting angiogenesis and ECM deposition Collagen fibers are now evident at the incision margins By day 5, neovascularization reaches its peak Migration of fibroblasts to the site of injury is driven by chemiokines, TNF, PDGF, TGF-beta, and FGF Their subsequent proliferation is triggered by multiple growth factors, including PDGF, EGF, TGF-beta and FGF and the Cytokines IL-1 and TNF

Answer 110

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring In wounds causing large tissue deficits, the fibrin clot is large, and there is more exudate and necrotic debris in the wounded area Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed Much larger amounts of granulation tissue are formed Larger defects require greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium A greater volume of granulation tissue generally results in a greater mass of scar tissue At first a provisional matrix containing fibrin. plasma fibronectin, and Type III Collagen is formed But in 2 weeks, this is replaced by a matrix composed of primarily of Type I Collagen Ultimately, the original granulation tissue scaffold is converted into a pale, avascular scar, composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components The dermal appendages that have been destroyed in the line of the incision are permanently lost. The epidermis recovers its normal thickness and architecture By the end of the first month, the scar is made up of acellular connective tissue devoid of inflammatory infiltrate, covered by intact epidermis

Answer 111

Persistent tissue injury leads to chronic inflammation and loss of tissue Architecture Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other extracellular matrix proteins The net results is replacement of normal tissue by fibrosis The major cytokine involved in Fibrosis is TGF-Beta

Answer 112

Dehiscence (rupture of wound) Ulceration

Answer 113

Rupture of a wound Although not comon, occurs most frequently after abdominal surgery and is due to increased abdominal pressure Vomiting, coughing, or ileus can generate mechanical stress on theabdominal wound

Answer 114

Wounds can Ulcerate because of inadequte vascularization during healing For example: - Lower extremity wounds in the individuals with atherosclerotic peripheral vascular disease typically ulcerate Non healing wounds also form in areas devoid of sensation These neuropathic ulcers are occasionally seen in patients with Diabetic Peripheral Neuropathy

Answer 115

Excessive formation of the components of repair process can give rise to hypertrophic scars and KELOIDS The accumulation of excessive amounts of COLLAGEN may give rise to a raised scar known as a hypertrophic scar If the scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a KELOID

Answer 116

Exuberant Granulation is another deviation in wound healing consisting of the excessive amounts of GRANULATION TISSUE, which protrudes above the level of the surrounding skin and blocks reepithelialization (this process has been called, more literary fervor, PROUD FLESH Excessive granulation must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium. Fortunately rarely, incisional scars or traumatic injuries may be followed by exuberant proliferation of firoblasts and other connective tissue elements that may in fact recur after excision Called DESMOIDS or Aggressive Fibromatoses - these neoplasms lie in the interface between benign and malignant (though low-grade) tumors