8_Inflammation 2

Question 1

how are chemical mediators produced locally?

Answer 1

• produced locally by cells at site of inflammation
  
  • Stored in intracellular granules and rapidly released (e.g. histamine)
  • Synthesized de novo in response to a stimulus (e.g. prostaglandins, cytokines produced by macrophages, mast and lymphocytes)

Question 2

how are mediators derived from circulating inactive precursors?

Answer 2

derived from circulating inactive precursors that are activated at the site of inflammation.

• Plasma protease systems (complement, coagulation system, kinins)

Question 3

what do chemical mediators bind to?

how are they regulated?

Answer 3

• bind to: specific receptors on target cells.
  
  • Some mediators bind a very select population of cells, other mediators can bind various cells in different tissues, resembling a hormone.
  • Some mediators (ROS, lysosomal proteases) do not require receptors
• regulation: tightly regulated, short-lived:
  
  • enzymatically activated mediators quickly decay,
  • are inactivated by enzymes,
  • bound by inhibitors,
  • scavenged or eliminated by antioxidants.

Question 4

which cell types produce cell-derived chemical mediators?

Answer 4

• Tissue macrophages,
• mast cells,
• endothelial cells, and
• recruited leukocytes produce the cell-derived mediators.

Question 5

what are the plasma protein-derived chemical mediators?

Answer 5

• •complement,
• kinin,
• coagulation/ fibrinolysis system

Question 6

what are the 9 categories of chemical mediators?

Answer 6

1. arachidonic acid metabolites
2. cytokines/chemokines
3. lysosomal constituents
4. neuropeptides
5. nitric oxide
6. plasma proteins
7. platelet activating factor
8. reactive oxygen species
9. vasoactive amines

Question 7

vasoactive amine:

HISTAMINE

(derived, storage, use, characteristics, inactivation)

Answer 7

• derived from cells
• stored in preformed secretory granules in perivascular mast cells, circulating basophils, and platelets
• use:
  
  • first mediators released in acute inflammation
  • released by stimuli incl taumra, cold/heat, immune rxn, C3A or C5a, cytokines, neuropeptides
  • causes arteriolar vasodilation
• inactivated by histaminase soon after its release

Question 8

which chemical mediator is the main mediator of “immediate reversible” phase of increased vascular permeability in post-capillary venules, via endothelial cell contraction?

Answer 8

histamine is main mediator of immediate reversible phase

Question 9

vasoactive amine:

SEROTONIN

(derived, storage, release, fxn)

Answer 9

• derived: preformed vasoactive mediator, (neurotransmitter)
  
  • produced mainly in some neurons and enterochromaffin cells
• stored in platelet granules
• released from platelets during platelet aggregation
• fxn
  
  • induces vasoconstriction during clotting.
  • Platelets induced to aggregate when come in contact w/ extravascular collagen, Platelet Activating F, Adenine Diphosphate, antigen-antibody complexes.
  • regulates intestinal motility

Question 10

arachidonic acid metabolites:

EICOSANOIDS

Answer 10

• Derived from cells and newly synthesized (synthesis is increased at sites of inflammation and agents that prevent their synthesis diminish inflammation)
  
  • sources: Leukocytes, mast cells, endothelial cells, platelets
• Fxn: affect a variety of biologic processes, incl inflammation and hemostasis.
  
  • can mediate virtually every step of inflammation.
  • Act locally then spontaneously decay or enzymatically destroyed.
  • Released from cell membrane phospholipids by phospholipaseA2 activated by mechanical/physical stimuli, or by inflammatory mediators as C5a.
    
    • AA then cleaved by 1 of 2 pathways
      
      • Cyclooxygenase pathway stimulates the synthesis of prostaglandins and thromboxanes and
      • Lipoxygenase pathway produces leukotrienes and lipoxins

Question 11

what are the 2 cleavage pathways of arachidonic acid metabolites, and what does each pathway produce?

Answer 11

• Cyclooxygenase pathway stimulates the synthesis of prostaglandins and thromboxanes and
• Lipoxygenase pathway produces leukotrienes and lipoxins

Question 12

arachidonic acid is a substrate for enzymes resulting in which products?

Answer 12

• leukotriene 4 series (involves multiple steps)
  
  • Lipoxins inhibit inflammation, inhibiting PMN chemotaxis and adhesion to endothelium.
  • Platelets activated and adherent to leukocytes are important sources of lipoxins
• prostaglandin 2 series, both of which are pro-inflammatory.

Question 13

what effect do NSAIDs and Glucocorticoids have on arachidonic acid metabolites?

Answer 13

• NSAIDs (aspirin, ibuprofen), inhibit cyclooxygenase activity,
  
  1. thereby blocking all prostaglandin synthesis
  2. (therefore, efficacy in treating pain and fever).
• Glucocorticoids are potent inhibitors of various aspects of inflammation.
  
  1. Up-regulate gene for lipocortin 1 which
  2. inhibits activity of phospholipase A2 and thus
  3. inhibits release of AA from membrane phospholipids.

Question 14

platelet-activating factor:

(derived, fxn, effects)

Answer 14

named for ability to cause platelets to aggregate and degranulate

• Derived from membrane phospholipids by phospholipaseA2 in endothelium, neutrophils, platelets, macrophages.
• Acts on target cells expressing a specific receptor.
• Many pro-inflammatory effects:
  
  • Platelet aggregation/release reaction
  • Increases leukocyte adhesion, leukocyte degranulation activation/chemotaxis
  • Bronchoconstriction
  • 1000x more potent than histamine in inducing vasodilation, increased vascular permeability
  • Enhances synthesis of other mediators, particularly AA metabolites

Question 15

CYTOKINES:

derived, secretion stim by, fxn, major cytokines,

Answer 15

• Polypeptides secreted by cells (lymphocytes, macrophages & others) to modulate the function/differentiation of other cells.
  
  • produced during immune and inflammatory reactions to noxious stimuli and in specific immune response.
• Secretion stimulated by bacterial endotoxin, immune complexes, T-cell products generated during immune response
  
  • enter the circulation and act at distant sites to induce the systemic acute-phase response via endocrine action
• Fxn:
  
  • stimulate bone marrow precursors, thus replacing leukocytes
  • activation of endothelium to express adhesion molecules, enhance production of chemokines and eicosanoids, other mediators. TNF increases thrombogenicity of endothelium.
• The major cytokines in acute inflammation are IL-1, TNF, IL-6 and chemoattractant cytokines called chemokines.
  
  • IL-1 and TNF are produced by activated macrophages, mast cells, endothelial cells, some other cell types.
  • IL-1 activates tissue fibroblast, increase ECM
    *

Question 16

CYTOKINES as chemotaxins:

define, produced, functions, subsets

Answer 16

• define: family of small peptides acting as chemotactic agents for different subsets of leukocytes.
• production: produced transiently at sites of inflammation recruit particular cell populations to the site
• fxns:
  
  • Recruit leukocytes to sites of inflammation, activation, chemotaxis
  • Control normal anatomic segregation of t and b lymphocytes in different areas of lymph nodes and spleen
• subsets:
  
  • CXC subset act mainly on neutrophils (IL-8).
  • CC subset attract monocytes, eosinophils, memory T cells

Question 17

REACTION OXYGEN SPECIES:

derived, released, fxn, damage

Answer 17

• derived: via the NADPH (phagocyte) oxidase pathway
• released from neutrophils and macrophages activated by microbes
  
  • low levels, are proinflammatory and increase expression of other mediators like chemokine, cytokine, adhesion expression.
  • high levels –> cause tissue injury:
    
    • Endothelial damage, increasing permeability
    • Inactivation of anti-proteases, protein denaturation, ECM breakdown
    • Direct damage to various cells like red cells, tumor cells
• fxn: Aid in killing of ingested microorganisms and necrotic cells.
• damage: Extent of damage related to amount of ROS released and presence of sufficient quantities of antioxidants.

Question 18

NITRIC OXIDE:

define, half-life, isoforms

Answer 18

* define: soluble free radical gas produced enzymatically by NO synthetase (NOS)

• half-life: Half-life is seconds, so short- lived/range
• isoforms: 3 isoforms of NO w/ tissue distribution

1. In CNS, it regulates neurotransmitter release and blood flow
2. Endothelial cells produce NO (eNOS) constantly in low levels which causes smooth muscle relaxation/vasodilation.
3. NO synthesis is also inducible (iNOS) in macrophages, endothelium and other cells, induced via cytokines
   
   • Vasodilation
   • Inhibits all stages of platelet activation(adhesion, aggregation & degranulation)
   • Reduces leukocyte recruitment at inflammatory sites
   • Microbiocidal agent in activated macrophages.

Question 19

LYSOSOMAL CONSTITUENTS:

define, release, types

Answer 19

• Define: Enzymes and other bacteriocidal factors are potential mediators of inflammation and tissue destruction.
• Released from activated leukocytes during phagocytosis and cell death
• TYPES:
  
  • Acid proteases active in low-ph environment of phagolysosomes
  • Neutral proteases (elastase, collagenase, cathepsin) active in EC locations and cause tissue injury by degrading elastin, collagen and basement membrane

Question 20

NEUROPEPTIDES:

DEFINE, FXN, EX

Answer 20

• Fxn: can initiate inflammatory response
  
  • Small protein substance P that transmit pain signals
  • Nerve fibers containing substance P are common in the lung and GIT
  • Bind a specific receptor on endothelial cells and important in regulating vessel tone and can modulate vascular permeability.

Question 21

PLASMA PROTEASES:

mediators,

Answer 21

• Plasma protein derived mediators: complement, kinins, proteases activated during coagulation

Question 22

Complement:

define, initiation, and fxn of the following:

• C3a & C5a
• C3b
• C5-9

Answer 22

• define: series of inactive plasma proteins C1-C9 and their enzymatically activated derivatives that play an imp role in host defense and inflammation.
• Cascade can be initiated by the classical pathway, alternate pathway and a lectin pathway, all activating C3 to C3a and C3b
• Types
  
  • C3a & C5a: (anaphylatoxins), vasodilation and increase vascular permeability via inducing mast cells to release histamine
  • C5a: leukocyte activation, adhesion to endothelium, chemotaxis
  • C3b: acts like opsonin to enhance phagocytosis
  • C5-9: membrane attack complex (MAC), is made by multiple copies of C9 and kills bacteria by creating pores

Question 23

PLASMA PROTEASES:

Kinin Cascade

(define, and the following: X11a, Hageman factor, Bradykinin, Kallikrein)

Answer 23

• Kinin System is activated when Hageman Factor (XII) a ptn synthesized by liver and is activated by bm, collagen, platelets.
• Factors
  
  • Activated X11a initiates 4 systems kinin, clotting, fibrinolytic, and the complement
  • Hageman factor cleaves prekallikrein to kallikrein which in turn cleaves high molecular weight kininogen (HMWK) to form bradykinin.
  • Bradykinin causes early vasodilation, increased vascular permeability of venules and causes pain. Also, extravascular smooth muscle (bronchial) contraction like histamine.
    
    • Action of bradykinin is short lived coz degraded by kininases present in plasma and tissues.
  • Kallikrein, an intermediate in kinin cascade with chemotactic activity is a potent activator of XII, and thus links kinins to clotting system.

Question 24

PLASMA PROTEASES:

Clotting cascade

(define, mechanism (fibrin/fibrinogen, thrombin, factor Xa)

Answer 24

• Define: the clotting system consists of intrinsic and extrinsic pathways that culminate in thrombin cleaving fibrinogen to fibrin and small fibrinopeptides.
  
  • Fibrin forms the clot
  • Fibrinopeptides increase vascular permeability and chemotactic for leukocytes
• Thrombin participates by binding to protease-activated receptors on endothelium, enhancing leukocyte adhesion.
• Thrombin can convert C5 to C5a (links coagulation with complement) .
• Factor Xa, an intermediate in clotting system increases vascular permeability, transmigration of leukocytes from venules.

Question 25

chronic inflammation:

duration, simultaneous processes, characterized by

Answer 25

• Prolonged duration (weeks/months/years)
• May follow acute, but often begins on its own. Can be insidious, asymptomatic
  
  • Continuing inflammation, tissue injury and healing (often by fibrosis) proceed simultaneously.
• Characterized by:
  
  • Infiltration by mononuclear cells, tissue destruction, repair, fibrosis.

Question 26

CHRONIC INFLAMMATION:

during which processes is chronic inflammation the primary process?

Answer 26

• Persistant infections by bacteria, fungi, some viruses that evoke Delayed-type hypersensitivity
• Immune-mediated inflammatory diseases (autoimmune, allergy)
• Prolonged exposure to potentially toxic agents, foreign materials (silica)
• Mild chronic inflammation may be important in pathogenesis of Alzheimer disease, atherosclerosis, metabolic syndrome and type II diabetes, tumor development, etc.

Question 27

what are the chronic inflammatory cells and mediators?

Answer 27

• *Macrophage is the dominant cell. It is a component of both inflammatory and immune reactions.
• Blood monocytes derived from circulating blood monocytes, after they emigrate from blood to ECM to become resident tissue macrophages which are larger, more phagocytic and live longer.
  
  • Macrophages diffusely scattered in connective tissue, but more concentrated in liver, lung, spleen and lymph nodes, CNS and together form the mononuclear phagocyte system
  • Act like filters for particulate matter, microbes, as well as effector cells that eliminate microbes in both immune reponses.

Question 28

by which pathways are chronic inflammatory cells activated?

(classical vs. alternative)

Answer 28

• Tissue macrophages are activated by diverse stimuli and perform a range of functions. 2 major pathways of macrophage activation
• Classical macrophage activation is induced by bacterial LPS, foreign material, interferon-g secreted by T cells.
  
  • Classically activated macrophages produce lysosomal enzymes, ROS, NO to kill ingested microbes, secrete IL-1, IL-12, chemokines to increase inflammatory response.
• Alternative macrophage activation is induced by other cytokines such as IL-4 and IL-13 produced by T , other cells, mast cells, eosinophils.
  
  • Not actively microbiocidal, more involved in tissue repair by secreting growth factors promoting angiogenesis, activation of fibroblasts with increase in collagen secretion

Question 29

macrophage:

role(s) in host defense and inflammation

Answer 29

• ingest and eliminate microbes and dead tissues like neutrophils.
  
  • respond to T cell signals and are the most important phagocytes in cell-mediated immunity.
• Initiate the process of tissue repair and involved in scar and fibrosis
• Secrete many mediators of inflammation; cytokines like TNF,IL-1, chemokines and others important in initiating and propagating the inflammatory response.
• Display antigens to T cells and respond to signals from T cells; important for defense against many microbes by cell-mediated immunity.

Question 30

what happens to macrophages when:

1. when intiating stimulus is eliminated/inflammation abates
2. in chronic inflammatory sites

Answer 30

1. When initiating stimulus eliminated and inflammation abates, macrophages die or wander off into lymphatics.
2. In chronic inflammatory sites, macrophages accumulate. IFN-g can also induce macrophages to fuse to become multinucleated giant cells.

Question 31

LYMPHOCYTE:

functions; process of differentiation

Answer 31

• Lymphocytes (B & T) are mobilized in setting of any specific immune stimulus as well as non-immune mediated inflammation.
  
  • Major drivers of inflammation in autoimmune and other chronic inflammatory diseases.
• Lymphocytes leave bloodstream and travel through sites of inflammation.
  *

Question 32

describe the following differentiated lymphocyte functions?

• B cells
• CD4+ T cells
• TH1
• TH2
• TH17

Answer 32

• B cells differentiate to plasma cells with antibody production
• CD4+ T cells secrete cytokines that can promote inflammation and influence the nature of the inflammatory reaction. 3 types of CD4+ helper T cells
• TH1 cells produce cytokine IFN-g, activating macrophages by classical pathway.
• TH2 cells secrete IL-4, IL-5, IL-13 that recruit/activate eosinophils and stimulate alternative pathway of macrophage activation.
• TH17 cells secrete IL-17 that induces secretion of chemokines that recruit neutrophils and monocytes

Question 33

what is the purpose of interaction b/w lymphocytes and macrophages?

Answer 33

bi-directional interactions to propagate and expand chronic inflammation if stimulus persists

Question 34

what are the 3 chronic inflammatory cells and their respective mediators

Answer 34

• Eosinophils are characteristically found in inflammatory sites caused by parasitic infections, immune reactions mediated by IgE.
  
  • Eotaxin a chemokine derived from leukocytes and epithelial cells recruits eosinophils
  • Granules contain major basic protein which are toxic to parasites and cause epithelial cell necrosis.
• Mast cells are sentinel cells distributed widely throughout the body in connective tissue, respond to many stimuli and important in both acute and chronic inflammation
  
  • Bind IgE and important in type I hypersensitivity reactions (allergies)
  • Can secrete TNF, other cytokines
• Although neutrophils are hallmark of acute inflammation, can see some neutrophils in chonic inflammation due to persistance of bacteria, necrotic tissue or mediators elaborated by macrophages.
  
  • “Subacute” inflammation, “acute on chronic” inflammation.

Question 35

GRANULOMATOUS INFLAMMATION:

histo, predominant cell type, clinical presentation

Answer 35

• Distinctive histologic pattern of chronic inflammation.
• Activated macrophage is predominant cell (w/pale pink cytoplasm, resembling epithelial cells (epithelioid macrophages), arranged in aggregates called granulomas.
• Granulomas are surrounded by collar of lymphocytes, plasma cells and outer rim of fibroblasts, fibrosis.
• Multinucleated giant cells may be present. Nuclei arranged as a semi-circle around cell periphery are Langhans-type giant cells and common in TB.

Question 36

GRANULOMATOUS INFLAMMATION:

when is it encountered? describe the 3 settings under which it’s formed?

Answer 36

• Encountered in relatively few chronic immune and infectious diseases
• Form under 3 settings:
  
  1. Persistent T cell responses to certain infections (TB, leprosy, syphilis, cat scratch disease, deep fungal infections) in which T cell derived cytokines maintain chronic macrophage activation.
  2. Certain immune-mediated inflammatory diseases (Crohn’s disease)
  3. Disease of unknown etiology (sarcoidosis) and develop in response to inert foreign bodies (foreign body granulomas).

Question 37

purpose of granuloma formation, and what is the granuloma called in tuberculosis?

Answer 37

• Granuloma formation does not always eradicate the offending agent; merely walls it off.
  
  • but multiple destructive granulomas can damage tissues.
• In tuberculosis, the granuloma is referred to as a tubercle and often exhibits central caseous necrosis.

Question 38

what is the purpose of lymphatics (in relation to inflammation)?

when could lymphatics become secondarily inflamed?

Answer 38

• role of lymphatics in inflammation
  
  1. Drain the inflamed area –> reducing edema,
  2. carrying away debris and antigens to lymph nodes to initiate immune response (lymph node hyperplasia).
• secondary inflammation of lymphatics: can occur if microorganisms gain access, creating lymphangitis and lymphadenitis.

Question 39

bacteremia/septicemia:

define

Answer 39

occurs when microorganism is in blood and the mononuclear phagocytic system gets involved.

Question 40

Acute-phase reaction/ systemic inflammatory response syndrome:

define, most important mediators

Answer 40

• def: is a collection of systemic effects brought on by mediators in more widespread inflammation (severe bout of a viral illness like influenza)
• mediators:
  
  • Cytokines TNF, IL-1 and IL-6 are most important mediators of acute phase reaction and produced by leukocytes

Question 41

Acute-phase reaction/ systemic inflammatory response syndrome:

symptoms

Answer 41

• **Fever
  
  • develops when pyrogens (IL-1/TNF, LPS) stimulate PGE2 synthesis in vascular/perivascular cells in hypothalamus.
• Elevated plasma levels of acute-phase proteins
  
  • IL-6 stimulated hepatocytes secrete C-reactive protein (CRP)
  • Leukocytosis is common especially in bacterial infections
• Initial increased output of leukocytes from bone marrow, followed by increased production of white cells in bone marrow via Colony Stimulating Factor (CSF), thus compensating for consumption.
• Other manifestations of acute phase reaction
  
  • Increased heart rate & blood pressure,
  • decreased sweating,
  • shivering and chills, lethargy, malaise, anorexia (Likely due to cytokines affecting brain)

Question 42

tissue repair:

what initiates the process, and why is it important?

Answer 42

• Inflammation sets the process of repair in motion.
  
  • Repair/healing refers to the restoration of tissue architecture and function after an injury
• Critical to survival is ability to repair the damage caused by toxic agents and inflammation.

Question 43

what are the two process of tissue repair, and how are they similar/different?

(regeneration, vs. scar formation)

Answer 43

• Both regeneration and scar formation involve cell proliferation, a key feature of tissue repair.
• Regeneration: some tissues can replace damaged cells and return to a normal structure and function. Occurs by replication of uninjured cells that can divide and replacement from tissue stem cells.
  
  • Typical in rapidly dividing epithelia, some parenchymal organs (liver).
• Scar formation: if injured tissue is incapable of regeneration and/or there has been extensive damage to the supporting connective tissue matrix, repair occurs with some degree of scar formation.
  
  • Scar cannot function like lost parenchymal tissue, but helps maintain structural stability for what remains.
  • Fibrosis = scarring. Fibrosis is the extensive deposition of collagen in lungs, liver , kidney, others

Question 44

in cell proliferation,

which cell types proliferate, and what drives proliferation?

Answer 44

• Which cell types proliferate?
  
  • Remnants of the injured tissue, endothelial cells to form new blood vessels for nutrients, and fibroblasts to create new EC matrix/scar.
• Proliferation of these cell types is driven by polypeptide growth factors
  
  • The ability of the cells to respond to growth factors and divide determines the nature of the repair process.

Question 45

what are the key events in cell proliferation?

what controls this progression?

Answer 45

• Key events in cell proliferation are DNA replication and mitosis
  
  • These events are controlled by sequential steps of the cell cycle
  • Non-dividing cells are in G1 arrest or have left the cycle and in G0.
  • Growth factors push cells from G0 into active G1 phase and beyond.
• Progression of the cell cycle is controlled by cyclins and cyclin-dependent kinases.

Question 46

what affects the ability of tissues to repair themselves?

what are the 3 categories of tissues (based on the above)?

Answer 46

• intrinsic proliferative capacity –> affects ability of tissues to repair themselves
• 3 groups:
  
  • Labile tissues: composed of continuously dividing stem cell population to replace lost cells; readily regenerates after injury
  • Stable (quiescent) tissues: cells are in G0 with minimal replicative activity in normal state, but can be activated to proliferate rapidly by re-entering G1
  • Permanent tissues: are composed of terminally differentiated cells that are nonproliferative in post-natal life. Have left the cell cycle.

Question 47

Examples of labile tissues

Answer 47

• Labile tissues: composed of continuously dividing stem cell population to replace lost cells.
  
  • Surface epithelia in ducts, skin, GIT, GUT, airways.
  • Hematopoietic cells in bone marrow

Question 48

examples of stable/quiescent tissues

Answer 48

• stable: cells are in G0 with minimal replicative activity in normal state, but can be activated to proliferate rapidly by re-entering G1
  
  • Parenchymal cells of most solid organs, (liver, kidney, pancreas)
  • Mesenchymal cells (fibroblasts, endothelium, smooth muscle), important in wound healing

Question 49

examples of permanent tissue types

Answer 49

• permanent: are composed of terminally differentiated cells that are nonproliferative in post-natal life. Have left the cell cycle.
  
  • Most nerve cells, Cardiac muscle
• Limited stem cell proliferation occurs in brain and stem cells noted in cardiac tissue, but essentially, with no (or very little) ability to regenerate, repair in these tissues is dominated by scarring

Question 50

what type of tissue is skeletal,

and what types of tissue are found in MOST MATURE TISSUES?

Answer 50

• Skeletal muscle has some regenerative capacity with satellite cells, but scarring dominates.
• Most mature tissues contain 3 cell types, continuously dividing cells, quiescent cells that return to the cell cycle, and cells that have lost replicative ability

Question 51

how are stem cells characterized?

how are the two key types of stem cells different (embryonic vs. adult)?

Answer 51

• Stem cells characterized by 2 properties: self-renewal & asymmetric replication.
• Embryonic: Most undifferentiated, present in blastocyst, have extensive self renewal, can be cultured and induced to form specialized tissues of the 3 germ layers.
• Adult stem cells/ tissue stem cells
  
  • Less undifferentiated than ES cells
  • Lineage potential is often restricted to replacing cells in that particular organ (act primarily to maintain tissue homeostasis, replacing lost cells)
  • Hard to isolate most tissue stem cells –> *Hematopoietic stem cells are the exception, can purify them and used to treat leukemia, lymphoma.
  • Bone marrow also has mesenchymal SCs–> give rise to osteoblasts, chondroblasts, myoblasts.

Question 52

what are induced pluripotent stem cells?

Answer 52

• induced pluripotent stem cells (iPS): when the “stem-cell-ness” genes have been identified, isolated and inserted into patient’s differentiated cells
  
  • clinical usefulness TBD

Question 53

growth factors:

define, activation, products, mechanism

Answer 53

• define: proteins that stimulate survival/ proliferation of particular cells, and may promote migration, contractility, differentiation, and enhance synthesis of proteins in prep for mitosis.
• Activation: Operate by binding specific receptors, which activates a signal transduction system, which in turn modulates DNA transcription factors that regulate the expression of genes involved in cell proliferation.
• Products of genes –>
  
  • promote entry of cells into the cell cycle,
  • promote replication,
  • prevent apoptosis and enhance the synthesis of cellular proteins in preparation for mitosis.
• Fxn: by binding to specific cell surface receptors and triggering biochemical signals in cells. Signaling can be autocrine, paracrine or endocrine.

Question 54

epidermal growth factor:

define, production, fxn

Answer 54

• define: a mitogen for fibroblasts and keratinocytes,
• produced by activated macrophages, SG, keratinocytes
• fxn: stimulates epithelial growth over an ulcer and formation of granulation tissue.

Question 55

Fibroblast Growth Factor (FGF) :

production and function

Answer 55

• produced by macrophages, and others,
• fxn:
  
  • is chemotactic and mitogenic for fibroblasts,
  • stimulates angiogenesis,
  • wound contraction,
  • deposition of ECM.

Question 56

Transforming Growth Factor-b :

production, define, fxn

Answer 56

• produced by many cells.
• def: a chemotaxin, stimulates fibroplasia, angiogenesis.
• fxn:
  
  • Likely plays large role in fibrosis during chronic inflammation.
  • Also has anti-inflammatory role.
  • Stimulates hepatocyte proliferation.

Question 57

Vascular Endothelial Growth Factor (VEGF):

production and function

Answer 57

• produced by mesenchymal cells,
• fx:
  
  • stimulates proliferation of endothelial cells,
  • increased vascular permeability.

Question 58

what is the role of EXTRACELLULAR MATRIX in repair?

define, fxn

Answer 58

• ECM is a complex protein that assembles into a network that surrounds cells and constitutes a significant proportion of any tissue.
• Fxn:
  
  • Sequesters water, provides turgor to soft tissues and minerals, giving rigidity to bone
  • regulates the proliferation, movement & differentiation of the cells, by supplying a substrate for cell adhesion and serving as reservoir for GF.

Question 59

what are the 2 basic forms of extracellular matrix?

(interstitial matrix and basement membrane)

Answer 59

• Interstitial matrix is present in the spaces between cells in CT, and between epithelium and supportive vascular and smooth muscle structres. Synthesized by fibroblasts and major constituents are fibrillar collagen
• BM- highly organized around epithelial cells, and endothelial cells. Major constituents are type 4 collagen and laminin

Question 60

what are the functions of extracellular matrix?

Answer 60

• Mechanical support for cell anchorage and cell migration and maintenance of polarity
• Control of cell proliferation and differentiation by acting on cell surface integrins or by binding to growth factors
• Scaffolding for tissue renewal- Integrity of bm is critical for organized regeneration of tissues
• Establishment of tissue microenvironments- BM acts like a boundary between epithelium and CT, and forms part of filtration apparatus
• **Intact ECM is required for tissue regeneration, and if damaged, repair can be accomplished only by scar formation.

Question 61

role of regeneration in tissue repair:

Answer 61

• In labile tissues such as epithelia, cells lost are rapidly replaced by proliferation of residual cells and stem cells.
• Tissue regeneration in most parenchymal organs with stable cell populations is usually a limited process (except liver).
  
  • Pancreas, adrenal, thyroid, kidney: compensatory hyperplasia
• Liver regeneration is unique in that can remove 40-60% of liver and remaining parenchymal and stromal tissue will grow back.
• Such regeneration or compensatory hyperplasia can occur only if residual c.t. framework is intact
  
  • If there has been destruction of the connective tissue framework (following infection/inflammation) regeneration is incomplete and accompanied by scarring. Even the liver becomes fibrotic (cirrhosis).

Question 62

scar formation:

when does it occur, and what is the multistep process?

Answer 62

• scarring occurs when damage to parenchyma and connective tissue framework is extensive in chronic inflammation, or when permanent tissues are damaged and regeneration alone cannot repair the damage
• Process:
  
  • Formation of new blood vessels (angiogenesis)
  • Migration and proliferation of fibroblasts amongst new blood vessels with deposition of new “loose” extracellular matrix
  • Maturation and reorganization (remodeling) of the ECM to progressively more type I collagen, forming a scar. Vascularity also decreases.

Question 63

granulation tissues:

define

Answer 63

Early tissue with newly forming blood vessels and proliferating fibroblasts in loose stroma is pink and granular

Question 64

angiogenesis:

define

Answer 64

• process of new blood vessel development from existing vessels, primarily venules.
  
  • Critical in healing at sites of injury, in development of collateral circulation at sites of ischemia, and in allowing tumors to increase in size beyond their original blood supply.

Question 65

what are the steps/mechanism of angiogenesis?

Answer 65

• Vasodilation by NO, increased permeability by VEGF
• Separation of pericytes surrounding the vessel
• Migration of endothelial cells toward area of tissue injury
• Proliferation of endothelial cells behind the leading front of migrating cells and remodeling into capillary tubes
• Recruiting pericytes, smooth muscle cells to complete vessel wall
• Suppression of endothelial proliferation, migration and deposition of the basement membrane.
• VEGF and FGF-2 are most important, angiopoietins, PDGF help stabilize the new vessels

Question 66

describe the:

• chemokines involved in scar formation,
• early ECM, and
• which processes are involved in creating scar?

Answer 66

• PDGF, FGF-2, TGF-b stimulate fibroblasts to proliferate and migrate into the repair zone and begin synthesizing ECM to support the vasculature.
  
  • Granulation tissue.
• The early ECM tends to be loose to permit cells to migrate through it (rich in hyaluronic acid), but it undergoes remodeling over time transforming it into dense fibrous tissue as quantity of collagen increases.
  
  • Remodeling involves ECM breakdown by matrix metalloproteinases and synthesis of new, different ECM components over time. Connective tissue matrix changes dramatically over time.
• During remodeling, vascularity decreases, resulting ultimately in a minimally vascular scar.

Question 67

how do the following factors influence tissue repair?

(infxn, nutrition, glucocorticoids, mechanical factors, circulatory status, foreign bodies, size, aberrations in cell growth)

Answer 67

• Infection is single most important cause of delay in wound healing. Prolongs inflammation and increases destruction.
• Nutrition: protein deficiency, vitamin C deficiency inhibits collag
• Glucocorticoids have an anti-inflammatory effect, can weaken scar by inhibition of TGF-b, decreased fibrosis
• Mechanical factors: early motion of wounds can cause them to pull apart, dehisce.
• Circulatory status: inadequate blood supply via atherosclerosis and diabetes, venous blockage in varicose veins.
• Foreign bodies in wound such as glass, steel, suture, bone
• Size, location and type of wound
• Aberrations in cell growth, ECM deposition causing fibromatosis, keloids

Question 68

describe healing by first intention:

example, mechanism

Answer 68

ex: a clean, uninfected or sterile surgical wound, closed by sutures. Edges are approximated.

1. Narrow surgical space fills with fibrin clot.
2. Within 24 hours neutrophils have migrated into the clot, the epidermis is mitotically active and after 48 hours the epithelium has covered the wound with a basal layer.
3. By Day 3 neutrophils are replaced by macrophages, epidermis is thickening, granulation tissue invading the fibrin clot meshwork.
4. By Day 5 epithelium is normal thickness, angiogenesis is maximal
5. During the 2nd week fibroblasts and collagen become much more evident as edema, WBC, edema and vascularity on the decline.
6. By the end of a month a noticeable scar is present that is devoid of inflammation. Fibroblasts have decreased in number and blood vessels are sparse.
7. Skin appendages damaged are not replaced but are permanently lost.

Question 69

describe healing by second intention

(examples)

Answer 69

Ex: Wounds with separated edges

• Infarcts, ulcers, abscesses, surface wounds
• Larger tissue defect with more necrotic debris that has to be removed. Inflammation is generally more intense.
• Complex and involves regeneration and scarring
• Larger amounts of granulation tissue produced, with accumulation of ECM and formation of large scar.

Wound contraction by myofibroblasts is more obvious. Can decrease wound to 5-10% original size.

Question 70

wound strength after injury/inflammation?

Answer 70

• Sutured wounds have up to 70% of normal tissue strength
• When sutures removed at 1 week, wound strength is 10% normal tissue strength.
• Rapid increase in tensile strength of wound during next 4 weeks that gradually plateaus
  
  • Increased amount of collagen and increased crosslinking of collagen fibers.
• Final strength is about 70-80% original by 3 months and usually does not improve substantially beyond that point.

Question 71

describe the process flow of cell injury