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CMBM Exam 4 > Chronic Inflammation and Repair > Flashcards

Chronic Inflammation and Repair Flashcards

1
Q

Some products released by macrophages

A
  • Complement components (e.g., C1 to C5, properdin)
  • Enzymes
  • Cytokines, chemokines (IL-1, TNF, IL-8)
  • Growth factors (PDGF, EGF, FGF, TGF-beta)
  • Nitric Oxide
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2
Q

Actions of Chemokines

A
  • Activate adhesion molecules
  • Act thru G-protein coupled transmembrane receptors and caus Ca++ influx (actin effect)
  • Inude Haptotaxis (Cell migration along surface gradients)
  • Bind to proteoglycans and ECM
  • Induce oxygen burst
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3
Q

Chronic Inflammation therapies

A
  • Corticosteroids
  • Non-steroidals and other anti-inflammatories

*NSAIDS, aspirin, COX-2 inhibitors

*Nutrition; vit. D, E, C and folic acid are anti-inflammatory, Omega 3 fatty acids, Resveratrol

  • New therapies

*Pentoxifylline, thalidomide

*Infliximab, etanercept, adalimumab

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4
Q

Corticosteriods effect on chronic inflammation

A
  • Decrease transcription rates for IL-6 and IL-1Beta
  • Suppresses phospholipase A2, Cyclo-oxygenase 2, and NO synthase
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5
Q

Pentoxifylline and thalidomide effects

A
  • Suppress the release of TNF-alpha from phagocytes
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6
Q

Infliximab, Etanercept and Adalimumab effects

A
  • Block TNF-alpha, blocks the protein’s activity
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7
Q

Steps of the repair process (also known as organization)

A
  • Macrophages phagocytize necrotic debris and foreign matrial
  • At edges of damaged area proliferation of endothelia and fibroblasts
  • Endothelial cells grow into damaged area
  • Capillary formation and fibroblast migration form a loose connective tissue framework; this is called granulation tissue
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8
Q

Process of new vessel formation

A
  1. Proteolysis of parent vessel basement membrane; allows sprouting
  2. Migration of endothelial cells toward stimulus
  3. Proliferation of endothelial cells behind migrating edge
  4. Maturation of endothelial cells behind migrating edge
  5. Recruitment- pericytes for small vessels (capillaries), smooth muscle cells for large vessels- needed to support new vessels

*NOTE* All above steps depend on vascular cells, growth factors and extracellular matrix interactions

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9
Q

Growth factors regulating the repair process

A
  • VEGF

*receptors are confined to endothelial cells

*induced by hypoxia

*promotes angiogenesis, endothelial cell migration and proliferation, increased vascular permeability

  • TGF-beta

*induced by hypoxia

  • PDGF

*induced by hypoxia

  • EGF
  • FGF
  • Other regulators; Cytokines

*TNFa and IL-1 are fibrogenic cytokines- promote migration and proliferation of fibroblasts in granulation tissue

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10
Q

VEGF-C

A
  • Selectively induces hyperplasia of lymphatic vessels
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11
Q

Transforming growth factor-beta (TGF-B) Functions

A
  • Most widespread in mammals
  • Promotoes monocyte chemotaxis, fibroblast migration, collagen synthesis; inhibits collagenase secretion
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12
Q

Platelet-derived Growth Factor (PDGF) Functions

A
  • Dimers A and B
  • Stored in platelets alpha granules, released upon activation
  • Promotes monocyte chemotaxis, fibroblast migration and proliferation, collagen synthesis and collagenase secretion

*making collagen and breaking it down b/c the early collagen thats layed down is an immature collagen that is not forming a super-structure, its forming the initial ECM that needs to be digested away and put down in a more organized fashion

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13
Q

Epidermal Growth Factor (EGF) Functions

A
  • Binds to cERB1 receptor (has tyrosine kinase activity)
  • Distributed in tissue secretions (sweat, saliva, urine, intestinal contents)
  • Promotes fibroblast migration and proliferation
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14
Q

Fibroblast Growth Factor (FGF) Functions

A
  • Acidic FGF (FGF1) and basic FGF (FGF2) are two best characterized forms
  • Made constitutively; binds onto ECM proteins; hanging around waiting to release and bind to FGF receptors
  • Associates/binds to heparan sulfate proteoglycans in ECM- serves as a reservoir for local cell proliferation
  • Bound receptors have intrinsic tyrosine kinase activity
  • Promotes monocyte chemotaxis, fibroblast migration and proliferation, angiogenesis and collagenase secretion

*NOTE* Important in new blood vessel formation, wound repair, development and hematopoiesis

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15
Q

ECM Proteins

A
  • Proteoglycans- heparan sulfate, condroitin sulfate, dermatan sulfate

*Syndecan; a cell surface proteoglycan example

  • AlphavBeta3 integreins- critical for maintaining new blood vessels
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16
Q

Fibrosis

A

A. Fibroblast proliferation; collagen for the most part that is being layed down in response to damage and repair

*provisional stroma for fibroblast in-growth; granulation tissue

*growth factors promote migration and proliferation to site of injury of the fibroblasts

*TGFB most important- being made by the fibroblasts and other cells to turn on fibroblast to now lead to this massive production of collage to repair

*Expressed in chronic fibrotic diseases*

B. Extracellular matrix deposition

*more fibrillar collagen (Types I, II, III) made at this time; important for wound strength

*net collagen accumulation; a function of collagen synthesis + collagen degradation

C. Tissue remodeling

*replacing granulation tissue w/a scar; replacing immature w/mature

*Net result of ECM synthesis versus degradation

*degradation of collagen and other ECM proteins; matrix metalloproteinases (Zn++ dependent); e.g., interstitial collagenases, gelatinases, stromelysins

*MMPs are rapidly inhibited by tissue inhibitors of metalloproteinase (TIMPs)

17
Q

Wound Healing Summary of processes

A
  1. Induction of inflammation by injury
  2. Regeneration of parenchymal cells
  3. Migration and proliferation of parenchymal cells + connective tissue cells
  4. Synthesis of ECM
  5. Remodeling
  6. Collagenization and increased wound strength
18
Q

Healing by first intention (surgical incision example)

A

A. Incision- death of epithelial and connective tissue cells- basement membrane disruption- blood clot filled w/fibrin and blood cells- scab upon dehydration

B. 24hrs- PMNs at margins- migrate to clot- epidermis thickens at cut edge- mitotic activity of basal cells increased

C. 24-48hrs- epithelial spurs migrate and grow along margins of dermis- basement membrane laid down- epithelial cells fuse at midline

D. Day 3- PMNs replace by macs- granulation tissue invades incision space- vertically oriented collagen fibers apear at margins- epithelial cell layer thickens

E. Day 5- space filled w/granulation tissue- max. neovas.- more abundant collagen fibrils begin to bridge incision- epidermis obtains normal thickness- surface differentiates (normal architecture and keratinization)

F. Second week- collagen continues to accumulate- fibroblast also continue to proliferate- leukocyte infiltrate, edema, increased vessels have disappeared- blanching begins

G. End of first month- scar makes up cellular connective tissue- no inflammatory cells- wound covered by intact epidermis- dermal appendages in incision line permanently lost- tensile strength increases

*NOTE* maximal strength may take months to achieve

19
Q

Healing by second intention (wounds w/opposed edges)

A
  • Represents a large tissue defect that must be filled- as parenchymal cells cannot completely fill, abundant granulation tissue grows in from margins
  • Differences b/w this and first intention healing:
    i. inflammatory reaction more intense- more necrotic debris and exudates to be removed
    ii. larger amounts of granulation tissue formed
    iii. wound contraction- occurs in lg surface wounds- presence of myofibroblasts

*NOTE* Primary and secondary intention wound healing is determined by the nature of the wound, not by the healing process itself

20
Q

Wound Strength timeframe

A
  • Upon removal of sutures at end of first week- 10% strength of unwounded skin
  • Increases rapidly over next 4wks- 20% by 3rd wk
  • At third month rate slows, 60% by 4th month

*plateau reached at 70-80% of original tensile strength

  • Mature scare at 6-12 months (80% of original- defined now as maximal strength)
21
Q

Factors influencing wound healing

A
  • Local:
    a. persistent infection or foreign material
    b. inadequate blood supply
    c. excessive movement
    d. irradiation
    e. locally applied drugs, e.g., corticosteroids
  • Systemic:
    a. age- healing slower and less effective w/increasing age
    b. nutritional deficiencies, e.g., vit. C, Zinc, protein
    c. metabolic disease, e.g., renal failure, diabetes mellitus
    d. catabolic state assoc. w/malignancy
    e. systemic drugs, e.g., corticosteroids

CMBM Exam 4 (14 decks)

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