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Med 105 > Mediators of Inflammation > Flashcards

Mediators of Inflammation Flashcards

1
Q

where are mediators of inflammation secreted from (2)

A

cells or platelet derived mediators

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2
Q

which cell derived mediators

a) normally sequestered in intracellular granules & rapidly secreted by exocytosis
b) synthesized de novo

A

a) histamine

b) leukotriens, prostaglandins, cytokines

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3
Q

what are examples of mediator producing cells

A

macrophages, dendritic c, mast c, platelets, neutrophils, endothelium, some epithelial c

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4
Q

where are platelet derived mediators produced and give an example

A

produced mainly in liver & are present in circulation as inactive precursors e.g. complement proteins

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5
Q

what are the vasoactive amine mediators

A

histamine and serotonin (5-hydroxytryptamine)

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6
Q

what cells are histamine found in

A

mast cells, blood basophils & platelets

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7
Q

what do mast cells, blood basophils & platelets degranulate in response to

A
  • physical injury; trauma, cold, heat
  • binding of Ab to mast c→ immediate hypersensitivty reaction
  • complements C3a & C5a (=anaphylotoxins)
  • neuropeptides e.g. substance P
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8
Q

what receptor does histamine act on

A

H1 receptors are on microvasculature

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9
Q

what does histamine cause

A

dilation of arterioles, increase permeability of venules, contraction of some smooth muscle

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10
Q

what is the function of serotonin

A

functions as a neurotransmitter in gastrointestinal tract (GIT)

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11
Q

what are the arachidonic acid metabolites

A

arachidonic acid
prostaglandins (PG)
leukotriens (LT)
lipoxins

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12
Q

where are arachidonic acids derived from

A

from dietary sources or by conversion from essential fatty acid linoleic acid

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13
Q

how is arachidonic acid stored

A

present in esterified form in membrane phospholips, not free in the cell

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14
Q

how is arachidonic acid released

A

activation of kinases by external stimuli, mediators like C5a & increase in intracellular calcium levels which activate phospholipase A2 and stimulate release of AA from the membrane

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15
Q

how are prostaglandins generated

A

by the action of cyclooxygenases COX-1 & COX-2

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16
Q

what are important prostaglandins

A
  • Thromboxane A2=TxA2 present in platelets, is a potent platelet aggregating agent vasoconstrictor
  • Prostacyclin=PGI2 synthesized in endothelium. Functions are; vasodilator, potent inhibitor of platelet aggregation
  • PGD2 & PGE2 made by mast cells, are vasodilators, increase permeability of postcapillary venules→edema
  • PGF2 stimulates the contraction of uterine & bronchial smooth muscles & small arterioles
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17
Q

PGF2 is hyperalgesic. what does this mean?

A

makes the skin hypersensitive to painful stimuli, involved in cytokine induced fever during infection

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18
Q

how are leukotriens produced

A

in leukocytes , mast cells by the action of lipooxygenases

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19
Q

what is the function of leukotriens

A

mainly involved in vascular & smooth muscle reactions & leukocyte recruitment

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20
Q

how are leukotriens different from histamine

A

they are more potent than histamine in increasing permeability & causing bronchospasm

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21
Q

what is the function of LTB4 (leukotriens)

A

potent chemotactic,
activator of neutrophils→aggregation, adhesion
generation of ROS
release of lysosomal enzymes

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22
Q

what do LTC4, LTD4, LTE4 (leukotriens) do

A

cause intense vasoconstriction, bronchospasm, increase in vascular permeability

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23
Q

what do lipoxins do

A

they supress inflammation

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24
Q

what does lipoxin do

A

they inhibit
• the recruitment of leukocytes,
• neutrophil chemotaxis
• adhesion to endothelium

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25
Q

how are lipoxins synthesized

A

neutrophils produce intermediates in lipoxin synthesis →converted to lipoxins when platelets interact with leukocytes.

26
Q

how can prostaglandins and leukotriens be inhibited

A
  • by inhibition of cyclooxygenases & lipooxygenases with drugs like aspirin, non-steroidal anti-inflammatory drugs e.g. ibuprofen
  • Corticosteroid hormones reduce the transcription of genes coding for a type of cyclooxygenase
  • LT receptor antagonists used in asthma treatment
27
Q

what are some cytokines

A

tumor necrosing factor (TNF)

interleukin-1

28
Q

what synthesizes

a) TNF
b) IL-1

A

a) macrophages, dendritic c, T cells, mast c

b) macrophages, dendritic c, some epithelial c

29
Q

what are the roles of cytokines

A
  • endothelial activation
  • activation of leukocytes & other cells
  • systemic acute phase response
30
Q

how do cytokines lead to endothelial activation

A
  • increased expression of endothelial adhesion molecules e.g. E-selectin & P-selectin, ligand for leukocyte integrins
  • increased production of various mediators; other cytokines, chemokines, growth factors, eicosanoids
  • increased procoagulant activity of the endothelium
31
Q

how do cytokines lead to activation of leukocytes & other cells

A
  • TNF augments responses of neutrophils to other stimuli (s.a. bacterial endotoxins) & stimulate the antimicrobial activity of macrophages.
  • IL-1 -activates fibroblasts to synthesize collagen
  • stimulates proliferation of synovial & other mesenchymal c.
  • stimulates TH17 response to induce acute inflammation
32
Q

how do cytokines systemic acute phase response

A

injury or infection causes fever through activation of cytokines like TNF, Type 1 interferon, IL-6, IL-17. Sustained production of TNF causes cachexia

33
Q

what are the primary chemoattractants for specific leukocytes

A

chemokines

34
Q

what are the functions of chemokines

A
  • stimulate leukocyte attachement to endothelium
  • increase affinity of integrins on leukocytes
  • stimulate chemotaxis of leukocytes in tissue to the site of infection or tissue damage
  • Maintenance of tissue architecture
35
Q

what are the four groups of chemokines

A

C-X-C chemokines
C-C chemokines
C chemokines
CX3C chemokines

36
Q

what do C-X-C chemokines primarily act on and what are the secreted by

A

act primarily on neutrophils chemotaxis & are secreted by macrophages, endothelial c. e.g. IL-8

37
Q

what are examples of C-C chemokines

A

Monocyte chemoattractant protein MCP-1
Eotaxin
Macrophage Inflammatory Protein-1α (MIP1α)
RANTES (Regulated and normal T cell expressed & secreted)

38
Q

what do C chemokines specifically act on

A

lymphocytes e.g. lymphotactin

39
Q

what is the function of CX3C chemokines

A
  • promote strong adhesion of monocytes & Tc. ,

* chemoattractant for monocytes & Tc

40
Q

what is the complement system composed of

A

20 proteins; C1→C9

41
Q

describe the action of complement proteins

A

Complement proteins are present as inactive forms in the plasma & many are activated to become proteolytic enzymes→degrade other complement proteins =enzymatic cascade

42
Q

what are the three pathways of proteolysis in the complement system

A
  1. The Classical pathway→ triggered by fixation of C1 to Ab+Ag complex
  2. The Alternative pathway→triggered by microbial surface molecules(e.g. endotoxin, LPS), complex
    polysaccharides, cobra venom etc.
  3. The Lectin pathway→ plasma mannose-binding lectin binds to carbohydrates on microorganisms this directly activates C1
43
Q

how is C5 convertase formed

A

All 3 pathways of complement activation leads to the formation of an active enzyme C3 convertase which splits into 2 functional fragments C3a & C3b. C3b then forms C5 convertase & cascade progresses

44
Q

how does the complement system cause inflammation

A

C3a, C5a, C4a are called anaphylotoxins & their cleavage products stimulate histamine release→ increase vascular permeability→vasodilation

45
Q

what are the functions of C5a

A
  • is chemotactic for neutrophils, monocytes, eosinophils, basophils
  • activates lipooxygenase pathway of AA→further release of inflammatory mediators
46
Q

how does the complement system lead to Opsonization & phagocytosis

A

C3b & iC3b when fixed to a microbial wall act as opsonin and promote phagocytosis by neutrophils & macrophages

47
Q

how does the complements system lead to cell lysis

A

deposition of MAC (membrane attack complex composed of C9) on cells, increasing permeability leading to influx of water and ions causing lysis of cells

48
Q

Deficiency of _______causes susceptibility to Neisseria infections

A

MAC (complement system is important for killing of microorganisms with thin walls e.g. Neisseria)

49
Q

what circulating proteins control the complement system

A
  • C1 inhibitor (C1INH

* Decay accelerating factor (DAF)

50
Q

what does C1 inhibitor (C1INH) cause

A

Hereditary angioedema

51
Q

what does Decay accelerating factor (DAF) do

A

inhibits formation of C3 convertase & CD59 inhibits formation of MAC

52
Q

Decay accelerating factor (DAF) is connected to the plasma membrane by a ____________________

A

glycophosphatidyl anchor

53
Q

what happens if the glycophosphatidyl anchor is absent

A

excessive complement activation causing lysis of RBC leading to Paroxysmal Nocturnal Hemoblobinuria

54
Q

what other diseases are linked with regulatory protein absence

A

Macular degeneration and Hemolytic uremic syndrome

55
Q

what are four other mediators of inflammation

A
  • platelet activating factor
  • products of coagulation
  • kinins
  • neuropeptides
56
Q

what does platelet activating factor cause

A

platelet aggregation, vasoconstriction, bronchoconstriction, in low conc induces vasodilation, increase venular permeability

57
Q

how are kinins produced

A

produced from Kininogens by the action of kallikrein (protease)

58
Q

what is an example of a kinin and what is its function

A

Bradykinin which increase vascular permeability

59
Q

what is an example of neuropeptide and where is it found

A

substance P prominent in lungs & GIT

60
Q

what are the effects of kinin

A

smooth muscle contraction, vasodilation, pain when injected to the skin

Med 105 (16 decks)

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