Inflammation Part 1 Flashcards
1
Q
what are the four causes of inflammation
A
- infections: (bacterial, viral, fungal, parasitic) and microbial toxins cause distinct patterns of inflammation
- tissue necro - causes inflam regardless of cause
- foreign bodies: exogenous or endogenous
- immune rxns (hypersensitivity - autoimmune diseases or environmental substances (allergies or microbes)
2
Q
in general, three ways cells recognize need for inflammatory response?
A
- TLRs
- inflammasome
- complement
3
Q
where are TLRs present
A
- on cell membrane of the innate immune sys (macrophages and dendritic cells)
- endosomes
- on cells of adaptive immunity (lymphocytes)
4
Q
how are TLRs activated
A
by PAMPs that are commonly shared by microbes
5
Q
examples of a specific TLR
A
CD14 (a TLR) on macrophages recognizes lipopolysaccharide (a PAMP) on the outer membrane of gram-neg bacteria
6
Q
TLR activation results in upregulation of what
A
NF-KB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators
7
Q
what is the inflammasome
A
a multiprotein cytoplasmic complex
8
Q
what does the inflammasome do
A
senses dead cell products (uric acid, ATP from damaged mito etc.) and induces activation of IL-1 –> leukocyte recruitment
9
Q
what does inflammasome induce activation of
A
IL-1
10
Q
what does IL-1 do
A
leukocyte recruitment
11
Q
where is arachidonic acid (AA) released from and what is it released by
A
the phospholipid cell membrane by phospholipase A2
12
Q
after released from phospholipid cell membrane, what is AA acted upon by
A
- cyclooxygenase
- 5-lipoxygenase
13
Q
what does cyclooxygenase produce
A
- prostaglandins (PG)
- thromboxane A2 (TXA2)
14
Q
what do PGI2, PGD2, and PGE2 all mediate
A
vasodilation (at the arteriole) and increased vasc. permeability (at the post-capillary venule)
15
Q
what does PGE2 individually mediate
A
pain and fever
16
Q
what does PGI2 individually mediate
A
inhibits platelet aggregation
17
Q
what does TXA2 do
A
causes vasoconstriction and platelet aggregation
18
Q
what does PGI2 cause
A
vasodilation (at the arteriole) and increased vasc. permeability (at the post-capillary venule)
19
Q
what does PGE2 cause
A
vasodilation (at the arteriole) and increased vasc. permeability (at the post-capillary venule)
20
Q
what does PGD2 do (along with two others)
A
vasodilation (at the arteriole) and increased vasc. permeability (at the post-capillary venule)
21
Q
what does 5-lipoxygenase produce
A
leukotrienes (LT)
22
Q
what does LTB4 do
A
attracts (chemotaxis) and activates neutrophiles
23
Q
what do LTC4, LTD4, and LTE4 all do
A
(slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vasc. permeability
24
Q
what do lipoxins do
A
inhibit neutrophil chemotaxis and adhesion
- (counteracts LTB4)
25
what do corticosteroids do and examples
inhibit phospholipase
- cortisone and prednisone
26
what do NSAIDS do
inhibit cyclooxygenase (COX)
27
where is COX-1 expressed
in most tissues (homeostasis of electrolytes in kidney and protection of GI tract)
28
when is COX-1 increased
during inflammation
29
where is COX-2 expressed
absent from most normal tissues
30
when is COX-2 induced
during inflammation
31
examples of COX-1 inhibitors
aspirin, ibuprofen (advil, motrin) and naproxen (aleve)
32
example of COX-2 inhibitor
celebrex
33
what is used to treat asthma
lipoxygenase inhibitors and leukotriene receptor antagonists (singulair)
34
where are mast cells widely distributed
throughout connective tissue
35
what are mast cells activated by
1. tissue trauma
2. complement proteins C3a and C5a
3. cross-linking of cell-surface IgE by antigen
36
describe immediate response of mast cells
release of preformed histamine granules, which mediate vasodilation of arterioles and increased vasc. permeability
37
what does histamine do
1. vasodilation
2. increased vasc. permeability
38
describe delayed response of mast cells
production of arachidonic acid metabolites, particularly leukotrienes
---> this prolongs the inflammatory response over hours
39
what are cytokines secreted from
activated lymphocytes, macrophages, and dendritic cells but also endothelial, epithelial and CT cells
40
what are the major cytokines in acute inflammation
TNF, IL-1 and IL-6
41
what are the major cytokines in chronic inflammation
IFN-y, IL-12, and IL-17
42
what are the cytokines involved with negative feedback to downregulate inflammation
IL-10 and TGF-B
43
what do TNF and IL-1 both do
- activate endothelium
- induce secretion of other cytokines and chemokines
44
what do TNF, IL-1 and IL-6 all do
promote systemic inflammatory state
45
what is the systemic inflammatory state
- fever
- lethargy
- stimulate the liver to make acute phase proteins (ex. C-reactive protein)
46
what does TNF individually do
metabolic wasting (cachexia)
47
what are chemokines
cytokines that act as chemotactic agents for major imflammatory cells
48
example of a chemokine
CXCL8 (formerly IL-8)
49
what does nitric oxide (NO) do
vasodilation
50
what are the three complement pathways
- classical
- alternative
- mannose binding lectin (MBL)
51
specific steps of classical pathway
C1 binds IgG or IgM that is bound to antigen
52
specific steps of alternative pathway
microbial products directly activate complement without antigen/Ab complexes
53
specific steps of MBL pathway
MBL binds to mannose on microorganisms and activates complement
54
what are the steps in complement pathway that are common between all three pathways
- production of C3 converatse
----> which mediates C3 into C3a and C3b
- which produces C5 convertase
----> which mediates C5 into C5a and C5b
- C5b complexes with C6-C9 to form the membrane attack complex (MAC)
55
C3a and C5a are also called
anaphylatoxins
56
what do C3a and C5a both do
- trigger mast cell degranulation
---> histamine release causes vasodilation and increased vasc. permeability
- activate leukocytes
57
what does C5a individually do
chemotactic for neutrophils
58
is C3a or C5a more potent
C5a more potent that C3a
59
what does C3b do
opsonin for phagocytosis
---> acts as the 'eat me' signal
60
what does the MAC do
lyses microbes by creating a hole in the cell membrane
61
what is Hagemen Factor (Factor XII)
inactive proinflammatory protein produced in liver
62
when is Hageman Factor activated
upon exposure to subendothelial or tissue collage
63
what does Hageman Factor in turn, activate
- coagulation and fibrinolytic systems
- complement
- kinin system
64
what is the kinin system
- kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin
- bradykinin causes vasodilation, increased vasc. permeability and pain
65
what are the cardinal signs of acute inflammation
- redness (rubor)
- warmth (calor)
- swelling (tumor)
- pain (dolor)
- fever
66
what is redness and warmth due to
- vasodilation --> increased blood flow
- via relaxation of arteriolar s muscle
- key mediators = histamine, prostaglandins, and bradykinin
67
what is swelling due to
increased vasc. permeability causing leakage of fluid from postcapillary venules into the interstitial space
68
what is pain due to
bradykinin and PGE2 sensitize sensory nerve endings
69
what is fever due to
- pyrogens cause macrophages to release IL-1 and TNF, which increase COX activity in perivascular cells of the hypothalamus
- this leads to increased PGE2 which raises T set point
70
is acute inflammation delayed or immediate and short-term or long-term
immediate and short term
71
what is the hallmark cell of acute inflammation
neutrophils
72
what are the vascular changes during acute inflammation
- brief vasoconstr.
- vasodil.
- increased permea.
- exudate leaving the circulation
- increase in blood viscosity
- decrease in blood flow through the microcirculation
73
what are the cellular events of acute inflammation in order
1. margination
2. rolling
3. adhesion
4. transmigration and chemotaxis
5. phagocytosis
6. destruction of phagocytosed material
7. resolution
74
what happens during margination
- vasodilation of arterioles slows blood flow
- cells marginate from center of flow to periphery
75
what happens during rolling
-"aka loose attachment"
- selectin speed bumps are upregulated on endothelial cells
- selectins bind SIalyl-Lewis X on leukocytes
- interaction results in rolling of leukocytes along vessel wall
76
what does P-selectin do during rolling
P-selectin release from Weibel-Palade bodies (storage granules in endothelial cells) is mediated by histamine
77
what is E-selectin induced by
TNF and IL-1
78
what happens during adhesion (3)
- cellular adhesion molecules are upregulated on endothelium by TNF and IL-1
- integrins become high affinity and are upregulated on leukocytes by C5a and LTB4
- interaction between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall
79
what is a leukocyte adhesion deficiency a defect in?
defect in integrins
80
what are the cellular adhesion molecules and what are they upregulated by
ICAM and VCAM and upregulated by TNF and IL-1
81
what happens during transmigration and chemotaxis
- leukocytes transmigrate across the endothelium of postcap. venules and move towards chemical attractants
82
what are neutrophils attracted by
bacterial products, IL-8, C5a, and LTB4
83
what happens during phagocytosis
- consumption of pathogens or necrotic tissue
- pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes
84
what is phagocytosis enhanced by
opsonins (IgG and C3b)
85
what is Chediak-Higashi syndrome
impaired phagolysosome formation with increased risk of pyogenic infections
86
what is the most effective mechanism of destroying phagocytosed material
OXYGEN dependent killing
87
what is HOCL' (hypochlorous radical) generated by
oxidative burst in phagolysosomes and destroys phagocytosed microbes
88
how does oxygen go to superoxide
NADPH oxidase
89
what can superoxide go to and how
go to H2O2 by superoxide dismutase
90
what can H2O2 go to and how
go to HOCl' (bleach) by myeloperoxidase (MPO) which is contained in the azurophilic granules (lysosomes) of PMNs
91
what is chronic granulomatous disease characterized by
poor OXYGEN-dependent killing
--> due to inherited NADPH oxidase defect
--> leads to recurrent infection and granuloma formation
92
is oxygen-independent or oxygen-dependent killing more effective
oxygen dependent more effective
93
how does oxygen independent killing occur
via enzymes present in leukocytes secondary granules
94
what happens during resolution
neutrophils undergo apopto and disappear within 24 hrs after resolution of the inflammatory stimulus
95
what are the three main patterns of acute inflammation
- serous
- purulent or suppurative
- fibrinous
96
describe serous inflammation
- due to burn or viral infection, tend to be watery
97
what is effusion
fluid in a serous cavity
98
describe purulent or suppurative inflammation
- common in bacterial infections
- thick and yellow (rich in neutrophils)
99
describe fibrinous inflammation
- rich in fibrin which makes it sticky. covering called a pseudomembrane
- noted when inflammation occurs in a body cavity. can resolve but if scarring occurs could restrict function
100
