ICL 9.3, 9.4 & 9.5: Inflammation Flashcards
1
Q
what is inflammation?
A
complex reaction to injurious agents consisting of:
- vascular response
- migration and activation of leukocytes
- systemic reactions like pain or fever – these reactions are mediated by chemical mediators which lead to:
- accumulation of fluid AND leukocytes in extravascular tissue = swelling
2
Q
why can inflammation be harmful?
A
it can cause:
1. leak enzymes: certain ones can cause tissue damage
- anaphylaxis
- chronic processes: over time it will form adhesions and scars
- adhesions
3
Q
how is inflammation classified?
A
acute and chronic
4
Q
what are the 5 R’s of inflammation?
A
Recognition of injurious agent
Recruitment of leukocytes
Removal of agent
Regulation of the response
Resolution (healing)
5
Q
who are the players in acute inflammation vs. chronic inflammation?
A
acute: neutrophils
chronic: mononuclear cells like lymphocytes, eosinophils, etc.
6
Q
what are the 5 cardinal signs of acute inflammation?
A
- heat
- redness
- swelling
- pain
- loss of function
with chronic inflammation you do NOT have heat, swelling or redness – there will only be pain from adhesions/scars and loss of function
7
Q
what are the characteristics of acute inflammation?
A
- sudden onset
- short term
- exudates present rich in neutrophils
- prominent local signs
8
Q
what are the characteristics of chronic inflammation?
A
- slow onset
- no exudate
- mononuclear cells = no neutrophils
- usually fibrosis
- few local signs
9
Q
what are the two vascular changes that occur in acute inflammation?
A
- vasodilation
2. increased vascular permeability
10
Q
what is vasodilation mediated by?**
A
histamine
NO
11
Q
what does vasodilation do?
A
it’s mediated by histamine and NO
it slows blood flow and causes margination of leucocytes
**it is the cause of erythema
12
Q
what does increased vascular permeability lead to?**
A
swelling and edema
13
Q
what are the mechanisms that lead to increased vascular permeability?
A
- formation of endothelial gaps in venules
- direct endothelial injury with necrosis and detachment
- delayed prolonged leakage
- leukocyte mediated injury from oxygen radicals
- transport of fluid and protein is through the endothelial cells = trancytosis
- increased number and size of the channels = angiogenesis
14
Q
what mediates the formation of endothelial gaps in venules?
A
the formation of endothelial gaps in venules increases vascular permeability
it’s mediated by:
- histamine
- bradykinin
- leukotrienes C4, D4 and E4
15
Q
what mediates direct endothelial injury?
A
direct endothelial injury with necrosis and detachment increases vascular permeability
all small vessels are involved: arterioles, venules, capillaries**
it’s mediated by bacterial enzymes
16
Q
what are the 4 steps in extravasation of WBCs?
A
- rolling
- pavementing
- transmigration
- chemotaxis
17
Q
what happens during the rolling phase of WBC extravasation?
A
loose contact of white cells with endothelium
Sialyl-Lewis X molecules on WBC bind with E-selectin on endothelial cells**
18
Q
what happens during the pavementing phase of WBC extravasation?
A
it’s tight constant contact of white blood cells with endothelium
LFA-1 and integrin on WBCs bind to ICAM-1 and VCAM-1 on endothelial cells**
19
Q
what happens during the transmigration phase of WBC extravasation?
A
WBCs crossing through the endothelial layer
mediated by CD31 or PECAM
20
Q
what happens during the chemotaxis phase of WBC extravasation?
A
process by which the WBCs are drawn to the site of inflammation
mediated by exogenous bacterial polysaccharides and endogenous C5a-leukotrene, B4, and IL-8**
21
Q
what happens once the WBCs extravasate and get to the infected tissue?**
A
they’re activated!
they produce arachidonic acid metabolites
lysosomal enzymes are released
there’s activation of the oxidative burst
cytokines are secreted
22
Q
what are the 3 phases of phagocytosis?
A
- recognition and attachment
- engulfment
- killing and degranulation
23
Q
what happens during the recognition and attachment of phagocytosis?
A
opsonization of bacteria with C3b**
then high affinity receptors recognize the opsonized organism
24
Q
what happens during the engulfment phase of phagocytosis?
A
- binding to phagocytes receptors
- enclosure within the phagosome
- fusion with the lysosome
- degranulation –> oxygen burst happens during degranulation!
25
what are the two types of ways a phagocyte can kill a pathogen?
1. oxygen dependent
| 2. oxygen independent
26
what is the oxygen dependent way that phagocytes kill pathogens?
1. NADPH oxidase catalyzes the conversion of NADPH with 2 oxygen molecules into a superoxide radical
superoxide radical then gets converted into hydrogen peroxide
myeloperoxidase then turns H2O2 into HOCl
2. NO can also react with superoxide to generate ONOO free radical, peroxynitrite
27
what does myeloperoxidase do?
myeloperoxidase catalyzes H2O2 + HCl to HOCl
H2O2 + Cl − + H 3 O + → HOCl + 2H2O
this causes halogenation or lipid and
protein peroxidation
28
what does peroxynitrite do?
it's a free radical formed from NO + superoxide
peroxynitrite attaches and damages:
1. lipids
2. proteins of microbes**
3. nucleic acids
29
what are the oxygen independent mechanisms that phagocytes use to kill microbes?
1. lysozymes
2. major basic protein (eosinophils)
3. neutrophil extracellular traps
30
what are the two types of defects of leukocyte function?
1. adhesion defects
| 2. defects in phagolysosome function
31
what is leukocyte adhesion deficiency type I?
mutation in ITGB2 gene that leads to defects in the β chain of CD11/CD18 integrins
integrins are needed for WBC adhesion
32
what are the clinical features of leukocyte adhesion deficiency type I?
1. delayed separation of the umbilical cord
2. recurrent bacterial infections that LACK pus formation
there's no pus because there's no neutrophils there to form pus since there's no adhesion or pavementing
33
what is leukocyte adhesion deficiency type II?
impaired wound healing
fucosyl transferase required for synthesis of sialylated oligosaccharide (receptor for selectins)
34
what is the hallmark characteristic of Chediak-Higashi syndrome?
grey/blonde hair
35
what is Chediak-Higashi syndrome?
it's a defect in phagolysosome function
due to failure of lysosomes to fuse with phagosomes during phagocytosis
people who have this have recurrent bacterial infections
36
what is the inheritance of Chediak-Higashi syndrome?
autosomal recessive
37
what is chronic granulomatous disease?
defect in microbicidal activity due to an inability to produce an oxygen burst -- gene defect leads to no production of NADPH oxidase!
without NADPH oxidase you can't form superoxide or H2O2 to kill bacteria!!
patients have recurrent bacterial and fungal infections
may also have areas of inflammation (granulomas) in various tissues that can result in damage to those tissues
38
what test do you do to test for chronic granulomatous disease?
nitro-blue tetrazolium test
you incubate nitro-blue tetrazolium crystals with your patients WBCs so that the WBC will go and eat the crystals
if there's no oxygen burst, the crystals will remain colorless
if there is an oxygen burst, the crystals will turn blue
in a healthy person the crystals will turn blue because it means the oxygen burst is working!
39
what's the inheritance of chronic granulomatous disease?
x-linked recessive
OR
autosomal recessive
40
what is the mutation in the x-linked recessive form of chronic granulomatous disease?
NADPH oxidase has two components: membrane and cytoplasmic
in the X-linked mutation there is a defect in the **membrane-bound component gP9PHOX
41
what is the mutation in the autosomal recessive form of chronic granulomatous disease?
NADPH oxidase has two components: membrane and cytoplasmic
both must be brought together for the enzyme to function in the recessive form defect in the gene encoding two **cytoplasmic components P45PHOX AND P67PHONX
42
what are the types of plasma mediators?
1. plasma mediators: complement and kinins
these present as precursor forms that have to be activated
2. cell-derived mediators
- sequestered in intracellular granules and need to be secreted (histamine in mast cells)
OR
synthetized de novo (prostaglandins)
43
what do plasma mediators do?
plasma mediators = complement, kinins, histamine in mast cells, prostaglandins, etc.
they bind to specific receptors on target cells and have enzymatic activity
they mediate oxidative damage and can stimulate the release of secondary mediators by target cells
secondary mediators can amplify or inhibit the initial mediator action
44
what are the types of cell-derived mediators?
1. vasoactive amines
2. arachidonic acid metabolites
3. PAF
4. cytokines
5. chemokines
6. reactive oxygen products
7. NO
8. lysosomal enzymes
9. neuropeptides substance P
45
what are the two vasoactive amines?
1. histamine
| 2. serotonin
46
when is histamine released?
Physical injury (cold, heat, etc.)
Immune reactions
Fragments of complement (anaphylatoxins C3a and C5a)
Histamine-releasing proteins from leukocytes
Neuropeptides (substance P)
Cytokines (IL-1, IL-8)
47
what does histamine do?
it's a vasoctive amine
histamine is released from mast cells, basophils and platelets
histamine is involved in vasodilation which can lead to erythema and increased vascular permeability which can lead to swelling**
48
where does serotonin come from?
platelets
49
when is serotonin released?
it's released when platelets aggregate after contact with:
1. collagen, thrombin
2. ADP
3. PAF
50
what effects does serotonin have?
vasodilation
increased vascular permeability
these two things cause pain!
51
what are arachidonic acid metabolites?
products derived from the metabolism of arachidonic acid called eicosanoids
52
what are the two pathways involved with arachidonic acid metabolites?
1. cyclooxyrgenase pathway
| 2. lipoxygenase pathway
53
what is produced from the cyclooxyrgenase pathway?
prostaglandins and thromboxane**
54
what is produced from the lipoxygenase pathway?
leukotrienes
55
are prostaglandins vasodilators or constrictors?
vasodilators
56
what does thromboxane do?
vasoconstrictor
promotes platelet aggregation
57
what do leukotrienes do?
vasoconstrictors
increase vascular permeability
58
what do COX2 inhibitors do?
they inhibit prostaglandin 2 synthesis more than thromboxane synthesis -- they do NOT inhibit leukotriene synthesis
prostaglandin is a vasodilator that inhibits platelet aggregation so you need it to perfuse blood to your tissues and heart
if COX2 only inhibits PG2, this leaves thromboxane unchecked and it's a vasoconstrictor that also promotes platelet aggregation...
lots of vasoconstriction and platelet aggregation can cause coronary artery disease!!
59
what does PAF do?
induces vasodilation
increases vascular permeability
60
where does PAF come from?
generated from the membrane phospholipids of:
1. neutrophils
2. monocytes
3. platelets
61
what do reactive oxygen products do?
they're made via the NADPH oxidase pathway
they destroy phagocytosed microbes
but can also harm normal tissue
62
what does NO do?
1. relaxation of vascular smooth muscles
2. stops platelet activation
3. reduced cell recruitment
4. kills bacteria
kills bacteria because NO + superoxide forms peroxynitrite
63
what are the types of lysosomal enzymes?
1. proteases
2. elastase
3. collagenase
4. cathepsin
64
what causes emphysema?
unchecked production of proteases and elastase which breakdown the lung walls
elastase digests elastic tissue
proteases breakdown proteins
65
what does neuropeptide substance P do?
transmits pain signals
regulates vessel tone
66
what are the two types of plasma mediators?
1. complement
| 2. kinin
67
which complement protein is important for chemotaxis?
C5a
68
which complement protein is important for opsinozation?
C3b
69
what is arthralgia?
painful joints but it's NOT inflamed or red or swollen
70
what does C3 deficiency lead to?
infections
without C3 there's no C3b so you can't opsonize bacteria
71
what does C2 and C4 deficiency lead to?
autoimmune disease
72
what is SLE caused by?
failure to clear immune complexes that are formed
73
what causes an increased susceptibility to Neisseria infections?
C5/C6 deficiencies because MAC can't form
74
what is PNH?
it's a genetic deficiency of complement regulatory proteins
a deficiency of C1q esterase inhibitor (CD59)
mutation of the gene encoding of the enzyme required to synthesize phosphatidylinositol linkages for membrane proteins (CD59 deficiency)
at night, people become acidotic and this activates unchecked complement activity since there's no C1q esterase inhibitor around
this leads to RBC hemolysis and anemia!
75
how do you diagnose PNH?
flow cytometry
the cells in PNH will be CD59-
CD59 is one of the regulatory proteins for complement!
76
what happens when the kinin system is activated?
release of bradykinin which leads to:
- increases vascular permeability
- contraction of smooth muscles
- dilation of blood vessels
- pain
77
what is kinin?
vasoactive peptide produced by kininogen by the action of kallikreine**
78
how is kinin formed?
activated factor XII converts prekallikrein to kallikrein
kallikrein cleaves kininogen to produce bradykinins
kallikrein also activates factor XII which amplifies the initial pathway = positive regulation
79
what's another name for factor XII?
Hageman factor
80
activated factor XII initiates which four systems?**
1. kinin system
2. clotting system --> activation of thrombin
3. fibrinolyte system --> plasmin and inactivating thrombin
4. complement system producing anaphylatoxins (C5a and C3a)
81
what are examples of neuropeptides?
1. substance P
| 2. neurokinin A
82
what do neuropeptides do?
play a role in the initiation and regulation of inflammatory responses
they also regulate BP
they're produced in the central and peripheral nervous system
83
how is plasmin related to active factor XII?
plasmin breaks down fibrin which leads to fibrin degradation products
plasmin also activates the complement cascade which forms C3 and C3a
kallikrien activates plasmin
84
which mediators are vasodilators?
1. prostaglandins**
2. NO
3. histamine**
85
which mediators increase vascular permeability?
1. vasoactive amines
2. C3a & C5a (Anaphylatoxins)
3. bradykinin
4. leukotrienes C4, D4, E4
5. PAF**
6. substance P
86
which mediators are involved in chemotaxis and leukocyte activation?
1. C5a**
2. leukotriene B4 (LTB4)
3. chemokines, IL-1, TNF
4. bacterial products (lipoxin)
87
which mediators are involved in fevers?
1. IL-1, TNF**
| 2. prostaglandins
88
which mediators are involved with pain?
1. prostaglandins
2. bradykinin
3. neuropeptide substance P
89
which mediators are involved with tissue damage?
1. neutrophil and Macrophage lysosomal enzymes:
cationic proteins, acid proteases, neutral proteases
2. oxygen metabolites
3. NO
90
what are the two morphologic patterns of acute inflammation?
1. serous
2. fibrinous
3. suppurative or purulent
91
what is serous acute inflammation?
effusion
blisters
caused by viral infections and burns**
92
what is fibrinous acute inflammation?
occurs with large vascular leaks usually in body cavities like the pericardium meninges
ex. uremic pericarditis
93
what is suppurative or purulent acute inflammation?
neutrophils
necrotic tissue --> abscesses (staph aureus)
e dema fluid
bacterial and fungal infection
94
what are the three possible outcomes that could happen following acute inflammation?
1. complete resolution
2. healing by connective tissue replacement = scar
3. progression to chronic inflammation
95
what are the 3 things that can stop an acute inflammatory response?
1. production of anti-inflammatory lipoxins
3. liberation of an anti-inflammatory cytokine from macrophages (TGFβ)
3. neural impulses that inhibit the production of TNF in macrophages
96
what is chronic inflammation?
inflammation which persists for prolonged periods of time and lasts for weeks, months or years
has little fluid component = no exudate
97
what are the two possible pathways that can get you to a chronic inflammation state?
1. evolution from acute to chronic:
due to persistence of the inflammatory stimulus
interference with healing
repeated bouts of acute inflammation
2. chronic inflammation without any acute phase; insidious onset of the illness
98
in what 3 settings does chronic inflammation occur?
1. persistent infections
2. immune-mediated inflammatory diseases
3. prolonged exposure to potentially toxic agents
99
what are the characteristics of chronic inflammation?
1. mononuclear cells infiltrates = no lymphocytes
2. proliferation of fibroblasts
3. proliferation of blood vessels
4. deposition of collagen (fibrosis)
5. tissue destruction
100
which cells are mononuclear?
macrophages
lymphocytes
plasma cells
eosinophils
101
what do macrophages produce?
1. proteases
2. cytokines: IL-1 and TNF
3. growth factors
102
what do growth factors lead to?**
SCARS
1. proliferation of fibroblasts
2. proliferation of smooth muscle cells
3. production of ECM
103
what important mediators of inflammation do macrophages produce?
IFNγ
IL-12
104
what are eosinophils important for?
Parasitic infections
Allergies
Malignances
Sarcoidosis
Recruitment by adhesion molecules
Granules contain major basic protein
105
what is sarcoidosis?
sarcoidosis is an inflammatory disease that affects multiple organs in the body, but mostly the lungs and lymph glands
in people with sarcoidosis, abnormal masses or nodules (called granulomas) consisting of inflamed tissues form in certain organs of the body
hilar lymphadenopathy and nodules are common
106
what are mast cells?
involved in type I hypersensitivity reactions
present in connective tissue
participate in both acute and chronic inflammation
coated with IgE
release histamine
107
what would the lab results of someone with sarcoidosis show?
increased ACE
increased calcium
PTH-independent extra renal production of calcitriol by activated macrophages causes an increase in intestinal absorption of calcium
108
why do fevers happen?
occurs in response to pyrogens
1. exogenous bacterial products stimulate the leukocytes to release endogenous pyrogens (TNF & IL1)
2. pyrogens stimulate prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus
3. in the hypothalamus prostaglandins stimulate the production of neurotransmitter like cAMP which reset the temperature at a higher level
109
why are NSAIDs used to treat fever?
they inhibit prostaglandin
in the hypothalamus prostaglandins stimulate the production of neurotransmitter like cAMP which reset the temperature at a higher level
110
what are the systemic effects of acute inflammation?
left shift = more bands
increased acute phase reactants
increased cReactive protein
increased fibrinogen
111
what is regeneration?
growth of cells and tissues to replace lost structures
112
in adult tissues, the size of cell populations is determined by the rates of...?**
1. cell proliferation
2. differentiation
3. death by apoptosis
113
what are the three groups of tissues?
1. continuously dividing tissues
2. quiescent or stable tissues
3. non-dividing tissues
114
what are continuously dividing tissues?
they proliferate throughout life**
mature cells are derived from stem cells
they include:
1. epithelium
2. BM
3. hematopoietic tissues
115
what are quiescent or stable tissues?
low replication level; can regenerate a little
they include:
1. parenchymal cells: liver and kidney
2. mesenchymal: fibroblasts
3. resting lymphocytes
116
what are non-dividing tissues?
cannot undergo mitotic division in postnatal life**
they include:
1. neurons
2. skeletal muscles
3. cardiac muscles
117
what is the mechanism of tissue regeneration?
mediated by paracrine signaling via growth factors (e.g., macrophages secrete growth factors that target fibroblasts like INFγ)
interaction of growth factors with receptors (e.g., epidermal growth factor with growth factor receptor) results in gene expression and cellular growth
118
what are the steps in wound healing?
1. acute inflammation
2. regeneration of parenchymal cells
3. migration and proliferation of parenchymal and stromal cells
4. synthesis of ECM proteins
Remodeling of connective tissue and parenchymal components
5. Acquisition of wound strength
119
what does EGF do during wound healing?
EGF stimulates granulation tissue formation
it also induces blood vessel formation = angiogenesis
120
what is granulation tissue?**
it's a step in the healing process in-between acute and chronic inflammation; it's the bridge between the two!
if acute inflammation doesn't resolve --> granulation tissue --> scar
granulation tissue is made of:
1. new blood vessels
2. fibroblasts
3. mononuclear cells
121
what does VEGF do during wound healing?
angiogenesis is mediated by VEGF
122
what growth factor mediated granulation tissue formation?
EGF
123
what does TGF-β do during wound healing?
it's a a potent fibrogenic agent
it stimulates fibroblasts and chemotaxis
it has a strong anti-inflammatory effect
124
what are the steps in repair by scar formation?
1. normal
2. tissue injury
3. inflammation
4. formation of granulation tissue
5. scar formation by deposition of extracellular matrix
125
what are the two types of receptors for growth factors?
1. receptors with intrinsic kinase activity
| 2. receptors without intrinsic kinase activity
126
what do growth factor receptors with intrinsic kinase activity do?**
they ARE involved in the wound healing process
growth factors such as EGF and HGF bind to receptors with intrinsic kinase activity
this triggers a cascade of phosphorylating events through MAP leading to:
MAP = mitogen activated protein kinase
1. transcription factor activation
2. DNA replication
127
what do growth factor receptors without intrinsic kinase activity do?**
these receptors are NOT part of the healing processes
cytokines bind to receptors without kinase activity by interacting with cytoplasmic transcription factors
move into the nucleus by activating members of
JAK
128
what are the 4 things the ECM is made of?
1. collagen
2. elastic fibers
3. proteoglycans
4. fibronectin
129
what is the function of the ECM?
1. support
2. control cell growth so fibroblasts don't go crazy and give you giant scars
3. maintain cell differentiation
4. storage and presentation of regulatory molecules
130
how does tissue remodeling work?
degradation of collagen and other ECM by zinc dependent metalloproteinases
metalloproteinases: **
1. secreted in inactive form
2. activated by plasmin
3. inhibited by tissue inhibitors of metalloproteinases (TIMPs)
131
what are the two components of connective tissue repair?
1. angiogenesis
| 2. migration and proliferation of fibroblasts
132
ECM deposition depends on the balance between what three things?**
1. metalloproteinases
2. metalloproteinase inhibitors
3. fibrogenetic agents like TGFβ
133
what are the two types of wound healing?
1. first intention (primary union)
2. secondary union
3. delayed wound healing
134
what is primary union healing?
wounds with opposed clean edges, e.g., healing of surgical incision
result: small to nonexistent scar
135
what is secondary union?
lacerated wound, not a clean cut
probably a little infected too
result: scar
136
what causes delayed wound healing?
1. infection (S. aureus)
2. vitamin C, copper or zinc deficiency
3. steroids
137
why does vitamin C deficiency delay wound healing?
Vitamin C is an important cofactor in the hydroxylation of proline and lysine procollagen residues
hydroxylation is necessary for eventual collagen cross linking
138
why does copper deficiency delay wound healing?
copper is a cofactor for lysyl oxidase, which cross-links lysine and hydroxylamine to form stable collagen
139
why does zinc deficiency delay wound healing?
zinc is a cofactor for collagenase, which replaces the type III collagen of granulation tissue with strong type I collagen
140
why do steroids delay wound healing?
delays collagen deposition
141
what are three complications of wound healing?
1. deficient scar formation (steroids)
2. excessive formation of repair components (excessive scaring, keloids)
3. adhesions and contractures
142
what is a keloid?
Excess collagen deposition in the skin forming a raised scar known as keloid
143
what is exudate?
any fluid that filters from the circulatory system into lesions or areas of inflammation
it can be a pus-like or clear fluid
when an injury occurs, leaving skin exposed, it leaks out of the blood vessels and into nearby tissues
the fluid is composed of serum, fibrin, and WBCs
