respiratory toxicity Flashcards
1
Q
what are 5 main cell types in the respiratory system
A
ciliated cells, goblet cells, clara cells, Type 1 and 2 alveolar cells
2
Q
what do goblet cells do
A
produce mucous
3
Q
what do clara cells do
A
have P450 enzymes, act to regenerate other cells, secrete surfactant and mucus
4
Q
what is the structure/location of clara cells like
A
the major non-ciliated bronchiolar cells of terminal bornchioles
5
Q
what is another name for Type 1 and 2 alveolar cells
A
pneumocytes
6
Q
what are type 1 alveolar cells, structure location
A
cover a large surface area, very thin
7
Q
why do you want type 1 alveolar cells to be very thin
A
for efficient gas exchange
8
Q
what do type 2 alveolar cells do
A
secretes surfactant, they are like stem cells where they can convert into type 1
9
Q
which type of alveolar cells make surfactant
A
2
10
Q
which type of alveolar cells make are like stem cells
A
2
11
Q
what is the point of surfactant
A
reduce surface tension, prevents surfaces from sticking together
12
Q
what is the alveolar wall/septum
A
the interstitial space between adjacent alveolus and capillaries, consist of the alveolar epithelium and capillary endothelium.
13
Q
generally, what do lung toxicants do
A
decrease the efficiency of lung function by impairing gas exchange
14
Q
how can oxidative stress occur with lung toxicants
A
from the inhaled toxicants and phagocytic cells
15
Q
what kind of phagocytic cells cause oxidative stress and what are the effects
A
the ones associated with inflammation (neutrophils, monocytes, macrophages), causing cell injury and cell death
16
Q
what can the immune response do to the lungs
A
can trigger the relase of bronchoconstrictors like leukotrienes and histamine
17
Q
what 2 things about the toxicants determine the site of toxicity within the long
A
water solubility and size
18
Q
what happens physically in acute response to toxicants in airway
A
bronchoconstriction, decreased airflow, mucous secretion
19
Q
what is bronchoconstriction
A
reflex contraction of bronchial smooth muscle
20
Q
why do you increase mucous secretion with acute response to toxicants in airway
A
because you are trying to trap the irritant
21
Q
what 2 molecular pathways determine the acute response to toxicants in airway
A
the parasympathetic system and the tachykinin receptors
22
Q
what does the tachykinin receptors do in the acute response to toxicants in airway
A
TACT1 and 2 on smooth muscle mediate constriction, TACR2 mediate muscle secretion
23
Q
what does the parasympathetic system do in the acute response to toxicants in airway
A
ACh binds to M3, increases cGMP, activates PLC, increases Ca++, increase smooth muscle contraction
24
Q
what does TACR1 do
A
mediates smooth muscle contraction
25
what does TACR2 do
mediates smooth muscle contraction and mucous secretion
26
which receptors does ACh bind to with acute response
M3
27
what are 4 chronic responses to irritants in the conducting airways
asthma, fibrosis, COPD, cancer
28
what is asthma
increased airway sensitivity to bronchoconstriction, (ultrasensitive) causing attacks and shortness of breath
29
what is fibrosis
epithelial cell damage, collagen excess, tissues become non functional
30
what does COPD stand for
chronic obstructive pulmonary disease
31
what is COPD
progressive, non reversible airflow obstruction
32
where does ozone come from
mostly photochemical smog
33
what reaction makes ozone
NO2 + UV --> O* NO*
then
O* + O2 --> O3
34
what does ozone react with and where and what does it cause
polyunsaturated fatty acids (PUFAs) in the airways and propagates lipid radicals
35
what is the first product of ozone and PUFA
trioxolane
36
what is a breakdown product of tioxolane with no water present
criegee ozonides
37
what do criegee ozonides do
penetrate deeply into lung tissue and damage lipids
38
how/when is criegee ozonides formed
when one of the lipid reactive aldehydes from ozone breaks down/ transforms without water
39
what is a breakdown product of tioxolane with water present
reactive aldehydes and H2O2
40
how/when is reactive aldehydes and H2O2 formed
when one of the lipid reactive aldehydes from ozone breaks down/ transforms with water
41
is the reactive aldehydes and H2O2 or criegee ozonides pathway favored and why
reactive aldehydes and H2O2 because lungs have an aqueous environment, so that reaction is favored
42
what does trioxolane do
damage lungs
43
what 2 general things does ozone exposure cause
structural damage and promotes inflammation
44
what and WHERE kind of physical damage happens with ozone
The septum between alveoli break down, lose elasticity
45
what is the deal with nrf2 in the lungs with ozone
it is first upregulated, but 3-6weeks later, it is lost
46
what happens with ozone exposure initially
lung epithelial cells upregulate the electrophile response pathway (NRF2)
47
what happens with ozone exposure 3-6 weeks in
loses ability to do electrophile response pathway (NRF2)
48
why do you lose ability to do electrophile response pathway (NRF2) after time
carbonylation and damage to proteins that regulates expression of Nrf2 genes
49
which part of the cell gets high levels of nrf2 at first
nucleus
50
what is the deal with ozone and nrf2 (general)
initially activates nrf2 pathway but then inhibits it
51
what are 2 types of damage that ozone promotes
epithelial apoptosis and collagen deposition
52
where does collagen deposition happen with ozone
submucosal
53
what structure changes with collagen deposition in ozone
alteration of alveolar structure
54
how is ozone a powerful oxidant
via H2O2 and aldehyde formation
55
what does ozone do to TNFalpha + what does it cause
increases its expression which leads to inflammation
56
what does ozone do to inflammatory agents
increases the amount of them so there is increased inflammatory response in immune cells
57
what does ozone do to nitrogen species + how (explain)
increases iNOS which increases NO and peroxynitrite production
58
what is iNOS
inducible nitric oxide synthase
59
what does iNOS lead to
more NO and more peoxynitrite production
60
which cells are lost with ozone and how
epithelial cells along most of respiratory tract via apoptosis and necrosis
61
what is the water solubility of ozone like
lower water solubility
62
where is the greatest dose per unit of surface area occur for ozone
in deep regions of the lungs (alveolar zone)
63
where does foamy pink discharge occur + why
upper airway (like epiglottis), capillaries bleeding out
64
which sulfur oxide is the most important
SO2
65
what are 4 sources of SO2
coal combustion, paper mills, metal refineries, burning foam rubber
66
what does SO2 look like
colorless gas
67
what does SO2 smell like
pungent, like just struck match
68
what is the water solubility of SO2 like
very water soluble
69
what is SO2 to lungs at normal levels
upper respiratory system irritant
70
what is SO2 to lungs at high levels
DNA damage, potential carcinogen - cancer
71
what is the mechanism of SO2 and oxidative stress
unclear but likely free radical generation like SO3*
72
what is the deal with SO3*
it is a free radical that can be further oxidized to produce the hydroxyl radical OH*
73
what can SO3* induced OH* formation cause
lipid peroxidation and protein carbonyl formation
74
what happens to bax with increasing SO2
increasing (pro apoptotic)
75
what happens to bcl-2 with increasing SO2
decreasing (anti apoptotic)
76
what happens to p53 with increasing SO2
increasing (pro apoptotic)
77
what happens to caspase-3 with increasing SO2
increasing (pro apoptotic)
78
what are the 3 main anti apoptotic things we measure for SO2 damage
bax, p53, caspase-3
79
what is the main pro apoptotic things we measure for SO2 damage
bcl-2
80
what is asbestos
a group of silicate minerals with fibrous form
81
what was the use for asbestos
heat insulation, fire barrier
82
what does the health hazard of asbestos relate to
fiber shape, length and surface properties
83
what are the 2 types of asbestos
serpentine and amphiboles
84
what is serpentine asbestos
longer, curved
85
what is amphibole asbestos
short, straight, spikey
86
which form of asbestos is more damaging
amphibole
87
which form of asbestos is short, straight, spikey
amphibole
88
which form of asbestos is longer, curved
serpentine
89
what is asbestosis
a form of pulmonary fibrosis, many collagen nodules and presence of asbestos fibres with or without a coat of protein coating
90
what kind of asbestos exposed people get lung cancer
miners and smokers
91
what is malignant mesothelioma
a rare cancer in the pleural mesothelium
92
what is the pleural mesothelium
the protective lining of the lungs
93
is malignant mesothelioma related to smoking
no
94
what is the carcinogenicity of amphiboles like compared to chrysotile/serpentine
2 fold more
95
what are 3 ways that asbestos induced ROS production
- asbestos had iron on surface
- macrophage activation
- mitochondria and immune ROS
96
explain asbestos fibre surface reactivity and ROS production
diff types of asbestos have diff iron levels on their surface which contributes to ROS production via the fenton reaction
97
explain asbestos activation of alveolar macrophages
they attempt to engulf fibres and release ROS
98
explain asbestos with mito and immune making ROS
mitochondria in lung epithelial cells and immune cells start to generate and release ROS
99
how do they prove that asbestos can do fenton reactions
they produce OH in presence of H2O2 and reducing agent
100
what are 2 examples of iron chelators
EDTA and DES
101
what happens if you add EDTA and DES into a reaction
they prevent radical formation
102
what can asbestos do to DNA + what does this cause
DNA damage, leading to p53 expression
103
what happens to p53 with asbestos
increase expression
104
what is a way to prevent increased p53 by asbestos and why
give the alveolar cells phytic acid which is an iron chelator
105
what does phytic acid do
iron chelator
106
what does it mean that phytic acid reduces p53
it implies that iron on the surface of asbestos participates in ROS which initiates apoptosis
107
what do macrophages do to asbestos
attack them by invading and try to phagocytose them
108
what happens if the asbestos fibre cannot be swallowed by the macrophages
it traps the macrophages in the alveoli
109
what is frustrated phagocytosis and why does it happen
if it is too big to engulf, phagocytes will isntead released ROS RNS and other inflammatory signals
110
what happens once frustrated phagocytes release their inflammatory signals
stimulates collagen deposition in the airways
111
what are 3 main results of asbestos and immune cells
inflammation, fibrosis and cancer
112
what plays a large role in mitochondrial ROS production in response to asbestos (1 main type)
alveolar macrophages
113
what are 3 cell types that play a role in mitochondrial ROS production in response to asbestos
lung epithelial and mesothelial cells
114
what is the mechanism of ROS and asbestos
unclear, likely mitochondria and macrophages
115
which components of the cell may be part of ROS and asbestos + how did they know
they made mitochondrial ETC non function - reduced ROS production in response to asbestos
116
what is a way to reduce asbestosis
block H2O2 production
117
what needs to happen for mitochondrial ROS production to occur
hints of asbestos fibers need to be internalized for mitochondrial ROS production to occur
118
what 2 responses does asbestos initiate
macrophage and epithelial cell response
119
what 4 things does asbestos induced macrophage and epithelial cell response cause
ROS RNS cytokine and growth factor production and release
120
what is an example of a cytokine released by macrophage and epithelial cell response
TNF alpha
121
what is TNF alpha
tumor necrosis factor alpha, inflammatory cytokine
122
what does TNF alpha cause
NFKB translocation to nucleus (more inflammation and anti apoptosis)
123
what does NFKB translocation to nucleus cause
increase transcription of inflammatory and anti apoptotic genes like bcl2
124
what 2 things does TGF beta do
makes more collagen and prevents it from being broken down
125
where does TGF beta act
autocrine paracrine function (same cell and local area)
126
what do alveolar macrophages release with early asbestos exposure
TNF alpha
127
what do alveolar macrophages release with late asbestos exposure
TNF beta
128
what is the formula for crystalline silica
SiO2
129
what causes silicosis
inhalation of crystalline silica, often quartz
130
what kind of disorder is silicosis
chronic, progressive and fibrotic disorder of the lung
131
when does fibrosis develop with silicosis
following an initial inflammatory process
132
what do macrophages do with silicosis
ingest silica into phagosomes, cant digest, frustrated phagocytosis again
133
what does frustrated phagocytosis in silicosis look like
burst of inflammatory cytokine release which kills macrophages, releasing the silica and starting the cycle again
134
how does collagen synthesis happen in silicosis
alveolar macrophages release growth factors that induce fibroblast proliferation and collagen synthesis
135
how does cardiorespiratory failure happen in silicosis
silicotic nodules develop throughout the lung
136
where does silica come from
mining, masonry, sand blasting
