The lung as a target organ for toxic effects Flashcards
(121 cards)
1
Q
What are the two main divisions of the respiratory tract?
A
Upper respiratory tract and lower respiratory tract
The upper respiratory tract includes the airway passages above the neck, while the lower respiratory tract includes passages and lung parenchyma below the pharynx.
2
Q
What is the primary function of the upper respiratory tract?
A
Conduct, heat, humidify, filter, and chemosense incoming air
The upper respiratory tract warms air to about 33°C and humidifies it to about 98% water saturation.
3
Q
How does the nasal passage filter air?
A
By absorbing highly water-soluble gases and depositing particles on the nasal mucosa
Particles can be deposited by impaction or diffusion.
4
Q
What sensory functions are performed by the nasal passages?
A
Detection of odors and chemosensory functions
Humans can distinguish more than 5000 odors.
5
Q
What are the five major subtypes of chemosensory receptors in the nasal passages?
A
- Olfactory receptors
- Trace amine–associated receptors (TAARs)
- Membrane guanylyl cyclase GC-D
- Vomeronasal receptors
- Formyl peptide receptors (FPRs)
6
Q
What type of receptors mediate the transduction of odorant signals?
A
Olfactory receptors
These are 7-transmembrane domain G-protein–coupled receptors.
7
Q
What do TRP channels in the upper respiratory tract detect?
A
Irritant chemicals, temperatures, and mechanical stress
TRP channels are ion channels permeable to cations.
8
Q
What are the main types of taste receptors?
A
- Type 1 receptors for sweet and umami
- Type 2 receptors for bitter
- Hydrogen ion channels for sour
9
Q
What are the components of the conducting airways in the lower respiratory tract?
A
Trachea, bronchi, and distal bronchioles
These airways have a bifurcating structure.
10
Q
What happens to airflow in the conducting airways as the diameter decreases?
A
Airflow becomes slower in smaller distal airways
Larger diameter proximal airways allow faster airflow.
11
Q
What is bronchoconstriction and what causes it?
A
Contraction of airway smooth muscle leading to reduced airflow
Caused by acetylcholine release from vagal nerve endings.
12
Q
What do mucociliary clearance and antimicrobial functions involve?
A
Formation of a mucous layer that traps and removes inhaled material
The mucous layer consists of ciliated, mucous, and basal cells.
13
Q
What is the role of cilia in the respiratory tract?
A
Propel harmful inhaled material out of the nose and lung
Ciliated cells have a beat frequency of about 720 to 900 beats/minute.
14
Q
What are alveolar type I and type II cells responsible for?
A
- Type I cells: Gas exchange
- Type II cells: Produce surfactant and can replace damaged type I cells
15
Q
What constitutes the gas exchange region of the lung?
A
Terminal bronchioles, respiratory bronchioles, alveolar ducts, alveoli, blood vessels, and lung interstitium
Gas exchange occurs primarily in the alveoli.
16
Q
What is the principal function of the lung?
A
Gas exchange
Gas exchange consists of ventilation, diffusion, and perfusion.
17
Q
What happens during inhalation?
A
Fresh air moves into the lung through the upper respiratory tract and conducting airways
This occurs when the thoracic cage enlarges and the diaphragm moves downward.
18
Q
What is total lung capacity (TLC) for women and men?
A
4 to 5 L (women) and 6 to 7 L (men)
TLC is the total volume of air in an inflated human lung.
19
Q
What is the residual volume (RV) for women and men?
A
1.1 L (women) and 1.2 L (men)
RV is the amount of air retained in the lung after maximum expiration.
20
Q
Define vital capacity (VC).
A
Air volume moved into and out of the lung during maximal inspiratory and expiratory movement
VC is about 3.1 L (women) and 4.8 L (men).
21
Q
What is the tidal volume (TV) during quiet breathing?
A
~0.5 L with each breath
TV is a small fraction of the vital capacity.
22
Q
What is the typical respiratory frequency for resting humans?
A
12 to 20 breaths per minute
Resting ventilation is about 6 to 8 L/min.
23
Q
What are the three components of gas exchange?
A
- Ventilation
- Diffusion
- Perfusion
These components are essential for effective gas exchange in the lungs.
24
Q
What factors influence the penetration of gases into the lung?
A
- Solubility
- Diffusivity
- Metabolism/reactivity in respiratory tissues
- Breathing rate
These factors are critical in determining the toxicity of gases.
25
What are the primary cell types involved in lung biotransformation?
* Bronchial epithelial cells (BSCs)
* Alveolar type II cells
## Footnote
These cells have the most cytochrome P450 (CYP) enzymes.
26
What are the two types of pulmonary enzymes that facilitate detoxification?
* Phase I enzymes
* Phase II enzymes
## Footnote
Examples include cytochrome P450 for Phase I and glutathione-S-transferases for Phase II.
27
How does particle size affect deposition in the respiratory tract?
Particle size determines where a particle will be deposited
## Footnote
Larger particles are typically trapped in the upper airways, while smaller particles can reach deeper regions.
28
What are the classifications of aerosols based on particle size?
* Dusts (≥1.0 μm)
* Fumes (≤0.1 μm)
* Smoke (≤0.5 μm)
* Mists (2-50 μm)
* Fog (≤1.0 μm)
* Smog (≥0.01-50 μm)
## Footnote
Aerosols can have various sources and sizes affecting their deposition and toxicity.
29
What mechanisms facilitate particle deposition in the lungs?
* Impaction
* Interception
* Sedimentation
* Diffusion
* Electrostatic deposition
## Footnote
These mechanisms determine how particles are retained in various parts of the respiratory system.
30
What is the role of glutathione in lung function?
It modulates acute and chronic chemical toxicity
## Footnote
Glutathione S-transferases are crucial for detoxification in the lung.
31
What is the significance of the transcription factor NFE2L2 (NRF2)?
It regulates the expression of many detoxifying enzymes
## Footnote
NRF2 plays a crucial role in lung protection from injury.
32
Where does impaction occur in the respiratory tract?
In the upper respiratory tract and large proximal airways
33
What is the mechanism of particle deposition for particles >10 μm in humans?
Deposited in the nose or oral pharynx
34
What are the mechanisms of particle deposition in the respiratory tract?
* Impaction
* Interception
* Sedimentation
* Diffusion
35
What is the role of interception in particle deposition?
Brings particles near enough to a surface for contact
36
Which mechanism controls deposition in smaller bronchi and alveolar spaces?
Sedimentation
37
What is terminal settling velocity?
The constant velocity at which a particle settles when gravitational force equilibrates with buoyancy and air resistance
38
What is diffusion's role in particle deposition?
Important for particles ≤0.5 μm, especially in the nose, airways, and alveoli
39
What happens to particle deposition during exercise?
Increased impaction, sedimentation, and diffusion
40
What is the effect of electrostatic deposition on positively charged particles?
Minor mechanism due to negatively charged airway surfaces
41
What is the primary method of lung defense against deposited particles?
Particle clearance
42
How are particles deposited in the nose cleared?
* Extrinsic actions (wiping, blowing)
* Mucociliary clearance
43
What is tracheobronchial clearance?
Removal of particles by mucociliary clearance and upward movement of macrophages
44
What type of immune response is involved in alveolar clearance?
Both innate and adaptive immune systems
45
What is phagocytosis?
The process by which macrophages engulf and remove foreign particles
46
What are the steps involved in phagocytosis?
* Particle binding to macrophage membrane
* Receptor activation
* Actin polymerization and cytoskeletal movement
* Vesicular membrane closure to form a phagosome
47
How quickly do macrophages engulf particles after alveolar deposition?
≥50% within 3 hours and nearly 100% by 24 hours
48
What happens to most macrophages after engulfing particles?
They move to the airways and are removed by mucociliary clearance
49
What can happen to insoluble particles in the lungs?
They may be sequestered for long periods, often in macrophages
50
Fill in the blank: The only mechanisms by which deposited particles can be removed from the body are _______.
nasal wiping and coughing
51
What receptors are involved in the phagocytic uptake of micrometer-sized particles?
Fc receptor and pattern-recognition receptors (PRRs) including complement, mannose, scavenger receptors, and other PRRs.
52
What are opsonins?
Binding enhancers (e.g., antibodies) that coat negatively charged molecules, especially those on bacterial membranes.
53
What are pattern-recognition receptors (PRRs)?
Receptors that recognize pathogen-associated molecular patterns (PAMPs) present on microbial surfaces.
54
What is nasal irritation mediated by?
Irritant receptors (e.g., TRPA1) that trigger trigeminal nerve responses.
55
What symptoms are associated with bronchoconstriction?
* Coughing
* Wheezing
* Rapid shallow breathing
* Chest tightness
* Substernal pain
* Dyspnea
56
How does bronchoconstriction affect airway diameter?
It decreases airway diameter and increases airflow resistance.
57
What neurotransmitter is released by postganglionic parasympathetic fibers to regulate bronchial smooth muscle tone?
Acetylcholine
58
What effect does increased cGMP have on bronchial smooth muscle?
It increases intracellular calcium concentrations, leading to contraction of smooth muscle cells.
59
What does bronchoprovocation testing measure?
Airway resistance following inhalation of increasing doses of a methacholine aerosol.
60
What is acute lung injury characterized by?
Alveolar epithelial and endothelial cell perturbation and inflammatory cell influx, leading to surfactant disruption.
61
What is pulmonary edema, and how does it affect gas exchange?
It thickens the alveolar capillary barrier, limiting O2 and CO2 exchange.
62
What defines asthma?
Sporadic bouts of airflow obstruction measured as increased airway resistance.
63
What immune systems are involved in the pathogenesis of asthma?
The adaptive and innate immune systems.
64
What triggers severe airway obstruction in asthma?
Cross-linking of IgE molecules upon reexposure to an antigen.
65
What is bronchiolitis obliterans?
Fibrotic obstruction of the small diameter airways (bronchioles).
66
What chemicals are associated with bronchiolitis obliterans?
* Diacetyl
* Sulfur mustard
* Chemicals released during burn pit combustion
67
What is chronic obstructive pulmonary disease (COPD) characterized by?
Airway (bronchitis) and alveolar (emphysema) pathology.
68
How is chronic bronchitis defined?
Presence of sputum production and cough for at least 3 months in each of 2 consecutive years.
69
What is emphysema physiologically defined by?
Airflow obstruction leading to dyspnea accompanied by diminished FEV1.
70
What is the pathogenesis of emphysema linked to?
A proteinase—antiproteinase imbalance leading to remodeling of supportive connective tissue.
71
What is the role of TGFB1 in lung injury?
It is a profibrotic growth factor activated during acute lung injury.
72
What are some common triggers for asthma attacks?
* Irritants
* Cold-dry air
* Exercise
73
What environmental factors increase lung cancer risk in nonsmokers?
* Environmental tobacco smoke
* Biomass cooking
* High-temperature oil cooking
* Coal heating
74
What are the two major forms of lung cancer?
* Non-small-cell lung cancer (NSCLC)
* Small-cell lung cancer (SCLC)
75
What morphological changes occur in epithelial lung cancers?
* Hyperplasia
* Dysplasia
* Squamous metaplasia
* Carcinoma in situ
76
What is the consequence of DNA damage in lung cancer?
It can lead to persistent mutations and genomic instability
77
Which mutation is more common in never-smokers with lung cancer?
EGFR mutation
78
What are TLVs in occupational health?
Occupational airborne concentrations of substances that nearly all workers may be repeatedly exposed to without adverse health effects
79
What are the acute effects of acrolein exposure?
* Cough
* Shortness of breath
* Extreme oronasal irritation
* Pulmonary edema
80
What lung diseases are associated with asbestos exposure?
* Asbestosis
* Lung cancer
* Malignant mesothelioma
81
What are the critical features of asbestos fibers that contribute to toxicity?
* Fiber shape
* Fiber length
* Surface properties
82
What is a major risk factor for developing lung cancer?
Cigarette smoking
83
What do macrophages release upon activation by fibers?
Cytokines, chemokines, and growth factors
## Footnote
These mediators attract immunocompetent cells or stimulate collagen production.
84
What is the significance of particle size in coal dust exposure?
Particles 2 to 5 µm in diameter can trigger an immune response when clearance mechanisms are overwhelmed.
85
What is silicosis caused by?
Inhaled particles of silicon dioxide
## Footnote
Silicosis is characterized by fibrogenic potential linked to crystalline SiO2.
86
What are the three principal crystalline forms of silica?
* Quartz
* Tridymite
* Cristobalite
87
What characterizes acute silicosis?
Exposure to very high levels of silica over a short period
## Footnote
Symptoms include worsening dyspnea, fever, cough, and weight loss.
88
What common tests are used to evaluate toxicant-induced lung damage in humans?
* FEV1
* FVC
* Airway resistance
* Maximal flow rates
* Diffusion capacity
* Oxygen and carbon dioxide content
89
What is the purpose of bronchoscopy?
Direct visual inspection of the airways
## Footnote
It allows for cellular and molecular analysis through bronchoalveolar lavage.
90
What does an increase in airway resistance indicate?
Bronchoconstriction
91
What techniques are used for morphological examination of lung injury?
* Gross inspection
* Microscopic analysis
* Histopathological analysis
* Staining techniques
92
Define nanotechnology.
Nanotechnology is the understanding and control of matter at the nanoscale, between approximately 1 and 100 nm, where unique phenomena enable novel applications.
93
What is nanotoxicology?
Nanotoxicology studies the adverse effects of nanomaterials on living organisms and the environment, focusing on dose, dose rate, and dosimetry.
94
Which factors influence susceptibility to ambient particulate air pollution?
* Pre-existing disease (asthma, cardiovascular disease, diabetes) * Age (very young, elderly) * Genetic background (polymorphism)
95
What mechanisms are involved in the deposition of nanoparticles in the respiratory tract?
Nanoparticles diffuse throughout the respiratory tract, while larger particles sediment, impact, and intercept.
96
How do nanoparticles differ from larger particles in terms of clearance?
Nanoparticles may clear through mucociliary action and lymphatic circulation, while larger particles are cleared efficiently by alveolar macrophages.
97
What physicochemical property of nanomaterials is relevant for toxicity?
Particle size, distributions, geometry, and dimensions impact transport and exposure phenomena.
98
What is the significance of surface area in nanoparticles?
High surface area leads to increased surface reactivity, stronger catalytic activity, and enhanced dissolution rates.
99
What natural barrier do NPs encounter when inhaled or ingested?
A mucus layer that provides a barrier to penetration of particulates and microorganisms.
100
What is a common mechanism of toxicity associated with NPs?
Oxidative stress due to the generation of ROS.
101
What can be a consequence of exposure to NPs?
* Minimal and reversible responses
* Activation of adaptive responses
* Severe cellular changes leading to cell death
102
What role do carbon nanomaterials play in nanoparticle toxicity?
They are proposed to act as 'nanodarts' creating holes in the plasma membrane.
103
How can NPs be engineered to improve drug delivery?
By coating with pH-sensitive polymers, viral capsids, cations, or biodegradable carriers.
104
What can sustained elevation in intracellular calcium lead to?
Cell death by necrosis.
105
What is a key mechanism leading to cell toxicity from NPs within mitochondria?
Disruption of electron transport and generation of excess endogenous ROS.
106
What is the concern regarding zinc oxide NPs in sunscreens?
They are considered environmental toxicants due to rapid dissolution in water releasing Zn2+ ions.
107
What is the particle overload hypothesis?
When the volume of phagocytized particles exceeds a certain threshold, macrophage function becomes impaired.
108
What is the gold standard for exposure to airborne materials in laboratory studies?
Inhalation.
109
What is the concept of differential adsorption?
Physicochemical properties of nanomaterials influence protein and lipid adsorption patterns.
110
What factors affect the deposition efficiency of inhaled particles?
* Particle characteristics
* Anatomical structure of the airways
* Breathing parameters
111
What is the maximum particle size that will reach the alveolar region in humans?
About 15 μm
## Footnote
In contrast, in rats, this size is about 5 µm.
112
What factors influence the deposition efficiency of inhaled particles?
Particle size, size distribution, density, shape, anatomical structure of airways, breathing parameters
## Footnote
These factors govern deposition in the respiratory tract through inertial impact, gravitational settling, and diffusion.
113
What physiological mechanisms clear nanoparticles once deposited in the respiratory tract?
Alveolar macrophages, pulmonary interstitium, blood and lymph circulation
## Footnote
Nanosized particles may be too small to generate chemotactic signals for macrophage attraction.
114
What is the most efficient pathway for nanoparticle translocation to the CNS?
Via olfactory sensory neurons from the nasal olfactory mucosa to the olfactory bulb
## Footnote
This pathway bypasses the blood-brain barrier.
115
What are the primary elimination pathways for engineered nanomaterials (ENM) from the body?
Feces, urine
## Footnote
Urinary excretion is restricted to nanostructures <5.5 nm in size.
116
What can lead to significant inflammatory and fibrogenic responses in the pleural cavity?
Retention of longer fibers in the pleural cavity
## Footnote
This can induce inflammatory responses and potentially lead to mesothelioma.
117
What is the major exposure route for carbon nanotubes (CNTs)?
Inhalation
## Footnote
Other routes include ingestion and dermal exposure, but these have not received much attention.
118
What is the goal of predictive toxicology for engineered nanomaterials?
Hazard characterization and establishment of predictive tests
## Footnote
Incorporation of in silico models is a long-term goal.
119
In what common products are nanomaterials frequently found?
Cosmetics, clothing, personal care products, and sporting goods
## Footnote
Silver and carbon nanomaterials are among the most common types used.
120
What mechanism of toxicity is commonly associated with nanomaterials?
Oxidative stress
## Footnote
This can occur through the generation of free radicals or changes in cellular chemistry.
121
How do environmental conditions affect the toxicity of metal oxide nanomaterials?
Dissolution is impacted by media characteristics such as pH and salt content
## Footnote
This influences bioavailability and toxicity of other contaminants.
