4/15/10
Respiratory Toxicology 1
J Paul Seale MB BS PhD FRACP
Professor of Clinical Pharmacology
COMMONWEALTH OF AUSTRALIA
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Outline of 2 lectures
•
•
•
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The respiratory system as a target organ
The anatomy & structure / function
Host defence : mucus & muco-ciliary clearance
Vulnerable cell types
– & their pathological responses
• Damage to lung cells
– Chemical
– immunological
• Disease states
Respiratory system as target organ
• in contact with external environment
Respiratory system & inhaled toxins :
2 categories of effects
• Local effects
– Nasal
– Upper airways : larynx/trachea
– Lower airways & alveoli
– all the way from nostrils to alveoli
• samples a large volume of air
– >10,000 L per day
• has defense system
• Distant effects
– toxin absorbed into the body
– toxic effects on “distant organs” (e.g. CO)
– but can be over ridden
Anatomy : Respiratory Tract
Respiratory system & injury
• Injury to the lungs can occur via
Naso-pharynx
Nasal
cavity
– inhaled toxins
– toxins in the blood (e.g. paraquat)
pharynx
Larynx
“voice box”
Airways
Trachea
“windpipe”
Alveoli
“gas exchanging
units”
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CT scan of nasal cavity
Nasal cavity
Middle turbinate (MT)
Inferior turbinate
Uvula (U)
- soft palate
Nasal breathing
Mouth breathing
tongue
• Showing maxillary sinuses
F. Netter Textbook of Human Anatomy from "Respiratory Specialists Slide Set"
Thryoid cartilage
Cricoid cartilage
Nasal function
~27 generations of asymmetrically
branching airways
Generation 1
• Air-conditioner of inhaled air
– heats air
– humidifies air
Trachea
Longitudinal mucosal folds
• Filter
– captures large particles
• Captures water soluble gases
• Nasal epithelium has cytochrome P450s
bronchi
Right upper lobe
Left upper lobe
– 1A1, 2B1, 4B1 in several species
Right lower lobe
Left lower lobe
Bronchi
Bronchioles
Acinus
education.vetmed.vt.edu/.../labs/Lab25/lab25.htm
Dr Thomas Caceci, VM8054: Veterinary Histology.
Dept. of Biomedical Sciences & Pathobiology,
Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA
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Bronchioles and alveoli
Alveolar spaces
Trachea Bronchi Bronchioles (<1mm diameter, no
cartilage in walls) alveoli (terminal sacs)
Alveolar septum
SPACE
Photograph courtesy of Prof M Saetta
Moore, K.L. & Dalley, A.F.. 2003, Clinically Oriented Anatomy, Instructor’s resource DVD ROM 5th Edn, Lippincott Williams and Wilkins, Philadelphia.
O2
Interstitial cell
Epithelial
Cell: Type 1
CO2
Alveoli cells
• Type 1 cells: line the airspaces
• Type II cells : located in corner of alveoli
– Produce surfactant
– Transform into Type 1 cells if necessary
ENDOTHELIUM
Endothelial cell
• E.g. if Type 1 cells are damaged
nucleus
Type II cell
Mucus
• Where does it come from ?
– Goblet cells
– Mucous glands
Lamella
body
• What does it do ?
– host defense
mitochondria
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Respiratory mucosa
Mucociliary system
cilia
Goblet cell
? Direction of flow
Mucus
Cilia
Ciliated Cell
Ciliated Cell
periciliary fluid
layer
Goblet Cell
basement
membrane
Submucosal glands
submucosa
Direction of flow
Direction of mucociliary flow : nasal cavity
• Nose : backwards
• Trachea & lower airways : Upwards
• To nasopharynx
VISUALISATION
swallowed
Mucociliary clearance : lung
Clearance
is
“upwards”
Dye in oropharynx at peak intensity
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Mucus
• From goblet cells & mucous glands
• Traps pollutants & debris (physical properties)
• Other properties
– Anti-oxidant
– Acid neutralising
– Free radical scavanging
Measuring muco-ciliary clearance
• Patient inhales radiolabelled particles
• counter continuously
records emission
• Segment into “areas of
interest”
peripheral
central
Measuring muco-ciliary clearance
Damage from inhaled noxious agents
#
##
Intervention
Colonization with bacteria, virus and besides impairment
of the mucociliary-clearance
Inflammation (Neutrophils)
Cardinal symptoms: cough, sputum and (micro-) infections.
Respiratory Clearance
• Nasal
– Anterior : wiping / blowing
– Posterior ; muco-ciliary
• Tracheobronchial : mucociliary
– trapped in mucus
– phagocytosed by macrophages ----> mucus
• Pulmonary- peripheral
– phagocytosed by alveolar macrophages ---> lymph drainage
• via lymph nodes
– Dissolve from surface of particles & enters
• lymphatics OR
• blood
Vulnerable cells & damage
• Particle size determines site of deposition
– Large particles in upper airways
– Small particles reach small airways / alveoli (distal
lung)
– Gases can cause damage along the entire tract
• And may be absorbed (affecting distant organs)
• Site of deposition will determine which cells are
at risk of damage
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Mechanisms for deposition
• Interception
– particle trajectory brings it contact with airway epithelium
(Large airways)
PARTICLE
DEPOSITION
• Sedimentation
– as flow diminishes gravity leads to sedimentation(small
airways)
trachea
Very abrupt
bronchi
bronchioli
1-5 μm
less abrupt
+
Effective deposition
Leach CL, et al. [REF T/C]
Vulnerable cells : damage by chemicals
– mediated by oxygen free radicals generated by :
• ozone
• nitrogen dioxide
• tobacco smoke
– also from lung defense cells
• neutrophils, monocytes, macrophages
0
-labelled particles : lung deposition
Large particles
Small particles
• Oxidative burden
++
Periphery /Alveoli
1 μm
diffusion
99Tc
++++
+++
mild
– No flow (alveoli)
(HFA propellant, radiolabelled)
interception/
impaction
sedimentation
• Diffusion
Deposition of inhaled
Airflow
Directional change
• Impaction
– at sites of airway bifurcation (large airways)
Particle size
Naso-pharynx
5-30 μm
Ineffective deposition
Lung defense cells
• Convert molecular oxygen to :
– Reactive oxygen species (ROS)
• ROS are part of host defense
O2 ----> ROS
Kill microbes (host defence)
“appropriate”
If “excessive” ----> lung damage
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Immune System Basics
Vulnerable cells : immunological damage
Response phases
Cell
Number
• Immune response is part of host response
– Humoral (antibodies)
– Cell mediated (T lymphocytes)
• Normal cells can be affected
– “collateral damage”
Reprinted
from:
Abbas & Lichtman, “Phases of adaptive immune response”
Cellular and Molecular Immunology, 2005
L
Toxicity of inhaled gases :
site of injury depends on water solubility
Highly soluble
(e.g. SO2)
-captured in
nasal fluid
- not very toxic
Relatively water insoluble
(e.g Ozone, NO2 )
-penetrate deep into lung
- small airway/alveolar damage
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Lung toxicology 1 : summary
• Respiratory tract in contact with external
environment ; vulnerable
– also at risk from some blood born substances
• Well developed host defense
Very water insoluble
(e.g.CO )
- reach alveoli
– But this can be depleted or overwhelmed
• Damage can occur via :
binds to haemoglobin
– Particles, gases, or mis-directed immune response
blood
Tissue hypoxia
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