Toxic Responses of the

Respiratory System

air mineral spirit and are the first to be

keenly aware of the injury

Overview of respiratory toxicity

they are liable of the same diseases,

though in less acute form because
they perform their tasks in open air
(1964)

Lung Structure and Function

Airway organization and
functional units
o Cell types
o Gas exchange
Types of toxicant exposure
Dosimetry
o Role of lung
structure/airflow/metabolism
o Gases and particles\
Effects of toxicants on
respiratory tract
Lung response(pathogenesis)
Direct mediators
e.g. oxidants
Indirect mediators:
role of
inflammatory cells
Acute responses of the lung to
injury
Airway
reactivity,pulmonar
y edema
Chronic reposnses of the lung to
injury
bronchitis,fibrosis,p
neumoconiosis,em
physema,asthma,
cancer
Historical perspective
Bernardino Ramazzini (1713)
In 1713,Bernardino Ramazzini
provided detailed and narrowing
accounts of the suffering of miners.
Two of his quotations remain
noteworthy..
Occupational Disease
the lungs and brains of that class of
workers are badly affected, the lungs
especially,since they take in with the

Inhalation toxicology
Route of exposure
Respiratory tract toxicology
Target organ toxicity
Abnormal changes in the
respiratory tract produced by
airborne and occasionally bloodborne agents
Lung structure and function
Nasal and oral passages
o Mouth,nose
Conducting airways
o Trachea,bronchi
Gas-exchange region
o Alveoli
Nasal and oral passages
FUNCTIONS
1. filter for particles,which may be
collected by diffusion or
impaction on the nasal mucosa.
2. Nasal turbinates- first defensive
barrier against many toxic
inhalants
3. Associated mostly with the 5th
cranial nerve
4. Ready target site for
metabolite-induced lesions.
Conducting AIRWAYS
FUNCTIONS: trachea/bronchi
delivery and structural
support
defense:
mucociliary
escalator
inflammatory cells

Gas exchange region

Lungs divided into:
Superior left lobe
Inferior left lobe
Superior right lobe
Middle right lobe
Inferior right lobe
subdivided at the periphery of
bronchial tree
Bronchopulmonary segments
Lobules
Acini----terminal
bronchiole,alveolar
ducts,alveolar sac
Ventilatory unit (ALVEOLI)
Anatomical region that includes
all alveolar ducts and alveoli
distal to each bronchiolaralveolar junction
Gas exchange occurs in the
alveoli,which compromise 8090% of the total parenchymal
lung volume
*Junnction. It represents the smallest
common denominator when the
distribution of inhaled gases to the
gas-exchanging surface of the lung is
modeled.

GAS EXCHANGE REGION:

FUNCTION:
surfactant production
defense
FUNCTION: GAS EXCHANGE
Ventilation
Inhale-exhale
Perfusion
Right ventricle
output
Diffusion
Exchange of gases
across alveolar
surface
Main task: bringing essential oxygen
to organs and tissues of the body and
eliminating its most abundant waste
product CO2 (Weibel,1983)

VENTILATION
In pulmonary edema or part of the
lung collapses TLC and VC are reduced

In emphysema, the alveoli overextend

and more air is trapped. While the TLC
may stay the same or even increase,
the volume of air that is actually
moved during breathing is diminished;
this results in decreased VC with
concomitant increase in RV.

The balance of metabolic activation

and detoxification is critically
important determinant of lung
protection as well as lung injury

PERFUSION

DEFENSE MECHANISM AGAINST

TOXICANTS

Lung receives the entire output from

the RV,aprox 70-80cm3 of blood per
heartbeat and thus may be exposed to
substancial amounts of toxic agents
carried In the blood.
DIFFUSION
Gas exchange takes place
across the entire alveolar
surface.
Contact to
Water
an airborne
toxic
chemical

occurs
over a
surface
aprox.
140m2.

PATHOGENESIS OF LUNG DAMAGE

CAUSED BY CHEMICALS

Toxic inhalants,gases and

dosimetry
Particle deposition
Nanotoxicology
Deposition mechanism
Particle clearance

Action

Example

do not penetrate
farther than the nose

SO2

solubility
Highly
soluble
Insoluble
gas
Very
insoluble

Distribution of
metabolic
competence in
the respiratory tract

Toxic
inhalants,gases
penetrate deeply into
Ozone,N
and dosimetry
the lung and reach
O2
Site of
the alveoli
deposition
effeciently pass
CO,H2S)
of gases in
through resp. tract-the
pulmonary blood
respiratory
supply----body
tract
define the pattern of toxicity of
those gases

Water solubility is the critical

factor in determining how
deeply a given gas penetrates
into the lung
Amount of the gases

-Occurs when the trajectory of a

particle brings it near enough to a
surface
Impaction and Sedimentation
-Fiber diameter
(bronchi,bronchioles,alveolar spaces)
Diffusion(Brownian movement)
-Important factor in deposition of
submicrometer
Occurs when the trajectory of a
particle brings it near enough to a
surface(deposition of fibers length)
Defense mechanism against
toxicants

Deposition on the surface of the lung

and airways is brought about by a
combination of lung anatomy and
patterns of airflow in the resp. system
Determinants of particle
deposition
Particle size
Density
Respirable particle
particles of a particular size,
mass and
shape that can
be inhaled or exhaled,
reaching the terminal bronchioles
and alveoli.
Deposition Mechanism
Interception

Nasal clearance
Particles cleared depending on
the site of deposition and
solubility
Tracheobronchial:
Transports deposited particles
and particle-laden macrophages
upward to the oropharynx
where they are swallowed and
pass through the GI tract.
Mucocilairy clearance is
relatively rapid in healthy
individuals and is completed
with in 24-28hrs for particles
deposited in the lower airways
Infection and injury impair
clearance
Lower..
Paticles are trapped on the
lining layer of conducting
airways and cleared upward in
tracheobronchial tree via
mucociliary escalator

Phagocytized by macrophages
and cleared by mucociliary
escalator
Phagocytized by alveolar
macrophages and removed via
lymphatic drainage
Materials may dissolve from
surfaces of the particles and be
removed by
bloodstream/lymphatics
Small particles direclty
penetrate epithelial membrane

RESPONSES OF LUNG TO INJURY

1. Acute events
collection of liquid or inflammatory
cells in the alveolar space
2. Chronic toxicity
abnormal increase in formation and
deposition of extracellular subs
(collagen/edema fluid)
ACUTE RESPONSES OF LUNG TO
INJURY

Pulmonary Edema
acute,exudative phase of lung
injury produces the thickening
of the alveolar capillary barrier.

alters ventilation-perfusion ratio

limits diffusive transfer of O2
and CO2 even in normal alveoli
*cause abnormalities that remain after
resolution of edematous process

CHRONIC RESPONSES OF LUNG

TO INJURY

Pulmonary fibrosis
Increase amount of collagen
fibers in alveolar interstitium
Cause
Fibroblast proliferation
Increased collagen synthesis or
deposition
Decreased collagen
Degradation

PULMONARY FIBROSIS: SILICOSIS

Agent: SILICA
Influential Factors (size and
concentration)
Mechanism:

1. Macrophage phagocytizes
particles
2. Lysosomes release enzyme or
mediators
3. Additional macrophages incite
fibroblasts to proliferate and
synthesize increased collagen
a. Size: 1 micron range
b. Concentration: direct
relationship to histologic
reaction
PULMONARY FIBROSIS:
COAL WORKERS PNEUMOCONIOSIS
1. Agent: coal particles
2. Influential Factors
a. anthracite or hard coal
3. Mechanism:
a. Macrophage phagocytizes
particles
b. If clearance exceeded,
macrophages
accumulate in
alveoli
c. Fibroblasts entrap
macrophages in place
secreting reticulin and
collagen
PULMONARY FIBROSIS: ASBESTOSIS
1. Agent: asbestos fibers
2. Influential Factors
a. length:2 microns
diameter: <3 microns
3. Mechanism:
a. Macrophage phagocytizes
particles
b. Short fibers cleared,
macrophages accumulate
in alveoli that
incompletely ingested
long fibers
c. Mediators are released
that attract immunocells
or stimulate collagen
production

smooth muscle shortening

OBSTRUCTIVE LUNG DISEASE:

CHRONIC BRONCHITIS
1. Agent:
a. tobacco smoke;
b. air pollution
2. Influential Factors
a. Air pollution
b. infection
3. Mechanism:
a. Mucus gland hypertrophy
b. Goblet cell metaplasia

1. Agent:
antigen: pollen,dander
2. Fumes,dust,gases
3. Mechanism:
Lack of control of airway

OBSTRUCTIVE LUNG DISEASE:

EMPHYSEMA
1. Agent:
a. tobacco smoke
2. Influential factor
a. Alpha1-antiprotease
3. Mechanism:
a. Elastases break down
elastin
b. Toxicants accelarate
process

AIRWAY HYPERREACTIVITY:
HYPERSENSITIVITY PNEUMONITIS
1. Agent: Organic dust
2. Influential factor
Occupation: farmer, bird
breeder, chemical worker

3. Mechanism:
Neutrophils, mononuclear cells
increase
Release of proteolytic enzymes

OBSTRUCTIVE LUNG DISEASE: LUNG

CANCER
1. Agent:
a. tobacco smoke
b. Asbestos,
c. Metallic dust,
d. Radon gas
2. Mechanism:
a. carcinogens
b. Reactive oxygen species

AGENTS KNOWN TO PRODUCE

LUNG INJURY TO HUMANS
DIRECT EXPOSURE

INDIRECT EXPOSURE

 Total Lung Capacity

Functional Residual
Volume
Tidal volume
Airway resistance and
maximum flow

AGENTS KNOWN TO PRODUCE LUNG

INJURY
Airborne Agents That Produce Lung
Injury
Asbestos
Silica
Naphthalene
Blood-Borne Agents
Bleomycin
Cyclophosphamide
1,3 bis(2-Chloroethyl)-1Nitrosourea
EVALUATION OF TOXIC LUNG
DAMAGE
Measurement:
Vital Capacity