How
does ozone react in the respiratory tract?
Because
ozone has limited solubility in water, the upper respiratory tract is not as
effective in scrubbing ozone from inhaled air as it is for more water soluble
pollutants such as sulfur dioxide (SO2) or chlorine gas (Cl2).
Consequently, the majority of inhaled ozone reaches the lower respiratory tract
and dissolves in the thin layer of epithelial lining fluid (ELF) throughout the
conducting airways of the lung.
In the lungs, ozone reacts rapidly with a number of
biomolecules, particularly those containing thiol or amine groups or
unsaturated carbon-carbon bonds. These reactions and their products are poorly
characterized, but it is thought that the ultimate effects of ozone exposure
are mediated by free radicals and other oxidant species in the ELF that then
react with underlying epithelial cells, with immune cells, and with neural
receptors in the airway wall. In some cases, ozone itself may react directly
with these structures. Several effects with distinct mechanisms occur
simultaneously following a short-term ozone exposure and will be described
below.
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Figure
3: Ozone is highly reactive in the respiratory tract
When breathed into the airways, ozone interacts with proteins and lipids on
the surface of cells or present in the lung lining fluid, which decreases in
depth from 10 µm in the large airways to 0.2 µm in the alveolar region.
Epithelial cells lining the respiratory tract are the main target of ozone
and its products. These cells become injured and leak intracellular enzymes
such as lactate dehydrogenase into the airway lumen, as well as plasma
components. Epithelial cells also release a variety of inflammatory mediators
that can attract polymorphonuclear leukocytes (PMNs) into the lung, activate
alveolar macrophages, and initiate a train of events leading to lung
inflammation. Antioxidants present in cells and lining fluid may protect the
epithelial barrier against damage by ozone or its reaction products.
Source: Devlin et al., (1997)
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What
are ozone's acute physiological and symptom effects?
The
predominant physiological effect of short-term ozone exposure is being unable
to inhale to total lung capacity. Controlled human exposure studies have
demonstrated that short-term exposure - up to 8 hours - causes lung function
decrements such as reductions in forced expiratory volume in one second (FEV1),
and the following respiratory symptoms:
·
Cough
·
Throat
irritation
·
Pain,
burning, or discomfort in the chest when taking a deep breath
·
Chest
tightness, wheezing, or shortness of breath
The
effects are reversible, with improvement and recovery to baseline varying from
a few hours to 48 hours after an elevated ozone exposure.
Current thinking is that changes in symptoms and lung
function are due to stimulation of airway neural receptors (probably airway
C-fibers) and transmission to the central nervous system via afferent vagal
nerve pathways. Although ozone exposure results in some airway narrowing,
neural inhibition of inhalation effort at high lung volumes is believed to be
the primary cause of being unable to inhale to total lung capacity.
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Figure
4: Ozone induces neurally mediated responses in the bronchial airways
Stimulation of nociceptive interepithelial nerve fibers by ozone leads to
reflex cough and a decrease in maximal inspiration that is relieved by opioid
agonists, which block sensory pathways. Two possible mechanisms are involved:
(1) stimulation of irritant receptors contributes to cough and induces a
vagally mediated reflex that increases airway resistance, probably via airway
smooth muscle contraction that is blocked by atropine; (2) C fiber
stimulation releases neurokinins such as substance P that dilate nearby
capillaries, activate mucous glands, and contract airway smooth muscle via
neurokinin receptors. Prostaglandin E2 released by epithelial cells exposed
to ozone or to ozone reaction products also sensitizes C fibers.
Source: Devlin et al. (1997)
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The
overall effect is thus primarily restrictive in nature with a smaller
obstructive component that reflects itself in decreases in forced vital
capacity (FVC), FEV1 and other spirometric measures that require a full
inspiration. It is likely that these lung function changes and respiratory
symptoms are responsible for observations that short-term ozone exposure limits
maximal exercise capability.
Ozone-induced changes in breathing pattern to more rapid
shallow breathing may also be a manifestation of C-fiber stimulation and may be
a protective response to limit penetration of ozone deep into the respiratory
tract. Such effects may also contribute to changes in deposition pattern and
retention of other inhaled substances such as allergens and particle pollution
(also called particulate matter).
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Figure
5: Effects of ozone on lung function
Ozone reduces the maximal inspiratory position (at the left of the curves)
and may slightly increase the residual volume (at the right). Reduction in
maximum inspiration reduces forced vital capacity (FVC), and this causes a
reduction in expiratory flow measurements, such as flow at 50% of FVC expired
(FEF50%). Because ozone causes only a small change in resistance, the
relationship between flow and volume is not changed to a large extent. Source:
Devlin et al. (1997)
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What
effects does ozone have at the cellular level?
As a
result of short-term exposure, ozone and/or its reactive intermediates cause
injury to airway epithelial cells followed by a cascade of other effects. These
effects can be measured by a technique known as bronchoalveolar lavage (BAL),
in which samples of epithelial lining fluid (ELF) are collected during
bronchoscopy on volunteers experimentally exposed to ozone. Cells and
biochemical markers in the lavage fluid and in the blood can be analyzed to
provide insight into the effects of exposure.
Evidence for airway inflammation following ozone exposure
includes visible redness of the airway seen during bronchoscopy as well as an
increase in the numbers of neutrophils in the lavage fluid. Cellular injury is
suggested by an increase in the concentration of lactate dehydrogenase (LDH),
an enzyme released from the cytoplasm of injured epithelial cells, in the ELF.
Mediators (e.g., cytokines, prostaglandins, leukotrienes) that are released by
injured cells include a number that attract inflammatory cells resulting in a
neutrophilic inflammatory response in the airway. In addition, ozone reaction
products as well as some mediators produced in the lung can be detected in the
blood providing a possible mechanism for extrapulmonary effects of ozone
exposure.
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Figure 6: Effects of ozone on lung function
These photos show a healthy lung airway (left) and an inflamed lung airway
(right). Photos courtesy of PENTAX Medical Company.
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Other
documented ozone-induced effects that may be related to the underlying injury
and inflammatory response are:
·
An
increase in small airway obstruction
·
A
decrease in the integrity of the airway epithelium
·
An
increase in nonspecific airway reactivity
·
A
decrease in phagocytic activity of alveolar macrophages
The
decrease in epithelial integrity can be measured by an increase in the
concentration of plasma proteins appearing in the ELF following exposure and by
more rapid clearance of inhaled radio-labeled markers from the lung to the
blood. This has the potential for allowing increased movement of inhaled
substances (e.g. allergens or particulate air pollution) from the airway to the
interstitium or the blood and could modify the known effects of inhaled
allergen on asthma and particulate matter on mortality.
Although
the significance of increased nonspecific airway reactivity to substances such
as methacholine or histamine is not understood in healthy individuals, it is
clearly of concern for people with asthma, as increased airway reactivity is a
predictor for asthma exacerbations. (See section entitled How does ozone affect people with asthma?).
A
decrease in macrophage function has the potential to interfere with host
defense. Over a period of several days following a single short-term exposure,
inflammation, small airway obstruction, and increased epithelial permeability
resolve; damaged ciliated airway epithelial cells are replaced by underlying
cells; and damaged type I alveolar epithelial cells are replaced by more
ozone-resistant type II cells. Over a period of weeks, the type II cells
differentiate into type I cells, and following this single exposure, the airway
appears to return to the pre-exposure state.
