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OCR for page 441
Relation of Pulmonary
Emphysema and Small
Airways Disease
to Vehicular Emissions
JOANNE L. WRIGHT
University of British Columbia
Lung Anatomy and Defense Mechanisms / 442
Airway Cells / 442 Alveoli / 443 Deposition of Particulates / 443
Pathologic Conditions: Concepts and Quantification / 443
Emphysema / 443 Small Airways Disease / 446 Mucus
Hypersecretion / 446
Animal Models of Human Disease / 446
Emphysema / 448 Small Airways Disease / 449
Emphysema and Small Airways Disease: Relations to Vehicular
Emissions / 449
Lung Disease Produced in Animals by Vehicular Emissions / 449
Animal Exposure to Diesel Exhaust / 454
Summary / 454
Summary of Research Recommendations: Discussion / 455
Pathogenesis of Pulmonary Disease / 455 Pathobiology / 457
Animal Studies / 457 Human Studies / 458
Summary of Research Recommendations: Priorities / 458
In Vitro Experiments / 458 In Vivo Experiments / 459 Human
Studies / 460
Air Pollution, the Automobile, and Public Health. ~ 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
441
OCR for page 442
442 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
The ability of gasoline and diesel engine
emissions to cause pulmonary disease in
humans depends not only on the character
and components of emissions but also on
the structure of the lung and the adequacy
of its defense mechanisms. This defense
system can be modulated by other factors
such as age, general health, or the presence
of specific lung diseases.
To understand the effects of emissions, it
is necessary to understand the mechanisms
of damage and their relationship, if any,
with such lesions as emphysema or small
airways disease. In this chapter, lung struc-
ture is described as it pertains to disease
processes, and then methods of diagnosis
and mechanisms thought to be involved in
the production of pulmonary diseases are
outlined.
The lesions of emphysema and small
airways disease produced by tobacco
smoke inhalation in humans are similar to
those that appear in animals experimentally
exposed to emissions. To investigate the
effects of emissions on human lungs it is
necessary to use animal models. A review
of similarities and disparities between ani-
mal models and humans is followed by a
discussion of similarities between human
lung disease and diseases produced by ma-
nipulation of animal models.
Finally, a summary description of the
lesions that have been identified in animals
. . . .
exposer . to emissions or emission compo-
nents is followed by a discussion of areas in
which knowledge is lacking and recom-
mendations for further experiments.
Lung Anatomy and Defense
Mechanisms
Lung anatomy has been elegantly described
by Nagaishi et al. (1972~. Grossly, the lung
is divided into lobes and segments. The
smallest structures are the secondary lob-
ules, consisting of lung tissue confined by
lobular septa.
Embedded within the lung tissue is
supported by cartilage rings or plates,
whereas the more distal airways are mus-
cular. There are approximately 13 divisions
from the trachea to the membranous bron-
chioles, characterized by a complete wall
formed of fibromuscular tissue. At approx-
imately the eighteenth generation, respira-
tory bronchioles are identified. These air-
ways are alveolated; that is, they have
alveoli budding from the wall. The mem-
branous and respiratory bronchioles less
than 2 mm in internal diameter have been
termed "the small airways." The respira-
tory bronchioles branch and form alveolar
ducts which in turn divide to form alveolar
sacs and finally alveoli. The airway branch-
ing patterns are well described by Horsfield
(1976), and are reviewed by Schlesinger in
this volume.
Airway Cells
The mucus-secreting cells and ciliated epi
thelial cells are the most important cellular
structures in lung defense mechanisms
(Gail and Lenfant 1983~. The epithelial mu
cous cells and serous cells secrete some of
the components of airway mucus, but the
major source of mucus is the submucosal
mucoserous glands. The ciliated epithelial
cells, which occur from the trachea to the
respiratory bronchioles, contribute to the
mucociliary transport system. These air
way components are known to react to,
and be damaged by, inhaled particles and
gases.
In addition to epithelial cells, macro
phages and polymorphonuclear neutrophils
contribute to lung defenses. Neutrophils
originate in the blood and migrate onto
airway surfaces. Macrophages originate as
blood monocytes and enter the pulmonary
interstitium where they mature. A contin
ually renewing population of matured cells
migrate onto pulmonary surfaces. Under
conditions of inflammation, the numbers
and functional capacities of cell types in
crease. (For a more detailed discussion of
cellular components and their products see
Last, this volume.)
the bronchial tree, a complex structure
formed of approximately 15 million ~ Recommendation 1. In vitro cell exper
branches. The more proximal airways are iments should be directed to basic cell
OCR for page 443
Joanne L. Wright
443
biology wherein pollutant constituents are
introduced to cell cultures of epithelial
and/or inflammatory cells.
Alveoli
There are two types of alveolar epithelial
cells. Type I are attenuated cells covering
93 percent of the alveolar surface. They are
highly susceptible to injury and their death
is followed by proliferation of type II cells
which then differentiate into type I cells.
Type II cells are responsible for the synthe-
sis of the phospholipid and protein compo-
nents of surfactant. These cells are thought
to play a role in initiation of fibrotic repair
reactions in the lung.
The lung matrix is composed of colla-
gen, elastin, glycosaminoglycans, and fi-
bronectin (Turing 1985~. Collagen and
elastin provide the tissue structural ele-
ments and together form what have been
loosely termed the lung "scleroproteins."
Types I and III are the most common of the
multiple subtypes of collagen. The balance
of these two types appears to be important
in lung repair reactions. The other sub-
stances appear to induce and modulate the
responses of the matrix to injury.
Elastin is formed as a soluble protein
which is secreted into the extracellular
space. The soluble elastin is converted into
mature elastic fiber by a cross-linking proc-
ess that is mediated by the enzyme lysine
oxidase. The signal that stimulates elastin
synthesis is unknown. Elastin degradation
releases peptides which can be measured in
the plasma, urine, or broncho-alveolar lav-
age fluid.
a Recommendation 2. Studies should be
undertaken to ascertain whether the pep-
tides present in body fluids can be measured
accurately, and whether the measured pa-
rameters do, in fact, relate to the degrada
. .
t1on anc . repair process.
Deposition of Particulates
Deposition in the lung of the particulate
components of inhaled material depends on
the mean diameter of the particles and the
distribution of particle diameters. There are
a number of experimental techniques for
measuring deposition (Brain and Valberg
1979~. Particles less than 1 ,um in diameter
may reach the alveoli, but particles less than
5 ,um in diameter are deposited in the
airways by processes of sedimentation and
inertial impaction. A large fraction of the
particles emitted by gasoline and diesel
engines is less than 5 ,um in diameter.
The main defense mechanism in the air-
ways is the mucociliary escalator. In the
alveoli, it is the macrophage. The balance
between particle deposition and action of
the defenses can be altered by pathological
changes in the airways or in the lung pa-
renchyma. These changes affect the mech-
anisms of deposition and clearance. (For a
review of deposition and clearance, see
Schlesinger, this volume.)
Pathologic Conditions: Concepts
and Quantification
The definitions and pathophysiological
concepts of emphysema and small airways
disease have been formulated primarily in
the context of their relationship to tobacco
smoke. It has been postulated that tobacco
smoke produces three separate but highly
interrelated pathologic conditions: emphy-
sema, small airways disease, and mucus
hypersecretion. Furthermore, because to-
bacco smoke is the only source of air pollu-
tion where there is a large data base, it is
often used as a model for studying the
effects of inhaled pollutants such as auto-
motive emissions.
Emphysema
Emphysema has been defined as a condi-
tion of the lung characterized by abnormal,
permanent enlargement of airspaces distal
to the terminal bronchioles, accompanied
by destruction of their walls and without
obvious fibrosis. Destruction is defined as
nonuniformity in the pattern of respiratory
airspace enlargement, so that the orderly
appearance of the acinus and its compo-
nents is disturbed and may be lost (Snider
et al. 1985~.
OCR for page 444
444 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
There are three anatomic subtypes of
emphysema, of which two-panacinar and
. . . .
centrlaclnar emphysema- are pertinent to
this discussion. In panacinar emphysema,
all components of the acinus are equally
involved, whereas in centriacinar emphy-
sema, destruction is centered around the
respiratory bronchiole.
Panacinar Emphysema. Panacinar em-
physema has been observed in humans
with a-1-proteinase inhibitor C-1-PI defi-
ciency. Use of papain, pancreatic, neutro-
phil, or bacterial elastase in animal models
has produced anatomic lung destruction
identical to panacinar emphysema in hu-
mans (Snider et al. 1985~. The realization of
these facts led to a theory of proteolysis/an-
tiproteolysis imbalance as a pathogenic fac-
tor in pulmonary emphysema.
This theory has immediate bearing on
the question of effects of auto emissions on
the lungs. For instance, what are the effects
of emissions on a population with altered
levels of c-1-PI? And what are the effects
on a-1-PI of direct emissions that alter the
balance of proteinase and antiproteinase?
In relation to proteinase, researchers have
shown that cigarette smokers have an in-
creased number of neutrophils, both in the
peripheral blood (Sparrow et al. 1984) and
within the lung, as seen by broncho-alve-
olar ravage (Hunninghake and Crystal
1983~. Smoke is chemotactic (that is, an
attractant) for macrophages and neutro-
phils, and the neutrophilic response can be
amplified by macrophage-secreted chemo-
tactic factors and stimulated by a comple-
ment that has been activated by cigarette
smoke. The idea that these neutrophils
show increased enzymatic activity is more
controversial.
Although elastase-like activity has been
found in the ravage of smokers, it was
metallo-enzyme in type, implicating the
pulmonary macrophage as its source. This
is not surprising, since macrophages in the
lumens of respiratory bronchioles are a
prominent feature in young healthy ciga-
rette smokers (Niewoehner et al. 1974~.
This response may reflect early disease, and
may be important in the pathogenesis of
emphysema.
Recommendation 3. Cell damage and
its relation to inflammation should be stud-
ied through further research on exposure-
related increases in neutrophils and macro-
phages, including collagen and elastin
biomechanics, and the dose/time relation-
ship between exposure and neutrophil and
macrophage increase.
There are several proteinase inhibitors in
the respiratory tract, including low molec-
ular weight (MOO) bronchial mucus inhib-
itor, a-2-macroglobulin, and a-1-PI. It was
thought that `~-1-PI was the most impor-
tant inhibitor, but this may not be entirely
true Janoff 1985~. This is certainly an area
that needs further investigation in regard to
smoking as well as to the effects of emis-
sions. Cigarette smoke has been shown to
oxidize a methionyl residue on cY-1-PI, thus
rendering it essentially inactive. This
method of inactivation may be important
with regard to emissions, since nitrogen
dioxide (NO2) is able to inactivate cr-1-PI
in an in vitro situation, presumably
through an oxidative mechanism.
Recommendation 4. The relation of
oxidants to the proteinase/antiproteinase
balance should be studied.
Centriacinar Emphysema. There are two
morphologically similar subtypes of cen-
triacinar emphysema, both applicable to
this discussion. Exposure to coal dusts re-
sults in the dilatation of respiratory bron-
chioles with abundant collections of dust
particles. Whatever the pathophysiological
mechanism involved in this lesion, it is
conceivable that it may be related to, or
amplified by, exposure to the emissions
from the machinery used in mining or
processing. In recent years, the bulk of
investigation has been directed toward the
proteinase/antiproteinase hypothesis for
the causation of the second subtype of
centriacinar emphysema found in people
who smoke cigarettes.
Quantification of Pulmonary Destruction.
Indirect methods of quantifying pulmonary
destruction include pulmonary function
tests and radiographic examinations. Both
OCR for page 445
Joanne L. Wright
445
methods can detect abnormalities in estab-
lished disease but neither is particularly
useful in the identification of early disease.
Direct methods of estimation and/or
quantification of lung parenchymal de-
struction can be performed on several lev-
els. Most accurate are the methods based on
analysis oftissue parameters. However, these
methods can only be applied to experimental
animal models and human autopsy or surgi-
cal resection material, and the resulting data
represent a single point in a cross-sectional
study. These methods are not applicable to
case-control longitudinal studies.
Recommendation 5. Pulmonary me-
chanics should be assessed on excised lung
specimens obtained from human autopsies
or surgical specimens and results related to
data collected from live subjects. Morpho-
logical examinations of human lung tissues
could duplicate methods used to investigate
effects of tobacco smoke.
Gross and subgross methods involve ei-
ther whole lung slices or Gough sections in
which the degree of destruction is ranked by
comparison with a standard grading panel
(Thurlbeck et al. 1970~. These methods are
only truly applicable to inflated human lungs
and are by their very nature imprecise. Since
gross estimation of emphysema requires a
fully established lesion, methods in which the
earliest phases of disease can be defined and
quantified must be considered.
Measurements of tissue using micros-
copy include calculation of mean linear
intercept (Dunnill 1962), destructive index
(Saetta et al. 1985a), and analysis of alveolar
attachments (Saetta et al. 1985b). These
measurements are more precise than those
obtained by gross and subgross methods,
and they reflect airspace enlargement (mean
linear intercept), or alveolar destruction
(destructive index, alveolar attachments).
They can be performed on human and
animal tissues alike. A minor disadvantage
is that the methodology requires lungs in-
flated to a standard pressure.
Measurements of destructive index and
alveolar attachments show relatively good
separations of smoking and nonsmoking
populations. Since mean linear intercept
reflects dilatation of the airspace rather than
destruction per se, it is affected by aging.
However, it may be more sensitive than
other methods to scleroprotein alteration,
and it should not be abandoned.
An image analysis system can perform
detailed measurements of alveolar surface
area and surface density to provide infor-
mation relating both to alveolar space dila-
tation and destruction. This is a labor-
intensive technique, however, and it does
not yield data of greater value or accuracy
than the techniques mentioned previously.
Transmission or scanning electron mi-
croscopy techniques are applicable to assess
substructural alteration such as changes of
cell types, nuclear and/or cytologic alter-
ations, and collagen and elastin structural
changes. Such techniques may identify ex-
tremely early lesions in the microstructure.
Disadvantages include the potential for
sampling error because of the small sample
size, and the necessity for special fixation
and preparation. Potential advantages in-
clude applications for biopsy technique and
use in longitudinal studies.
~ Recommendation 6. Examination should
be made of epithelial cells, collagen, and
elastin by electron microscopy to docu-
ment possible progression of emission-re-
lated disease during a recovery period after
direct exposure ceases.
Biochemical techniques can be direct,
using portions of lung, or indirect, using
ravage fluid or urine. These techniques can
be used to assay hydroxyproline and fibro-
nectin and lung tissue collagen types. Mea-
surements of by-products of elastin turn-
over are more exciting, because of their
potential use in longitudinal studies. Uri-
nary desmosine correlates well with lung
destruction in an animal model, but its
applications in human investigations have
been less promising Janoff 1985~. How-
ever, elastin peptides in human blood have
been shown to separate nonsmokers from
smokers, and measurements of lysyl oxi-
dase as an indicator of elastin synthesis have
shown that cigarette smoke inhibits elastin
repair after initial damage with instilled
elastase Janoffl985~.
OCR for page 446
446 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
Small Airways Disease
The concept of small airways disease as a
major cause of airflow obstruction in ciga-
rette smokers arose from early work show-
ing that peripheral airways resistance was
markedly increased in patients with chronic
obstructive pulmonary disease (Hog" et al.
19681. This was initially thought to be due
to abnormalities in airways of less than
2-mm internal diameter and was associated
with inflammation and fibrosis of airway
walls as well as with epithelial changes
(Cosio et al. 1977~.
These initial reports were followed by
pathological description and semiquantita-
tive analysis of airways in the lungs of
patients with varying smoking histories,
degrees of emphysema, and abnormalities
of pulmonary function (Cosio et al. 1980;
Wright et al. 1984~. The most important
components of small airways disease now
appear to be an inflammatory response and
a fibrotic repair reaction.
The broncho-alveolar ravage fluid of
smokers shows greater numbers of poly-
morphonuclear neutrophils and macro-
phages. Some of these cells must represent
an airway inflammatory response. The
pathological abnormalities of inflammation
and fibrosis relate to perturbations of the
pulmonary function tests, including flow
rates and elastic recoil.
Pathological parameters in the small air-
ways can be assessed by semiquantitative
grading schemes or by direct morphomet-
ric analysis. The grading methodology is
subjective but easy to perform and has the
advantage of being usable on noninflated
lungs (Wright et al. 19851. In this method,
various degrees of abnormality are defined
and displayed as a poster format (figure 1~.
The test-case airways are compared to these
standards, and grade score is assessed. This
method isolates individual parameters such
as inflammation and fibrosis while also giv-
ing an overall estimation of abnormality.
Morphometric analysis is more precise
but requires standard inflation pressures of
fixation and some technical expertise. This
method allows the investigator to measure
directly the airway diameter and wall thick-
nesses, and in addition, to quantify the
types and numbers of inflammatory cells in
the airway walls and lumens.
Small airways disease can be assessed
indirectly with specialized pulmonary func-
tion tests including nitrogen wash-out
curve and forced expiratory flow of 25-75
liters/sec (FEF2~75~. It would be difficult to
detect minor degrees of injury in this fash-
ion, but the tests would be suitable for
longitudinal studies (Buist et al. 1984~. Fur-
thermore, the tests could be used to docu-
ment established disease.
~ Recommendation 7. Some of the more
detailed pulmonary function tests should be
used to identify progressive dysfunction.
Mucus Hypersecretion
Cigarette smoking increases the size of the
bronchial mucous glands (Reid 1960) and
the proportion of glands in the bronchial
wall and also causes goblet cell metaplasia
(Mitchell et al. 19761. The Reid index mea-
sures the thickness of the bronchial mucous
glands compared to the thickness of the
bronchial wall measured from perichon-
drium to basement membrane. This thick-
ness correlates with the presence of chronic
bronchitis (Reid 19601. The proportion of
mucous glands in the bronchial wall can be
estimated either by a point-counting tech-
nique or by direct measurement of the areas.
Although these changes are associated
with chronic cough and sputum production
(a process formerly referred to as chronic
bronchitis) with their attendant nonesthetic
qualities and psychological disabilities, they
have not been associated with airflow ob-
struction (Fletcher et al. 1976) and physical
disabilities. Since mucus hypersecretion ap-
pears to be a nonspecific response to an
irritant, and since this does not produce
pulmonary function abnormalities, it will
not be considered further.
A ni m al M odels of H u m an Disease
It is important to ascertain whether lung
disease produced in animals by manipula-
tions such as the instillation or inhalation of
OCR for page 447
Joanne L. Wright
447
:
~ :21
~0 _, ~At, ~.. ~ ~ ~ ~ ~ :~: ~ ~ I
Figure 1. Type of poster format applicable in the semiquantitative grading
technique for assessing pathological parameters in the small airways: top, normal
respiratory (A) and membranous bronchioles (MB) (B); middle, grade III intralu-
menal macrophages in the respiratory bronchioles (RB) (C) and grade III intramural
inflammation in the membranous bronchioles (D) (In the MB, the grading is based on
overall cellularity rather than the inflammatory cell types.); bottom, grade III fibrosis of
both the RB (E) and MB (F). (Adapted with permission from Wright et al. 1985. Arch.
Pathol. Lab. Med. 109:16~165. Copynght 1985 American Medical Association.)
various materials is similar to human dis-
ease. Animal models have been used exten-
sively to test specific hypotheses related to
the pathogenesis of emphysema and small
. .
airways c .lsease.
Comparisons of animal and human lung
structure have concentrated on two areas:
airway structure and airway surface epithe-
lial cells and glands. The casts of the tra-
cheobronchial trees of humans have a dis-
tinctive, almost spherical shape with a
relatively symmetrical branching pattern.
In contrast, most other mammals have
elongated casts with tapered monopodial
airways and small lateral branches.
Small airways and terminal units in spe-
cies other than rodents are similar to human
lung structure. In rodents, the respiratory
bronchiole is either absent or very short.
This may be significant since the respira-
tory bronchiole appears to be a target area
for injury after inhalation of dusts and fumes.
Various mammalian species, including
humans, have different cell populations in
the normal surface epithelium, and even
within an individual species there are
changes dependent upon maturation. There
are also species variations in the total vol-
ume of submucosal glands as well as in
their distribution within the airways. In
addition, differences in the histochemical
staining of the epithelial cells and glands
indicate different mucus secretions among
the species.
OCR for page 448
448 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
Emphysema
Elastin/Collagen Destruction. Elastin/col-
lagen destruction in animal models has
been studied primarily by using inflamma-
tory cell increases, elastase administration,
or reduction of ct-1-PI to test the relation-
ships between proteinases and antiprotein-
ases. Administration of elastases, either
pancreatic or leukocytic (endogenous or
exogenous), has produced airspace destruc-
tion morphologically similar to panacinar
emphysema Janoff 1985~.
Electron microscopy of enzyme-induced
emphysema shows elastic fiber disruption,
with beading and irregularity of the fibers
(Kuhn et al. 1976~. Biochemical analysis of
elastase-instilled lungs has shown a rapid
and marked decrease in total elastin content
with a lesser decrease in collagen (Karlinsky
et al. 1983~. After a postexposure recovery
period, however, lung elastin content re-
turned to normal limits.
Alterations in physiological parameters
show a dose/response effect (Raub et al.
1982), and age at exposure appears impor-
tant since the effects of elastase have been
shown to be greater in younger animals
(Goldstein 1982~. Administration of ciga-
rette smoke to animals previously given
elastase has augmented destruction (Hoidal
and Niewoehner 1983~. Chronic adminis-
tration of the oxidant chloramine-T to in-
terfere with the function of a-1-PI pro-
duces similar results. Cigarette smoke
itself, in high doses, has been shown to
produce enlargement of airspaces and ab-
normalities in pulmonary function (Huber
et al. 1981; Heckman and Dalbey 1982~.
These studies have also described, but not
quantified, changes in the small airway
walls.
~ Recommendation 8. Research should
be undertaken on the elastin and collagen
degradation/repair balance to determine
whether repair is affected by pollutants, and
if so, by what mechanism. Studies should
map the time course of collagen and elastin
degradation and repair, relating data to
type and concentration of exposure as well
as ascertaining the possibility of alteration
or repair by pollutants or other oxidants.
Elastin/Collagen Formation. Lysyl oxi-
dase, a copper-requiring enzyme that me-
diates the conversion of lysine to the
elastin-specific cross-links desmosine and
isodesmosine, is involved in the process of
elastin/collagen formation. Elastin synthe-
sis occurs rapidly after elastase-induced em-
physema, and there is an associated increase
in lysyl oxidase activity Janoff 1985~. De-
creased lysyl oxidase activity results in
poorly formed elastin and in lung lesions
morphologically and physiologically iden-
tical to panlobular emphysema in the
blotchy mouse (Snider et al. 1985~.
Recommendation 9. Pollutant interfer-
ence.with lysyl oxidase and impairment of
elastin resynthesis should be investigated as
a possible destructive mechanism.
Dietary insuff~ciencies have also pro-
duced pulmonary abnormalities. Protein/
calorie starvation produces enlargement of
the airspaces, but physiological alterations
are different from those seen in human
emphysema Janoff 1985~.
When exposed to cigarette smoke, exper-
imental animals with elastase-induced em-
physema show a greater degree of lung de-
struction. These data, in conjunction with in
vitro studies showing that cigarette smoke
can inhibit the activity of lysyl oxidase Janoff
1985), suggest that interference with elastin
synthesis contributes to the alteration of the
lung structure as seen in emphysema.
Administration of cadmium chloride to
experimental animals produces inflamma-
tion and a granulation tissue response fol-
lowed by airspace enlargement. Adminis-
tration of the lathyrogen beta amino
propionitrile (BAPN) appears to limit the
fibrosis (Niewoehner and Hoidal 1982~.
The mechanism for disease is unclear in this
model, but it appears to involve some
balance between destruction and repair re-
action with ultimate fibrosis.
The physiological requirements for the
diagnosis of emphysema in humans are
very controversial. Since these physiologi-
cal requirements have not yet been estab-
lished, only the morphology of human and
animal emphysema can be compared. This
comparison itself may be diff~cult, since the
OCR for page 449
Joanne L. Wright
lungs of the various species are not identi-
cal. Although physiological abnormalities
are often found in animal models, the pres-
ence or absence of emphysema is deter-
mined by whether airspace enlargement
can be documented.
Within these limits, instillation or inha-
lation of elastase is an excellent model for
panacinar emphysema; however, there is
no workable model for centriacinar emphy-
sema at the present time. Some animal ma-
nipulations produce airspace enlargement as
well as fibrosis. Although these manipula-
tions cannot be used as models for emphy-
sema, they are appropriate to assess condi-
tions where the balance of lung destruction
and fibrogenic reaction are important.
Recommendation 10. Research should
be undertaken on the balance between fi-
brosis and destruction and its relation to
particulates/oxidants.
Small Airways Disease
Two studies utilizing acid inhalation in
either acute or a short-term exposure cor-
relate airways inflammation with airways
dysfunction (Baile et al. 1982; Peters and
Hyatt 1986~. This model suggests that any
inhaled substance that results in an inflam-
matory response is capable of causing air-
flow obstruction. These data are similar to
those obtained from human studies of the
association between inflammation and air-
flow obstruction in cigarette smokers.
Use of an acid nebulization technique in
a dog model allowed researchers to ascer-
tain whether acute airway inflammation
could be detected by pulmonary function
tests. Inhalation of a weak hydrochloric
solution was associated with discernable
inflammation in the airways and with ab-
normalities in the tests for small airway
function (Baile et al. 1982~.
The acid inhalation technique was also
used with a semiquantitative grading tech-
nique to evaluate the airways. Researchers
found inflammation and fibrosis of the car-
tilaginous as well as the noncartilaginous
airways. These changes correlated with de-
creased dynamic compliance and increased
slope of phase III of the nitrogen wash-out
449
curve, as well as with a decrease in flow
rates (Peters and Hyatt 1986~.
Emphysema and Small Airways
Disease: Relations to Vehicular
· ~
Emlsslons
Data on pathophysiology of disease due to
cigarette smoking can help document the
presence of disease and the progression
from early to well-developed disease and
provide information on the mechanisms of
disease. Recent reports suggest key physi-
ological alterations relevant to production
of disease in animals.
The exhaust from diesel engines contains
most of the pollutants present in the emis-
sions of gasoline engines, but differs in that
it has a large particulate component. When
possible, studies involving effects of diesel
emissions are treated separately.
.
Lung Disease Produced in Animals by
Vehicular Emissions
.
It is important first to ascertain whether
lung diseases produced in animals by inha-
lation of vehicular emissions are similar to
human diseases suspected to be caused by
emissions. A comparison of the physiolog-
ical responses of NO2-induced disease in
several animal models to those of human
emphysema (figure 2) showed that the an-
imals had similar shifts in flow/volume and
pressure/volume curves as well as in lung
volumes (Mauderly 1984~. The author con-
cluded that animals provide data applicable
to humans. When he compared acute re-
sponses to NO2, the magnitude of the
effects was different, but all subjects
showed irritant effects at various doses.
An earlier study examined the morphol-
ogy of normal and experimentally induced
emphysema in animals and compared these
data to those on emphysema in horses and
in humans (figure 3~. Dilatation of airspaces
occurred in all species. Papain or continu-
ous NO2 exposure with peak increases or
followed by intermittent exposure, caused
similar lung destruction in all of the rodent
models (Port et al. 1977~. The morphology
OCR for page 450
450 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
-
.
_
400 _
300
-
IL
~ 200
6 ~
4 _
\\
rs Rabbit
,1~`-_
u ~N
100 80 60 40
FVC (%)
20 0
r--__
! Normal
\ Human
on, r an
| | \ Dog
t1:
1.5
.0
ns
c
12C
1nC
an
6a
2c
0 ~
100 80 60 40 20 0
FVC (%)
/ ~
\\
Figure 2. Companson of flow-volume curves in normal and emphysematous subjects, including humans, dogs,
rabbits, and rats. Flow rates of all species were reduced to a similar extent by emphysema. Maximum Expiratory Flow
(MEF); Forced Vital Capacity (FVC). (Adapted with permission from Mauderly 1984, and Hemisphere Publishing
Corp.)
of emphysema in rodents differs from that
in horses and humans, but the models are
certainly applicable for research on patho-
physiological relationships.
Evidence of Emphysema and/or Small Air-
ways Disease. Several studies have pro-
vided evidence of emphysema and/or small
airways disease by demonstrating changes
in physiological as well as morphological
parameters after the administration of var-
ious concentrations of NO2 (Freeman et al.
1968; Freeman et al. 1972; Kleinerman and
Niewoehner 1973; Coffin and Stokinger
1977; Evans and Freeman 1980~.
NO2 appears to exert its major damage
on the bronchioles and alveolar ducts, and
this seems related to a concentration gradi-
ent (Menzel 1980~. Loss of cilia is a subtle
airway change which occurs early in acute
experiments (Evans 1984), and is seen after
long-term exposures as low as 0.3 ppm
(Nakajima et al. 1980~. Not surprisingly,
these structural abnormalities are associated
with delayed mucociliary clearance (Gior-
dano and Morrow 1972~.
Bronchiolar epithelial cell damage from
NO2 appears to be repaired by proliferation
of nonciliated epithelial cells cells that act
as the progenitors for both ciliated and
nonciliated cells. Type I damage is repaired
by type II cell proliferation (Evans 1984~.
Physiological Charges. Pulmonary func-
tion tests in animals exposed to NO2 con
OCR for page 451
Joanne L. Wright
-~ (_j ~ ~ _ :,
Figure 3. Comparison of the light microscopic findings from (A) NO2-exposed
rat, (B) papain~xposed hamster, (C) NO2-exposed mouse, (D) emphysematous hu-
man, and (E, F) emphysematous horse. All lungs show dilatation of the airspaces.
(Reproduced with permission from Port et al. 1977, and Hemisphere Publishing Corp.)
sistently indicate airflow obstruction. A
large portion of this obstruction appears to
be due to airway disease and is potentially
reversible (Kleinerman and Niewoehner
1973; Kleinerman et al. 1976~. An early
study concluded that the pulmonary func-
tion changes in the rabbit model were due
to bronchiolitis (Davidson et al. 1967~.
In other studies of bronchiolar abnormal-
ities related to exposure to NO2, research-
ers have found massively enlarged collagen
fibrils underlying bronchioles and associ-
ated with thickened basement membranes
in rats (Stephens et al. 1971), and increased
thickness of the basement membrane with
increased collagen in the interstitium in
squirrel monkeys (Bils 1976~. In the latter
451
study, basement membrane thickness and
collagen in the interstitium increased even
during recovery. In contrast, a study by
Buell (1970) indicated that the morpholog-
ical parameters of collagen and elastin de-
naturation following exposure to NO2
were no longer present after a 7-day recov-
ery period.
Biochemical Changes. Biochemical find-
ings in animal exposure studies suggest that
the degradation or repair of collagen and
elastin do not necessarily occur at the same
time and that they can therefore be individ-
ually influenced by exogenous or endoge-
nous factors (Hacker et al. 1976; Kleiner-
man 1979~.
Hydroxylysine in either urine or ravage
OCR for page 454
454 Relation of Pulmonarv Emohvsema
Small Airways Disease to Vehicular Emissions
pollutants produced pulmonary injury and
loss of pulmonary function which contin-
ues following termination of exposure.
They further suggest that "due to the ubiq-
uitous nature of nitrogen and sulfur oxides
and auto exhaust (per se and photochemi-
cally reacted) in the ambient air of urban
communities, the chronic cardiopulmon-
ary changes . . . denote serious potential
health hazards to the populace of certain
communities." This statement underscores
the importance of these multidisciplinary
studies, and stresses the value of chronic
studies.
Animal Exposure to Diesel Exhaust
In studies involving the administration of
diesel exhaust to animals, researchers have
found abnormalities that appear to be fo-
cused on the centriacinar space (Wiester et
al. 1980; Barnhart et al. 1981; Vostal et al.
1981; Plopper et al. 1983~. Several of these
investigators have noted small foci of fi-
brosis in relation to large clusters of mac-
rophages (Wiester et al. 1980; Vostal et al.
1981~. Some (Barnhart et al. 1981) have
localized these changes to the bronchioles.
Others have found the bronchiolar fibrosis
to be progressive, even after a 6-month
recovery period; they also found a trend
toward increases in total lung collagen,
with a twofold increase in newly synthe-
sized collagen (Hyde et al. 1985~.
Pulmonary function testing in diesel-ex-
posed animals has produced conflicting re-
sults. Studies (Pepelko 1981) have shown
dose-dependent decreases in vital capacity
(VC) and diffusing capacity for carbon
monoxide (DLCO) associated with loss of
elastic recoil pressure in hamsters. Cat
models have shown decreases in VC and
Deco accompanied by decreased maximum
expiratory flow, but also accompanied by a
decrease in total lung capacity (TLC). This
suggests a combination restrictive/obstruc-
t~ve pattern.
A rat model showed evidence of de-
creased compliance, reduced DI no, and in-
homogeneity of airways emptying, with-
out evidence of airflow obstruction
(Mauderly et al. 1983~. A progressive in-
crease in hydroxyproline peptides as well as
in total lung collagen appeared to be a
function of increasing time as well as in-
creasing exhaust concentrations.
Tracheal muscle histamine dose/response
curves documented in rats exposed to diesel
exhaust and/or coal dust for 2 years dem-
onstrate an additive effect from coal dust
and diesel exhaust (Fedan et al. 1985~.
These data may reflect a role of the immune
system. A shortcoming of this study is the
lack of any morphological, physiological,
or biochemical data relating to the lungs of
these animals.
There is also evidence of nonspecific
dysfunction in exposed animals, with de-
creased spontaneous forced locomotor ac-
tivity (Pepelko 1981~. Data from the same
laboratory suggest that exposure during the
first week of life affected adult learning
abilities.
~ Recommendation 17. Studies should be
undertaken to determine whether the ef-
fects of diesel exhaust are different from the
effects of gasoline exhaust in regard to
disease progression, the effects of age at
exposure, and additional applied stress.
Summary
It is apparent that exposure to gasoline or
diesel emissions or their components has
the potential to produce disease. Animal
models of emphysema and small airways
disease, with some exceptions, are very
similar to the same diseases in humans.
Most histopathological, morphometric,
and electron microscopic data on effects of
emissions and their components have been
derived from animal models which provide
evidence of alveolar wall destruction with
loss of surface area, and of abnormalities of
the airways. Investigations of lung disease
and tobacco smoke have utilized fairly so-
phisticated measurements, and these meth-
ods can be, and in some areas have been,
easily utilized in emission protocols. Sim-
ple histological descriptions are no longer
justified.
The pulmonary disease produced in ex
OCR for page 455
loanne L. Wright
perimental animal models by vehicular
emissions appears to involve, as a first step,
inflammation and destruction at the level of
the respiratory bronchioles. The lesions
produced by exposure to emissions may
destroy the alveolar parenchyma and result
in emphysema. Lesions may also act on the
airways to produce fibrosis and subsequent
airway narrowing and airflow obstruction.
These morphological reactions to emis-
sions are very similar to those produced by
cigarette smoke, leading to speculation that
pulmonary disease caused by emissions in-
volves the same mechanisms as disease
induced by cigarette smoke.
The hamster model of Hoidal and Nie-
woehner (1982) suggests that the particu-
late component of smoke is important, not
only in inducing inflammation in the bron-
chioles, but also in activating macrophages.
NO2 itself results in macrophage accumu-
lation, but in that case, the chemotactic
stimulus may be the injured epithelial cells.
If both of these mechanisms are functional,
one would suspect that the addition of
particulates would amplify the inflamma-
tory response, perhaps making diesel ex-
haust dangerous. Indeed, this could be ex-
pected to happen with the addition of any
other injurious agent perhaps some of the
other components of gasoline exhaust, for
instance.
Vehicular emissions and their compo-
nents, like cigarette smoke, have oxidant
properties. Therefore emissions can injure
the lung through direct damage to the cell
membrane as well as through inactivation
of the antiproteolytic system. With inacti-
vation of antiproteinase as well as an in-
crease in the source of proteinases, the
proteolysis/antiproteolysis balance might
be tipped, resulting in lung destruction.
Other data suggest that the antioxidants
selenium and vitamins C and E may be
important in lung defense. Furthermore,
emissions produce an inflammatory re-
sponse involving neutrophils as well as
macrophages, with evidence for collagen
and elastin degradation and repair. Finally,
there is good correlation of disease (em-
physema and airway fibrosis and inflam-
mation) with abnormalities of pulmonary
.
tunctlon.
455
Summary of Research
Recommendations: Discussion
There are two main questions to ask about
the relation of pulmonary disease to vehic-
ular emissions. Although both questions
are studied in relation to cigarette smoke,
data are still sparse.
First, does significant disease occur, and if
so, what is it? This is difficult to determine
in a human population, as data on cigarette
smoking have shown. Second, what is the
cellular basis of this disease?
Other questions appropriate to the study
of pulmonary disease in relation to vehicu-
lar emissions are: What is the role of the
proteolysis/antiproteolysis balance in pol-
lutant exposure? What agent induces a re-
sponse by the inflammatory cells, and does
it have one or multiple components? What
roles do the particulates and the immune
system play? What is the role of the anti-
proteinases, and are they affected by the
oxidants in pollutants and which oxidants
are more Important?
Pathogenesis of Pulmonary Disease
The similarity of damage caused by vehic-
ular emission exposure to damage caused
by cigarette smoke has implicated the pro-
teolysis/antiproteolysis balance in the
pathogenesis of pulmonary disease. Mea-
surement of elastase and antiproteinases in
ravage fluids has been useful in investigat-
ing damage related to tobacco smoke and
to the adult respiratory distress syndrome,
and the feasibility of using this procedure to
analyze proteolysis/antiproteolysis imbal-
ance is an important subject for further
research (Recommendation 2~.
The inflammatory cells stimulated by
cigarette smoke are a source of proteinases
and represent a possible mechanism for
lung destruction. In addition, since ciga-
rette smoke, acting as an oxidant, is able to
inhibit cz-1-PI by binding to a methionine
residue, it is possible that the oxidants in
emissions can act in a similar fashion. This
in itself would not be harmful unless pro-
teolytic factors (that is, neutrophil and
macrophage enzymes) were also increased,
either by increasing the amount of enzyme
OCR for page 456
456 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
per cell, or by increasing the number of
cells. Both of these facts are true for ciga-
rette smokers, but it is not clear which
component of smoke is responsible (Rec-
ommendation 4~. Some information sug-
gests that gasoline and diesel exhaust expo-
sure increase neutrophils as well as
macrophages. This suggestion needs tur-
ther clarification relative to dose and time
as well as to collagen and elastin biomecha-
nics (Recommendation 3~.
The elastin and collagen degradation/re-
pair balance is another mechanism whose
operation elicits such questions as: Is repair
affected by pollutants, and if so, by which
component and by what mechanism? The
same primary agent can produce fibrosis as
well as destruction (Niewoehner and
Hoidal 1982~. That study was directed at
cadmium, but it is very tempting to sup-
pose that model would be applicable to
disease produced by emissions. Further
work on this hypothesis could use the
lathyrogen BAPN. ~ hIS manipulation
would allow assessment of any destructive
potential.
Collagen can be subtyped, and it is im-
portant to determine whether any subtype
in particular is affected. Hydroxyproline or
hydroxylysine from ravage can also be
quantified and may be indicators of lung
injury and repair. Fibronectin, which may
prove important in both degradation and
repair, can be quantified as well. Measure-
ment of collagen subtypes or hydroxy-
proline would allow mapping of the dose
response and the time course of the fibrotic
response (Recommendation 8~.
Initial data have suggested that in the
early stages of emission injury, collagen
and elastin degrade, but in different time
frames. Studies should map the time course
of degradation and repair and determine
whether repair could be altered by pollut-
ants or other oxidants such as cigarette
smoke. These data should be further quan-
tified and related to type and concentration
of exposure.
Other studies should attempt to quantify
degradation products such as elastin, pep-
tides, urinary desmosine, and hydroxyly-
sine for use in long-term animal and human
Investigations (Recommendation 11~.
Hi. . . . .
Cigarette smoke is thought to impair
elastin resynthesis by interfering with lysyl
oxidase. It is not known if this results from
air pollutant exposure, but it could be
an important mechanism underlying any
destruction that occurs (Recommendation
9~.
r How could these data relate to the cen
triacinar versus panacinar locations of de
struction in the lung? In c'-1-PI deficiency
or elastase administration the imbalance is a
generalized event. In cigarette smoke-in
duced emphysema, the imbalance is local
ized in the area of the proteinase excess
the respiratory bronchiole. This localiza
tion might be expected to occur also during
pollutant-induced lung destruction, where
the respiratory bronchioles do appear to be
abnormal, and there is an inflammatory
infiltrate of macrophages.
What is the balance between fibrosis and
destruction, and is this related to particu
lates rather than oxidants (Recommenda
tion 10~? This has been suggested by work
on diesel exhaust (Mauderly et al. 1986)
which shows that there is focal fibrosis in
the alveoli as well as in the bronchiolar
wall. There may be some differences in the
effects of gasoline and diesel emissions.
Such possible differences should be investi
gated in regard to disease progression, ef
fects of age at exposure, and additional
applied stress (Recommendation 17~.
Destruction of alveolar parenchyma has
not been a universal finding; indeed, foci of
alveolar fibrosis have been described (Mau
derly et al. 1986~. Perhaps if there is no
imbalance of the proteolytic system, and
there is particle stimulation of the intersti
tial cells, there will be fibrosis. But if there
is imbalance of proteolysis, the collagen/
elastin repair mechanism is hampered, and
destruction results.
Although there is evidence for dose de
pendency of injury, this should be further
quantified and related to the lower doses
(Recommendation 13~. Determining which
. . . . .
emission components are most Injurious
and the degree of synergism between com
ponents active in the causation of disease is
also important (Recommendation 14~.
Some data suggest progression of disease
even after the insult has been discontinued.
OCR for page 457
Joanne L. Wright
457
Such progression should be fully docu-
mented. Experiments could count and type
inflammatory cells in ravage or in tissue.
With electron microscopy, examinations
for early abnormalities in collagen, elastin,
and epithelial cells (Recommendation 6)
could be extended to analyze the repair
reaction and to identify agents that amplify
or ameliorate the response. The data ob-
tained would help to clarify whether dam-
age was related to the oxidant components
of the emissions.
Abundant evidence suggests abnormali-
ties of airflow and lung volumes in animals
exposed to emissions. Although measure-
ments of lung volume, compliance, and
resistance are important, their normal
range varies widely, so it is important to
analyze indicators of flow such as the pres-
sure/volume curve, as well as flow/volume
curves and tests such as the nitrogen wash-
out curve indicating inhomogeneity of air-
flow. Mauderly's group (1984) has used
these techniques to great advantage in their
experimental models and have been able to
identify subtle changes in pulmonary func-
tion.
Pathobialogy
In vitro cell experiments should be directed
to basic cell biology. Such studies might
focus on introducing pollutant constitu-
ents, gaseous as well as particulate, to cell
cultures of epithelial and/or inflammatory
cells (Recommendation 1~. Epithelial cells
could then be examined for damage and
production of inflammatory cell chemotac-
tic factors. The inflammatory cells could
also be examined for evidence of activation
with production of oxygen radicals. To
obtain obvious abnormalities, a dose range
should initially be broad, with some con-
centrations fairly high. These experiments
should measure biochemical parameters in-
cluding a-1-PI and elastase in ravage fluid,
elastin, desmosine, collagen type, and lysyl
oxidase in lung tissue. These data would
suggest which components of pollutants
are important and whether combinations
have greater effects than single exposures.
They could also form the basis for short-
and long-term animal experiments.
Animal Studies
Short-term animal experiments should be
designed to determine the pathobiology of
disease related to emissions (Recommenda-
tion 12~. Since age at exposure may be a
factor in disease, research should document
abnormalities produced by exposure begin-
ning at various points in the lifespans of
animals studied. Researchers should ana-
lyze the effects of additional stress such as
diesel particulates, cigarette smoke, infec-
tion, and nutritional deficiencies on the
production of pulmonary disease (Recom-
mendation 16~.
The influence of particle size and compo-
sition as well as the gaseous components of
the emissions need analysis. Brain and Val-
berg (1979), as well as others, have shown
that there are multiple factors, including
age and health of the experimental subject,
that influence the deposition and subse-
quent management of a particulate aerosol.
These workers have also described various
methods to assess deposition, and these
factors should be investigated.
Other necessary data include those on
morphological abnormalities at multiple
points over a long-term exposure, particu-
larly at the lower doses. The animal model
chosen should therefore have a long life-
span. Long-term animal studies should be
multidisciplinary and should include phys-
iological, morphological, and biochemical
analyses (Recommendation 15~. Study
hypotheses should be related to the pa-
thophysiology of disease and directed
toward a low concentration range of emis-
sions including single or multiple compo-
nents. Long-term experiments could an-
swer the question of severity of disease or
tolerance to emissions in relation to expo-
sure at an early age.
Since there are some data suggesting
disease progression very similar to the
postexposure progression of elastase-in-
duced emphysema, it is important to ana-
lyze a recovery period as well as several
. .
points c curing exposure.
Sacrifice at various time points would
provide information relating collagen and
elastin breakdown and repair to parenchy-
mal destruction and production of airway
OCR for page 458
458 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
abnormalities. These data would be corre-
lated with lung function. If proven helpful
in the short term, biochemical estimations
of elastin products would be useful to mon-
itor disease without the necessity for sacri-
fice. Similarly, certain types of pulmonary
function could be performed on a routine
basis without sacrifice, following the gen-
eral procedure of Mauderly (1984~. These
methods would allow a longitudinal study
and avoid potential artifact produced by
tracheostomy.
Data from such long-term animal exper-
iments would provide a basis for long-
term epidemiologic studies on humans.
They would help to develop a scheme to
suggest important variables and allow for
appropriate testing and analysis of human
data. The data obtained from such experi-
ments could also be important in assess-
ment of early disease and of the transition
between health and disease in a pollutant-
exposed population.
Although this list of recommendations
treats the areas of histopathology, bio-
chemistry, and physiology separately, re-
searchers performing animal experiments
should collect these data and correlate
them. In particular, the data provided by
the groups of dog model (beagle) studies at
the University of California at Davis have
evinced the need for study of the mecha-
nisms of pulmonary disease. This can only
be accomplished by carefully planned mul
. . . .. .
tic 1sclpllnary stuc lest
Human Studies
Physiological and morphological investiga-
tions form a major tool for human studies.
Although there are some difficulties in per-
forming the more specialized physiological
tests in a community or workplace envi-
ronment, these difficulties are not insur-
mountable, and the additional data pro-
vided are extremely valuable. These
specialized tests can certainly be performed
in the short-term-exposure laboratory set-
ting (Recommendation 7~.
Researchers performing structural/func-
tional correlations on human autopsies can
perform lung mechanics on excised speci-
mens and relate results to data collected on
the live subject. Morphological examinations
for human exposures could also be per-
formed on autopsy and surgical specimens,
duplicating the methods used for tobacco
smoke investigations (Recommendation 5~.
Summary of Research Recommendations: Priorities
The research recommendations are resummarized here by exper-
imental technique rather than by subject area, for the purpose of
focusing on a research program. In the following listing, the
needed experiments are ranked from high to low priority within
each category.
In Vitro Experiments
HIGH PRIORITY
Recommendation 1 Pollutant constituents should be introduced to cell cultures of
epithelial and/or inflammatory cells.
MEDIUM PRIORITY
Recommendation 3 Cell damage and its relation to inflammation should be studied
through further research on exposure-related increases in neutro
phils and macrophages, including collagen and elastin biomechan
ics, and the dose/time relationship between exposure and neutro
phil and macrophage increase.
OCR for page 459
Joanne L. Wright
459
Recommendation 8 Research should be undertaken on the elastin and collagen
degradation/repair balance to determine whether repair is affected
by pollutants, and if so, by what mechanism. Studies should map
the time course of collagen and elastin degradation and repair,
relating data to type and concentration of exposure as well as
ascertaining the possibility of alteration or repair by pollutants or
other oxidants.
LOW PRIORITY
Recommendation 4 The relation of oxidants to the proteinase/antiproteinase balance
should be studied.
In Vito Experiments
HIGH PRIORITY'
Recommendation 2 Studies should be undertaken to ascertain whether the peptides
present in body fluids can be measured accurately, and whether the
measured parameters do, in fact, relate to the degradation and
repair process.
Recommendation 12 Experiments should be performed to determine the pathobiol
ogy of emissions-related diseases by measuring biochemical param
eters in lung tissue and by counting and typing inflammatory cells
. .
in avage or tissue.
Recommendation 15 Long-term, multidisciplinary animal studies should be designed
to document abnormalities produced by exposure to emissions at
various points in the lifespans of subjects.
MEDIUM PRIORITY
Recommendation 9 Pollutant interference with lysyl oxidase and impairment of
elastin resynthesis should be investigated.
Recommendation 10 Research should be undertaken on the balance between fibrosis
and destruction and their relation to particulates/oxidants.
Recommendation 11 Degradation products such as elastin, peptides, urinary des
~ ~ ~ ,
mosine, and hydroxylysine should be quantified.
Recommendation 13 Dose dependency should be quantified and extrapolated to lower
doses.
.
LOW PRIORITY
Recommendations Epithelial cells, collagen, and elastin should be examined by
electron microscopy to document possible progression of emis
* Experiments are meant to be short term unless explicitly stated otherwise.
,.
OCR for page 460
460 Relation of Pulmonary Emphysema and Small Airways Disease to Vehicular Emissions
sion-related disease after the cessation of direct exposure, in both
short-term and long-term studies.
Recommendation 14 The degree of synergism between components and their relative
importance in causing disease should be investigated.
Recommendation 16 Experiments should be conducted to analyze the effects of
nutrition, stress, infection, exercise, and co-contaminants such as
diesel particulates and cigarette smoke on pulmonary disease.
Recommendation 17 Short-term and long-term studies should be undertaken to
determine whether the effects of diesel exhaust are different from
the effects of gasoline exhaust in regard to disease progression, the
effects of age at exposure, and additional applied stress.
Human Studies
HIGH PRIORITY
Recommendation 5 Pulmonary mechanics should be assessed on excised lung spec
imens obtained from human autopsies and results related to data
collected from live subjects. Morphological examinations of hu
man autopsies could duplicate methods used to investigate the
effects of tobacco smoke.
Recommendation 7 Some of the more detailed pulmonary function tests should be
used to identify progressive dysfunction.
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Representative terms from entire chapter:
pulmonary function
