You are on page 1of 15


Developmental physiology: lung function

during growth and development from birth
to old age

C. Calogero*, P.D. Sly#,"

*Section of Respiratory Medicine, Allergology and Pulmonology Centre, Anna Meyer University-Hospital
for Children, Dept of Paediatrics, University of Florence, Florence, Italy. #World Health Organization
Collaborating Centre for Research on Childrens Environmental Health, and "School of Public Health, Cutrin
University of Technology, Perth, Australia.

Correspondence: P.D. Sly, Telethon Institute for Child Health Research, P.O. Box 855, West Perth, WA
6872, Australia. E-mail:

A significant global challenge we face today is the escalating incidence of childhood

lung diseases and identifying and developing preventative strategies for children at
greatest risk.
There is an increasing recognition that most chronic adult diseases have their origin in
childhood; this is especially true for respiratory and cardiovascular diseases. Lung
function tracks along percentiles during the rapid growth period in childhood and, as
such, the lung function an individual is born with is a major determinant of lung
function throughout life. Thus factors that limit lung function at birth are likely to have
lifelong consequences. In addition, the lungs are immature at birth and have a prolonged
period of post-natal maturation. Thus factors that limit lung growth, especially during
the rapid growth period in early childhood, may reduce an individuals peak lung
function. Lung function declines with advancing age in adults at a rate that is influenced
by both genetic and environmental factors. If lung function declines to a critical level the
risk of chronic respiratory disease and respiratory failure increases. Thus factors that
limit peak lung function or accelerate the decline in lung function increase the
likelihood of chronic respiratory disease in later life.
The concepts outlined above will be reviewed in this chapter. An overview of pre- and
post-natal lung development and factors that influence this will be presented. The concept
of windows of susceptibility, which describes the influence of the developmental stage
of the lungs in determining the outcome of potentially adverse exposures will be discussed.
Other chapters in this European Respiratory Monograph (ERM) will deal with
environmental exposures and with gene by environment interactions. These factors
will only be discussed briefly in this chapter within the concept of lung growth.

Lung growth before birth

The lung starts to develop in the human embryo at 3 weeks gestational age and
continues in post-natal life to the early adulthood. Pre-natal lung growth can be
considered to occur in five stages [1]. The first is the embryonic stage, from 0 to 7 weeks
in utero. At around 3 weeks gestation, the laryngotracheal groove develops from the
foregut and the trachea is formed. Then the two main bronchi branch off from the

Eur Respir Mon, 2010, 47, 115. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2010; European Respiratory Monograph;
ISSN 1025-448x. DOI: 10.1183/1025448x.00011109


primitive trachea. With the same mechanism, lobar and segmental bronchi develop at
around the fifth week. At the end of this first stage it is possible to identify 18 major
lobules. At the same time vasculogenesis begins developing around the airway bud.
The second stage is the pseudoglandular stage, from 7 to 17 weeks in utero. During
this stage, the branching of the airways continues with the creation of the segmental
airways. Major blood vessels develop along with the airways. At 14 weeks gestational
age, y70% of the total airway tree has developed and by the end of this stage the
conducting airways are fully formed down to the terminal bronchioles. The
differentiation of the epithelial cells also occurs during this stage, with columnar cells
proximally and cuboidal cells distally replacing the pseudostratified epithelium. At this
stage the pre-acinar structure is complete with pre-acinar airway, artery and vein.
From the 17th to 27th weeks, the canalicular stage occurs, with the complete
development of the acini including the respiratory bronchioles, alveolar ducts and
primitive alveoli. The type I and II pneumocytes start to differentiate during this stage
and by the 24th week lamellar bodies begin to appear in type II pneumocytes, predating
the production of surfactant. The alveolarcapillary barrier develops during this stage,
allowing gas exchange to begin. The stage that follows is the saccular stage that goes
from the 28th to the 36th week. This period is mainly characterised by an increasing gas
exchange area and increased production of surfactant. The saccules develop from the
acinar tubules.
The final stage is the alveolar stage, starting at 36 weeks gestational age and
continuing after birth. The precise age at which alveolar development finishes is not
known with certainty.

Post-natal lung growth

Our knowledge about post-natal growth is limited by a relative lack of data in healthy
children. Most knowledge has come from measurements of lung function, supplemented
with limited anatomical data [25]. Few studies have systematically measured lung
function during the period of rapid growth during infancy and early childhood [6, 7].
Post-natal alveolar development occurs most rapidly during the first 1824 months of
life [4], but may continue up to 8 yrs of age [3], when the adult number of y300800
million alveoli are thought to be present. However, the wide variability in the alveolar
numbers reported in individual lungs provides uncertainty in just when alveolar
development finishes [4]. At birth the primary septa of the terminal sacs consists of a
central connective tissue core surrounded by a capillary on each side. Quite soon after
birth the secondary septation starts in the terminal saccules. This process leads to an
increased surface for gas exchange. At the same time, the surfactant is synthesised in
higher quantity and the capillaries undergo to a process of remodelling. The precise
mechanism of alveolarisation, including which mediators drive the process and the cells
involved, is not known with certainty [8].
Sex differences in alveolar development have been demonstrated. Boys have larger
lungs than girls at any given age or at any given body length [4]. However, alveolar size,
as judged by mean linear intercept, does not differ; meaning that boys have a larger
alveolar surface area than girls and boys have more alveoli than girls [4]. Body surface
area and alveolar surface area are closely correlated in both boys and girls; however,
boys have a larger alveolar surface area than girls for a given body surface area.
During the period of rapid post-natal alveolarisation, mean alveolar size remains the
same, i.e. lungs grow by developing new alveoli. During this period there is also a rapid
increase in the amount of air located in alveoli with a commensurate decrease in the


amount of air in alveolar ducts [4]. After 24 yrs of age a steady increase in alveolar size
is seen, with alveolar volumes doubling by the teenage years. The number of alveoli per
lung unit (the number of alveoli supplied from an individual respiratory bronchiole) is
the same in boys and girls, implying that boys have a greater number of respiratory
bronchioles than girls.
Development of the pulmonary microvasculature occurs during the first 23 yrs of
life. During this stage a gradual transformation of the capillary network surrounding the
alveoli occurs, with transformation from a double capillary network to a single capillary
layer. The process of vasculogenesis is intimately linked to alveologenesis; once the
alveolar septum is surrounded by a single capillary, no further septation can occur.
The influence of the pubertal spurt in somatic growth on lung growth is not known
with certainty but is likely to be significant. THURLBECK [4] calculated the projected
alveolar surface area for adults from the data in his seminal paper and reported a
systematic and substantial underestimation when compared to actual adult data.
Airways increase in size after birth but no increase in branching occurs [9, 10]. The
pre-acinar airways of infants are essentially scale models of adult airways with each
individual branch growing in a symmetrical fashion in both length and diameter as the
child grows [9]. This post-natal enlargement in airway size can be described by a linear
regression on body length from infancy to adulthood [10]. The length to diameter ratio
of individual airways does not change with growth. PHALEN et al. [10] have calculated
that flow through a given airway also increases linearly with body size and that
deposition of particles ,5 mm is likely to be six times greater in a resting infant than in a
resting adult for a given particulate concentration.

The normal changes in lung function from birth to old age

A true assessment of lung growth is virtually impossible in living children and we need
to make an assessment with substitutes, such as measurements of lung function using
techniques that only indirectly reflect airway size; lung volumes using plethysmographic
or gas dilution techniques; or radiographic assessments of airway dimensions and lung
size. A recent international effort has complied data sets from cross-sectional surveys of
lung function from both paediatric and adult populations in an attempt to more
accurately describe the changes in lung function, at least those reflected by standard
spirometry, that occur throughout life [11]. Data from 3,598 individuals ranging in age
from 4 to 80 yrs have been used to model the changes in lung function with age. These
data more accurately describe the transition from lung function growth in children to
lung function decline in adults and demonstrate that the normal range of lung
function is highly dependent on age [11]. The validity of standard spirometry relies of
achieving flow-limitation during forced expiration and if this condition is satisfied,
expiratory flow is independent of effort and reflects the mechanical properties of the
lungs and airways. While forced expiratory volume in 1 s (FEV1) is commonly
interpreted as reflecting large airway calibre and forced expiratory flow at 2575%
(FEF2575%) of forced vital capacity (FVC) as reflecting small airways, there is no
anatomically localising information in a forced expiratory flowvolume curve [12].
The interpretation of lung growth from measurements of lung function is also
complicated by the fact that different techniques are commonly used at different ages
and that most studies are cross-sectional rather than longitudinal. As mentioned earlier,
lung function tracks throughout childhood. HIBBERT and co-workers [13, 14] studied
growth in lung function from 8 yrs of age until early adult life using two overlapping
cohorts of children, each followed longitudinally for up to 8 yrs. Lung function was


shown to grow along percentiles [15] and the value of longitudinal assessment of lung
function demonstrated. The lung function data suggested that lung function growth
stopped in adolescence in girls (around 16 yrs of age) but continued into early adult life
in boys; this is consistent with the increase in airway size occurring in parallel with
somatic growth. This study also supported the concept of dysanaptic growth with an
uncoupling of airway and parenchymal growth after adjusting for height and age [15]. In
another longitudinal study measuring lung function in children aged 1119 yrs (430
boys and 125 girls) [16], the conclusion was somewhat different. MERKUS et al. [16]
reported that growth of airway, relative to lung volume, occurred faster in teenage boys
than in girls. The growth pattern was consistent with isotrophic growth in 92% of
healthy boys and in 44% of healthy girls. Dysanaptic growth was more common in girls
and was not related to the presence of mild respiratory symptoms during childhood [16].
Children in the Tucson Childrens Respiratory Study who had infant maximum flow at
functional residual capacity (Vmax,FRC) in the lowest quartile when measured at 2
3 months of age had lower values of lung function, assessed by standard spirometry at
22 yrs of age [17].
After adolescence, lung function achieves a plateau due to the fact that lung growth
levels off at around 18 and 20 yrs in females and males, respectively. In adulthood, a
decline in lung function with age has been observed. In particular, a rapid decrease in the
FEV1/FVC ratio with age has been reported [11]. However, similar studies measuring
lung function with forced oscillations show either a very mild or no increase in airway
resistance with age up to 80 yrs of age (Z. Hantos, Dept of Medical Informatics,
University of Szeged, Szeged, Hungary; unpublished observations) [18]. These data
suggest that there is no decrease in airway calibre with advanced age and the fall in
spirometric outcome variables is likely to be related to loss of lung elastic recoil and
decreased support of the airway wall.
Nutrients seem to play an important role in the lung health in adults. In a recent study,
MCKEEVER et al. [19] have shown that higher levels of antioxidant substances, such as
vitamins A, C and E and in particular selenium, were related to higher FEV1 measurements
and also to a decreased susceptibility to chronic obstructive pulmonary disease.

Windows of susceptibility
The lung is vulnerable to adverse exposures during fetal development. Exposures
occurring beforey18 weeks gestation may influence development of the airway tree and
major pulmonary vessels. Exposures occurring later in gestation may influence
development of lung volume, alveoli and pulmonary capillaries. As the lung continues
to develop after birth, post-natal exposures may also influence lung growth and the
pulmonary microvasculature, especially if these exposures occur during the period of
rapid alveolarisation in the first years of life. Thus the windows of susceptibility describe
the concept of developmental stage susceptibility, in which the developmental stage at
which an exposure occurs plays a major role in determining the consequences of that
exposure [20, 21]. Exposures in early life may have lifelong consequences.

Pre-natal exposures altering lung growth

The archetypal pre-natal exposure documented to adversely affect lung growth is
tobacco smoke. Maternal smoking during pregnancy and to a lesser extent maternal
exposure to environmental tobacco smoke (ETS) impair lung development and result in


altered lung function at birth [22, 23]. The major harmful components are nicotine and
carbon monoxide, which concentrate in the feto-placental circulation and decrease
oxygen supply to the developing fetus. The adverse effects of nicotine have been
demonstrated in animal studies where nicotine infusions have been given to pregnant
animals [24], resulting in increased collagen deposition in both large and small airways.
Fetal breathing movements, which are a vital component of normal lung development
by providing stretch stimuli that stimulate normal cellular differentiation and growth
of lung volume are inhibited by maternal smoking. Tobacco smoke exposure has been
shown to decrease birthweight; lower lung function [23] and alter control of breathing at
birth and in infancy [25].
More recently other maternal environmental exposures have been receiving increasing
attention. Increased exposure to household cleaning agents and other chemicals during
pregnancy have been shown to be associated with increased wheezing throughout
childhood and lower lung function at the age of 7 yrs [26]. SRAM et al. [27] have reviewed
the possible effect of air pollution on pregnancy outcomes. They concluded that strength
of evidence varied for different birth outcomes. For example, respiratory deaths in the
post-natal period seem to be related to particulate air pollution however the evidence
was not sufficient for other outcomes such as low birthweight, pre-term births, intra-
uterine growth restriction and birth defects. More recently, exposure to ambient air
pollution has been shown to reduce a number of indices of somatic growth in the fetus,
with the relationships varying with individual pollutants at different times during
gestation [28]. While the mechanism underlying the adverse effects of these maternal
exposures is unknown, the induction of oxidative stress in the maternal lung may be
involved. The impact of maternal exposure to ambient air pollution on infant lung
function has recently been assessed in a longitudinal birth cohort study in Switzerland
[29]. Maternal exposure to particulate matter (PM) with a mean aerodynamic diameter
of 10 mm (PM10), nitrogen dioxide (NO2) and ozone (O3) was measured during
pregnancy and related to lung function measured using tidal breathing techniques in
unsedated, sleeping 5-week-old infants [29]. Minute ventilation, mean tidal inspiratory
and expiratory flows, and respiratory rate were all increased in infants born to mothers
exposed to higher levels of PM10. Respiratory rate was increased and tidal volume
decreased in infants born to mothers exposed to higher levels of NO2. the amount of
nitric oxide (NO) in the exhaled breath of the infants and the NO output were increased
in infants born to mothers exposed to higher levels of NO2. Exposures did not have any
effect on lung volume or ventilation homogeneity and exposure to increased levels of O3
did not have any adverse impact on infant lung function [29]. These data suggest that
infants born to mothers exposed to higher levels of ambient air pollution have abnormal
airway development (smaller airways or stiffer airways) or altered control of breathing.
Further follow-up of these infants may help clarify these effects.
The impact of maternal respiratory infections on the infants lung function has
recently been reported. Infants born to mothers with a history of respiratory infections
during pregnancy had a reduced respiratory compliance measured with passive
mechanics [30].
Nutrition during pregnancy can also influence fetal lung growth with growth
restriction being associated with abnormal lung function. GAULTIER [31] reviewed the
animal data relating malnutrition to lung growth and concluded that inadequate
nutrition has the most impact on lung growth when it coincides with period of rapid
alveolar growth, possible by interfering with the deposition of elastin in alveolar crests
that is critical for alveolar septation. Thus, one might expect that malnutrition occurring
during the times of rapid alveolar development in humans, namely during late gestation
and the first 2 yrs of post-natal life, would have the most impact on human lung growth.
Few data are available to adequately address this question. Perhaps the best data come


from the Dutch Famine. LOPUHAA et al. [32] reported lung function measurement
from 733 adults who were born at term between November 1943 and February 1947 in
Amsterdam, the Netherlands. They found no difference in lung function at age 50 yrs in
those starved during early, mid or late gestation and those not starved. However, they
did find an increased prevalence of obstructive lung disease in those starved in early and
mid gestation [32]. The interpretation of these data is complex and may indicate an effect
of airway development.
HOO et al. [33] demonstrated that having a low birthweight for gestation was
associated with a reduced lung function, independent from any effects on somatic
growth. WALTER et al. [34] have recently reported that adults with a birthweight
,1,500 g were at increased risk (OR 1.83 (95% CI 1.282.62), p,0.001) of
hospitalisation for respiratory illnesses. The risk was slightly lower in those with a
birthweight of 1,5002,499 g (1.34 (1.171.53), p,0.0005) [34]. A reduction in fetal
nutrition due to different causes can interfere with the normal somatic growth and thus
the development of the respiratory system [35]. Birthweight is a predictor of adult lung
function [36] and the concept of the fetal origins of chronic disease in adults is becoming
increasingly popular.

Post-natal exposures altering lung function (growth)

Numerous studies have investigated factors affecting post-natal lung function. Most
studies in early life do not show a difference in lung function between boys and girls [33,
3739]. Sex differences do become apparent later in childhood, as discussed above.

Prematurity and low birthweight for gestation

Premature birth per se is associated with altered lung function and lung function
growth. The fetal lung is liquid filled, with expulsion of liquid and an influx of air
occurring at birth. Premature birth is associated with an earlier transition from a liquid-
filled to an air-filled lung, with unknown consequences on normal lung growth.
Depending on how premature the infants are when born, the lung may still be in the
cannalicular or saccular stage of gestation. A major consequence of premature birth
seems to be relative alveolar hypoplasia with decreased alveolar surface area and larger
less complex alveoli [40]. Premature birth per se is also associated with airways that are
small for post-natal age and that have an increase in airway smooth muscle and more
mucus-secreting glands than would be expected in normal children [40]. Mechanical
ventilation compounds these changes.
In addition, premature birth occurring before adequate surfactant is present in the
alveoli compromises the infants ability to make the transition to air breathing at birth
and frequently requires ventilatory support and oxygen supplementation. The
abnormal influences on lung development (increased oxygen, positive pressure
ventilation, etc.) relative to the developmental stage can damage lungs, compromise
normal lung development and result in chronic lung disease of prematurity.

The childs nutritional state seems to be a strong predictor of respiratory morbidity
and mortality. The impact of breastfeeding on respiratory health, especially on the
development of asthma, is controversial [41]. Data from phase II of the International
Study of Asthma and Allergy in Childhood (ISAAC) demonstrate how complex the


relationship between breastfeeding and respiratory health can be. Better lung function,
expressed as a higher FEV1, was associated with breastfeeding only in affluent countries
while protection from nonatopic wheeze was seen in nonaffluent countries [42]. A large
cross-sectional study conducted in Guangzhou, China, demonstrated a positive
association between fresh fruit, vegetable and milk consumption and a reduced
prevalence of respiratory symptoms. Better lung function, again expressed as a higher
FEV1, was seen with a higher intake of leafy vegetables [43].

Almost all longitudinal cohort studies following children with persistent asthma show
a deficit in lung function in the most severe group [17, 4446] that is present at the
earliest assessment and generally is not progressive, raising the possibility that either this
deficit predisposes to the development of asthma or occurs very early in life. Children in
the Dunedin cohort who had persistent asthma at 26 yrs of age had reduced lung
function throughout childhood; a deficit that was present at the earliest measurement at
9 yrs of age but was not progressive [45]. Similar data have been reported from the
Melbourne Longitudinal Asthma Study; an early loss of lung function was found in
those subjects with current severe asthma whereas in those childhood asthmatics who
were asymptomatic or only had mild symptoms the lung function did not differ from the
control group [44, 47]. In addition, adequate control of asthma has been reported to
promote normal growth of lung function [48]. Asymptomatic asthmatics with reduced
lung function at 18 yrs of age are at greater risk of recurrence of asthma and relapse of
symptoms [49].
Two longitudinal birth cohorts have measured lung function in the first few weeks
after birth and later in childhood. Children participating in a longitudinal birth cohort
in Perth, Australia, who had low lung function (Vmax,FRC) and expiratory flow
limitation during tidal breathing were more likely to have persistent wheeze when they
were 11 yrs old [6]. Similarly, in the Tucson cohort study, low lung function at 6 yrs of
age is predictive of a new diagnosis of asthma at 22 yrs of age [17].

Exposure to ETS during pregnancy, childhood and adult life is well known to be
associated with respiratory symptoms, reduced lung function, increased exacerbations in
respiratory and cardiopulmonary disease. ETS is represented by the products of
smouldering ends of cigarettes (sidestream smoke) mixed with exhaled mainstream
smoke. Over 4,000 different chemical components, such as polycyclic aromatic
hydrocarbons, carbon monoxide, PM, nicotine and cyanide, are contained in ETS.
ETS components can pass through the placenta and into breast milk so the child can be
exposed both in the fetal life and later [50]. Also, maternal smoking is associated with
increased risk for the infants for respiratory diseases, such as bronchiolitis [22].
Exposure to ETS in early childhood is also found to be associated with increases in
respiratory symptoms, increased production of mucus in the airways, airways
obstruction and reactivity and decreased lung function [22].

Ambient air pollution

Numerous epidemiological studies have reported adverse impacts of air pollution on
health. Sources of pollutants include fixed sources, such as industry, and mobile sources,


such as traffic. Pollutants that have been shown to have adverse effects on health include:
combustion-related pollutants, including PM, gaseous pollutants such as SO2, oxides of
nitrogen (NOx), CO, O3; volatile organic compounds (VOCs); persistent organic
pollutants, including pesticides, dioxins, polycholrinated biphenyls and others; and
heavy metals (lead, mercury, cadmium, silver, nickel, vanadium, chromium and
manganese). Diesel exhaust particles are thought to be especially detrimental to
respiratory health and associated with an incresased risk of allergic sensitisation [51].
The source of the pollutant may also play a role in determining the adverse health
outcomes. Children living near a major petrochemical production facility in Argentina
had lower lung function and worse respiratory health than children living in areas exposed
to heavy traffic pollution or living in relatively nonpolluted areas of the city [52].
Children are more vulnerable to the adverse effects of air pollution. Children have
higher ventilatory requirements and breathe more air per unit body weight than adults
[20, 53]. In addition, their smaller airways favour increased deposition [10]. Children
may also be more exposed because they spend more time outdoors, for example, doing
physical activity. A lot of research has been conducted on the effects that air pollution
can have on respiratory health in children focusing on possible effects on changes in
airway structure, lung growth and lung function [54].
Sophisticated studies conducted in primates have investigated the impacts of
pollutants on the epithelial-mesenchymal trophic unit (EMTU) of the tracheobronchial
airway wall. PLOPPER et al. [55] have shown in infant rhesus monkeys how early air
pollution exposure can interfere with airway growth and development. All the parts of
the EMTU were altered, with an increased number of mucous cells, disruption and
reorganisation of the basement membrane and the smooth muscle, downregulation of
epithelium innervations and altered cells involved in the immune response. Exposure to
O3 resulted in terminal bronchioles that were 38% narrower and 45% shorter than seen
in monkeys exposed to filtered air [56]. This was associated with a change in the
orientation of the airway smooth muscle bundles to the airway axis; the bundles were
orientated more horizontally instead of obliquely to the airway axis [56]. This change is
likely to result in increased airway narrowing from a given degree of smooth muscle
Numerous studies, both cross-sectional and longitudinal, have shown an adverse
effect of long-term exposure to air pollution on lung function in children. The most
comprehensive data come from studies in southern California. Children were recruited
in several waves from 12 communities and followed with annual spirometry. Children
living in more polluted communities were compared with those living in less polluted
areas. Exposure to higher levels of air pollution was associated with an altered growth in
lung function. Decrements in FEV1 in children aged 10 to 18 yrs of age were reported
with exposure to NO2 (mean (95% CI) of -104 (-164.5 -38.4) mL, p50.005), acid
vapour (-106 (-168.8 -42.7) mL, p50.004), elemental carbon (-88 (-146.4 -29.8) mL,
p50.007), and PM2.5 (-80 (-153.06.4) mL, p50.04) [57]. In the study, exposure to O3
did not have a statistically significant impact on lung function [57]. Decrements in lung
function have also been shown in school-aged children in Leicester, UK, exposed to
traffic-related pollution [58]. The amount of carbon seen in alveolar macrophages
collected by sputum induction was associated with a reduction in lung function; FEV1
was decreased by 17%, FVC by 12.9% and FEF2575% by 34.7% for each increase of
1 mm2 of macrophage filled with carbon.
Other data collected in Southwest Metropolitan Mexico City, Mexico, demonstrated
that prolonged exposure to high levels of O3 and PM10 was associated with a significant
decrease in FVC and FEV1 [59]. In the same population, y10% of children showed a
mild restrictive pattern, with reduced FVC and FEV1 and an increased FEV1/FVC ratio
associated with the radiological appearance of hyperinflation in y67% of the children.


Increased interstitial markings were seen in almost half of the children and these were
associated with lower lung function, with FEF2575%, FEF75% and FEV1/FVC ratio [60].
In addition, a 3-yr follow-up study conducted on preschool children in Mexico City
demonstrated that long-term exposure to some pollutants such as O3, PM10 and NO2
was associated with a mild restrictive defect, with an increased FEV1/FVC ratio [61].
Exposure to high levels of O3 have been associated with reduction in lung function
and increased respiratory symptoms in other populations [62]. Not all studies show an
adverse effect on lung function with exposure to O3, with some suggesting adverse
effects are only seen in the medium term [63] while other studies postulate a chronic
effect of O3 on childrens health, showing not only in a drop in lung function but also
recurrent alterations that can result in persistent changes in the airways [64].
Accurately assessing exposure to pollutants is difficult in children. Epidemiological
studies frequently use the distance children live from busy roads as a substitute for
exposure. Various studies have suggested a strong association between being living near
a busy road and an increased prevalence of respiratory symptoms, asthma exacerba-
tions, emergency room admission and other negative health outcomes [65, 66]. Children
living in more polluted areas have been shown to have increased airway responsiveness
[67]. Animal models have also suggested that exposure to high levels of pollutants can
result in an increased number of asthma exacerbations and further research is needed to
understand the possible underling mechanism in inducting this particular disease [68]. It
has been shown also that even children exposed at a low level of NO2 can have an
increased bronchial reactivity [69].

Indoor air pollution

The type of indoor air pollutants children are likely to be exposed to in their homes
differ between developed and developing countries. In developed countries, the most
likely pollutants include tobacco smoke; combustion-related PM from various sources
including cooking, candles, mosquito coils and incense; NO2 from gas cooking and
unflued gas heaters; VOCs from various sources including building materials, furniture
and furnishings; bioaerosols; and household chemicals. In developing countries, many
households rely on burning biomass and solid fuels for cooking and heating, frequently
in open fires of stoves without chimneys resulting in exposure to high levels of PM,
polyaromatic hydrocarbons, pesticides and organic pollutants, depending on what is
Support that the exposure to bioaerosols may limit lung growth comes from a
randomised control trial of house dust mite reduction in children at high risk of
developing asthma [70]. Families were randomised to either a stringent house dust mite
reduction strategy or no reduction. Lung function, measured in a small subgroup of
infants (n532) at 4 weeks of age did not differ between the groups. When lung function
was measured again at 3 yrs of age, children living in homes with reduced levels of house
dust mite had better lung function, i.e. lower specific resistance, than children from the
control group [70]. These data suggest that exposure to normal levels of bioaerosols in
the home environment limit growth of lung function during the phase of rapid lung
growth occurring in the first years of life. However, these data are, at best, proof of
concept data, as only a small number of children had their lung function measured.

Viral respiratory infections

The impact of viral lower respiratory infections (LRIs) on lung growth and
development has attracted a lot of attention. The debate on whether children who


wheeze with viral LRIs are susceptible hosts, either with low pre-morbid lung
function or inadequate innate immune responses, or whether viral factors are
responsible has not been settled [71].
Severe viral infections can damage the normal structure of the lung resulting in
chronic obstructive lung disease [72]. Adenoviruses, especially serotypes 3, 7 and 21, are
the most common cause of bronchiliotis obliterans in children and are associated with
high incidence of respiratory sequelae and mortality [73].
Acute viral bronchiolitis in the first year of life severe enough to require
hospitalisation, most commonly caused by the respiratory syncytial virus (RSV), is
associated with recurrent respiratory symptoms throughout early childhood [46, 74, 75].
Children with RSV infection in early life in the Tuscon respiratory study continued to
have recurrent wheezing throughout childhood and had low lung function that
normalised with bronchodilator at age 11 yrs [46]. These data have been interpreted as
suggesting the RSV infection in early life altered the vagal tone of the airways.
Both rhinoviruses (RV) and RSV have been shown to be common causes of wheezing
in early life [76]. RSV infection in early life has been associated with an increased risk of
bronchial hyperreactivity when the child is older [74]. Children who wheeze with RV
LRIs have an increased risk of asthma at age 56 yrs [76, 77] and lower lung function.
However, as all children have RV and RSV infections in the first year or two of life and
the minority wheeze or develop asthma, the true impact of these infections on lung
development and growth of lung function is not known and requires further study.

Exposures accelerating decline in lung function in adults

When spirometry is used to measure lung function, a decline is seen with advancing
age [11]. This decline is greater over the age of 50 yrs and is slightly greater in males than
in females [11, 78]. A more rapid decline in FEV1 is also seen in smokers [79], asthmatics
[79] and in those with chronic mucus hypersecretion [79]. Chronic exposure to higher
levels of air pollution is associated with lower lung function in adults [80]. Exposure to
indoor air pollutants, including ETS, PM from burning biomass fuel and bioaerosols
have also been associated with lower lung function and more rapid decline in FEV1 [80].

Genetic susceptibility, geneenvironment interactions and

epigenetic phenomena
Environmental factors interact with genetic susceptibility in the pathogenesis of many
respiratory diseases. The response of an individual to a given environmental exposure
varies and is determined, in part, by their genetic background [81] and by the
developmental timing of the exposure [20]. Variations in genes through single nucleotide
polymorphisms that alter gene function may result in increased susceptibility to adverse
environmental exposures. Often more than one gene will be involved in creating an
increased susceptibility to environmental exposures, for example, genegene interactions
are likely to occur in enzymes involved in xenobiotic metabolism, especially in the lung
defence against environmental exposures inducing oxidative stress resulting in oxidant-
dependent diseases [81]. For a more detailed discussion of geneenvironment
interactions, the reader is directed to the relevant chapters in this ERM.
Environmental factors may also impact on gene expression by epigenetic mechanisms,
commonly by inducing gene silencing by methylation of CpG moieties or alteration of
histone structure. One such environmental factor may be exposure to microbial products


in early life [82]. The immune system is immature at birth and relies on maturational
stimuli from normal environmental exposures to develop normally [83]. The ability of T-
cells to produce interferon-c is suppressed during pregnancy and in early infancy due to
gene silencing by hypermethylation [84]. Other environmental exposures, such as
tobacco smoke, may also increase the risk of respiratory disease in those exposed by
epigenetic effects. The extend to which epigenetic effects are heritable and the role they
play in inducing respiratory diseases such as asthma are not known with certainty [85].

The normal growth and development of the respiratory system occurs during both
pre-natal and post-natal life, providing prolonged windows of susceptibility to
environmental exposures. Lung function at birth determines lung function throughout
childhood, as lung function tracks as the child grows. Adverse environmental
exposures have the potential to decrease lung growth and decrease adult lung function.
An understanding of the normal process of lung growth and how adverse environmental
exposures may impact on this will help clarify the role of environmental exposures on
respiratory health throughout life.

Chronic respiratory disease has its origins in early life exposures that interfere with the
normal growth and development of the respiratory system. Airway development is
completed early in pregnancy but much of the alveolar development occurs after
birth, making the developing lung vulnerable to both pre-natal and post-natal
exposures. Lung function growth tracks along trajectories after birth and lung
function at birth is a major determinant of lung function throughout childhood.
Premature birth per se results in abnormal lungs and these changes are magnified by
mechanical ventilation and supplemental oxygen therapy. Environmental exposures
that may decrease lung growth include: environmental tobacco smoke; ambient air
pollution, especially traffic-related pollutants; indoor air pollution, including
exposure to household chemicals and bioaerosols; and viral lower respiratory
infections in early life. Lung function growth continues throughout childhood
reaching peak adult values earlier in girls than in boys. The rate of the normal decline
in lung function, when measured by standard spirometry, can be accelerated by
adverse environmental exposures, especially by tobacco smoking. An understanding
of the normal processes of lung development, of the windows of susceptibility and of
the adverse environmental exposures that may inhibit lung growth will allow a more
thorough knowledge of the processes underlying the development of chronic
respiratory diseases.

Keywords: Embryogenesis, environmental exposures, genetic susceptibility, lung

development, lung function, windows of susceptibility.

Statement of interest
None declared.


1. Joshi S, Kotecha S. Lung growth and development. Early Hum Dev 2007; 83: 789794.
2. Davies G, Reid L. Growth of the alveoli and pulmonary arteries in childhood. Thorax 1970; 25:
3. Dunnill MS. Postnatal growth of the lung. Thorax 1962; 17: 329333.
4. Thurlbeck WM. Postnatal human lung growth. Thorax 1982; 37: 564571.
5. Thurlbeck WM, Angus G. Growth and ageing of the normal lung. Chest 1975; 67: Suppl. 2,
6. Turner SW, Palmer LJ, Rye PJ, et al. Infants with flow limitation at 4 weeks: outcome at 6 and 11
years. Am J Respir Crit Care Med 2002; 165: 12941298.
7. Young S, Arnott J, OKeeffe P, et al. The association between early life lung function and
wheezing during the first 2 years of life. Eur Respir J 2000; 15: 151157.
8. Galambos C, deMello DE. Regulation of alveologenesis: clinical implications of impaired growth.
Pathology 2008; 40: 124140.
9. Hislop A, Muir DCF, Jacobsen M, et al. Postnatal growth and function of the pre-acinar airways.
Thorax 1972; 27: 265274.
10. Phalen RF, Oldham MJ, Beaucage CB, et al. Postnatal enlargement of human tracheobronchial
airways and implications for particle deposition. Anat Rec 1985; 212: 368380.
11. Stanojevic S, Wade A, Stocks J, et al. Reference ranges for spirometry across all ages: a new
approach. Am J Respir Crit Care Med 2008; 177: 253260.
12. Sly P, Flack F. Lung function. In: Silverman M, ed. Childhood Asthma and other Wheezing
Disorders. 2nd Edn. London, Arnold, 2002; pp. 125143.
13. Hibbert ME, Hudson IL, Lanigan A, et al. Tracking of lung function in healthy children and
adolescents. Pediatr Pulmonol 1990; 8: 172177.
14. Hibbert ME, Lannigan A, Landau LI, et al. Lung function values from a longitudinal study of
healthy children and adolescents. Pediatr Pulmonol 1989; 7: 101109.
15. Hopper JL, Hibbert ME, Macaskill GT, et al. Longitudinal analysis of lung function growth in
healthy children and adolescents. J Appl Physiol 1991; 70: 770777.
16. Merkus PJFM, Borsboom GJJM, van Pelt W, et al. Growth of airways and air spaces in teenagers
is related to sex but not to symptoms. J Appl Physiol 1993; 75: 20452053.
17. Stern DA, Morgan WJ, Wright AL, et al. Poor airway function in early infancy and lung function
by age 22 years: a non-selective longitudinal cohort study. Lancet 2007; 370: 758764.
18. Oostveen E, MacLeod D, Lorino H, et al. The forced oscillation technique in clinical practice:
methodology, recommendations and future developments. Eur Respir J 2003; 22: 10261041.
19. McKeever TM, Lewis SA, Smit HA, et al. A multivariate analysis of serum nutrient levels and
lung function. Respir Res 2008; 9: 67.
20. Environmental Health Criteria. 237. Principle for Evaluating Health Risks in Children Associated
with Exposure to Chemicals. Geneva, World Health Organization, 2006.
21. Selevan S, Kimmel C, Mendola P. Windows of susceptibility to environmental exposures in
children. In: Pronczuk-Garbino J, ed. Childrens Health and the Environment. Geneva, World
Health Organization, 2005; pp. 1725.
22. Le Souef PN. Pediatric origins of adult lung diseases. 4. Tobacco related lung diseases begin in
childhood. Thorax 2000; 55: 10631067.
23. Stick SM, Burton PR, Gurrin L, et al. Effects of maternal smoking during pregnancy and a family
history of asthma on respiratory function in newborn infants. Lancet 1996; 348: 10601064.
24. Sekhon HS, Keller JA, Proskocil BJ, et al. Maternal nicotine exposure upregulates collagen gene
expression in fetal monkey lung. Association with a7 nicotinic acetylcholine receptors. Am J
Respir Cell Mol Biol 2002; 26: 3141.
25. Ueda Y, Stick SM, Hall G, et al. Control of breathing in infants born to smoking mothers.
J Pediatr 1999; 135: 226232.


26. Henderson J, Sherriff A, Farrow A, et al. Household chemicals, persistent wheezing and lung
function: effect modification by atopy? Eur Respir J 2008; 31: 547554.
27. Sram RJ, Binkova B, Dejmek J, et al. Ambient air pollution and pregnancy outcomes: a review of
the literature. Environ Health Perspect 2005; 113: 375382.
28. Hansen C, Neller A, Williams G, et al. Low levels of ambient air pollution during pregnancy and
fetal growth among term neonates in Brisbane, Australia. Environ Res 2007; 103: 383389.
29. Latzin P, Roosli M, Huss A, et al. Air pollution during pregnancy and lung function in newborns:
a birth cohort study. Eur Respir J 2009; 33: 594603.
30. Van Putte-Katier N, Uiterwaal CSPM, De Jong BM, et al. The influence of maternal respiratory
infections during pregnancy on infant lung function. Pediatr Pulmonol 2007; 42: 945951.
31. Gaultier C. Malnutrition and lung growth. Pediatr Pulmonol 1991; 10: 278286.
32. Lopuhaa C, Roseboom T, Osmond C, et al. Atopy, lung function, and obstructive airways disease
after prenatal exposure to famine. Thorax 2000; 55: 555561.
33. Hoo A-F, Stocks J, Lum S, et al. Development of lung function in early life: influence of birth
weight in infants of nonsmokers. Am J Respir Crit Care Med 2004; 170: 527533.
34. Walter E, Ehlenbach W, Hotchkin D, et al. Low birth weight and respiratory disease in
adulthood: a population-based casecontrol study. Am J Respir Crit Care Med 2009; 180: 176
35. Harding J. Nutrition and growth before birth. Asia Pac J Clin Nutr 2003; 12: Suppl. 12, S28.
36. Tennant PWG, Gibson GJ, Pearce MS. Lifecourse predictors of adult respiratory function: results
from the Newcastle Thousand Families Study. Thorax 2008; 63: 823830.
37. Beydon N, Davis SD, Lombardi E, et al. An official American Thoracic Society/European
Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit
Care Med 2007; 175: 13041345.
38. Gangell CL, Horak F Jr, Patterson HJ, et al. Respiratory impedance in children with cystic
fibrosis using forced oscillations in clinic. Eur Respir J 2007; 30: 892897.
39. Hall GL, Sly PD, Fukushima T, et al. Respiratory function in healthy young children using forced
oscillations. Thorax 2007; 62: 521526.
40. Hislop A, Randya H. Structural development. In: Silverman M, ed. Childhood Asthma and other
Wheezing Disorders. 2nd Edn. London, Arnold, 2002; pp. 3756.
41. Sly PD, Holt PG. Breast is best for preventing asthma and allergies or is it? Lancet 2002; 360:
42. Nagel G, Buchele G, Weinmayr G, et al. Effect of breastfeeding on asthma, lung function and
bronchial hyperreactivity in ISAAC Phase II. Eur Respir J 2009; 33: 9931002.
43. He QQ, Wong TW, Du L, et al. Nutrition and childrens respiratory health in Guangzhou, China.
Public Health 2008; 122: 14251432.
44. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 19641999. J Allergy Clin
Immunol 2002; 109: 189194.
45. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of
childhood asthma followed to adulthood. N Engl J Med 2003; 349: 14141422.
46. Stein R, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze
and allergy by age 13 years. Lancet 1999; 354: 541545.
47. Oswald H, Phelan PD, Lanigan A, et al. Childhood asthma and lung function in mid-adult life.
Pediatr Pulmonol 1997; 23: 1420.
48. Merkus PJFM, Van Pelt W, Van Houwelingen H, et al. Inhaled corticosteroids and growth of
airway function in asthmatic children. Eur Respir J 2004; 23: 861868.
49. Taylor DR, Cowan JO, Greene JM, et al. Asthma in remission: can relapse in early adulthood be
predicted at 18 years of age? Chest 2005; 127: 845850.
50. Joad J. Effect of environmental tobacco smoke on lung development. In: Harding R, Pinkerton
K, Plopper C, eds. The Lung Development, Aging and Environment. London, Elsevier Academic
Press, 2004; pp. 291299.


51. Diat-Sanchez D. The role of diesel exhaust particles and their associated polyaromatic
hydrocarbons in the induction of allergic airway disease. Allergy 1997; 52: 5256.
52. Wichmann FA, Muller A, Busi LE, et al. Increased asthma and respiratory symptoms in children
exposed to petrochemical pollution. J Allergy Clin Immunol 2009; 123: 632638.
53. Landrigan PJ, Garg A. Children are not little adults. In: Pronczuk-Garbino J, ed. Childrens
Health and the Environment. Geneva, World Health Organisation, 2005; pp. 316.
54. Salvi S. Health effects of ambient air pollution in children. Paediatr Respir Rev 2007; 8: 275280.
55. Plopper CG, Smiley-Jewell SM, Miller LA, et al. Asthma/allergic airways disease: does postnatal
exposure to environmental toxicants promote airway pathobiology? Toxicol Pathol 2007; 35: 97110.
56. Fanucchi MV, Plopper CG, Evans MJ, et al. Cyclic exposure to ozone alters distal airway
development in infant rhesus monkeys. Am J Physiol Lung Cell Mol Physiol 2006; 291: L644L650.
57. Gauderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung development from
10 to 18 years of age. N Engl J Med 2004; 351: 10571067.
58. Kulkarni N, Pierse N, Rushton L, et al. Carbon in airway macrophages and lung function in
children. N Engl J Med 2006; 355: 2130.
59. Calderon-Garciduenas L, Mora-Tiscareno A, Fordham LA, et al. Respiratory damage in children
exposed to urban pollution. Pediatr Pulmonol 2003; 36: 148161.
60. Calderon-Garciduenas L, Mora-Tiscareno A, Fordham LA, et al. Lung radiology and pulmonary
function of children chronically exposed to air pollution. Environ Health Perspect 2006; 114:
61. Rojas-Martinez R, Perez-Padilla R, Olaiz-Fernandez G, et al. Lung function growth in children
with long-term exposure to air pollutants in Mexico City. Am J Respir Crit Care Med 2007; 176:
62. Galizia A, Kinney PL. Long-term residence in areas of high ozone: associations with respiratory
health in a nationwide sample of nonsmoking young adults. Environ Health Perspect 1999; 107:
63. Ihorst G, Frischer T, Horak F, et al. Long- and medium-term ozone effects on lung growth
including a broad spectrum of exposure. Eur Respir J 2004; 23: 292299.
64. Sunyer J. Chronic effects of ozone in children. Eur Respir J 2004; 23: 185186.
65. Brauer M, Hoek G, Smith H, et al. Air pollution and development of asthma, allergy and
infections in a birth cohort study. Eur Respir J 2007; 29: 879888.
66. Erbas B, Kelly A, Physick B, et al. Air pollution and childhood asthma emergency hospital
admission: estimating intra-city regional variations. Int J Environ Health Res 2005; 15: 1120.
67. Jang AS, Yeum CH, Son MH. Epidemiologic evidence of a relationship between airway
hyperresponsiveness and exposure to polluted air. Allergy 2003; 58: 585588.
68. Selgrade MK, Plopper CG, Gilmour MI, et al. Assessing the health effects and risks associated
with childrens inhalation exposures asthma and allergy. J Toxicol Environ Health Part A 2008;
71: 196207.
69. Ponsonby AL, Glasgow N, Gatenby P, et al. The relationship between low level nitrogen dioxide
exposure and child lung function after cold air challenge. Clin Exp Allergy 2001; 31: 12051212.
70. Woodcock A, Lowe LA, Murray CS, et al. Early life environmental control: effect on symptoms,
sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004; 170: 433439.
71. Martinez FDM. Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood
asthma. Pediatr Infect Dis J 2003; 22: Suppl. 2, S76S82.
72. Sly PD, Soto-Quiros ME, Landau LI, et al. Factors predisposing to abnormal pulmonary
function after adenovirus type 7 pneumonia. Arch Dis Child 1984; 59: 935939.
73. Murtagh P, Giubergia V, Viale D, et al. Lower respiratory infections by adenovirus in children.
Clinical features and risk factors for bronchiolitis obliterans and mortality. Pediatr Pulmonol
2009; 44: 450456.
74. Sigurs N, Bjarnason R, Sigurbergsson F, et al. Respiratory syncytial virus bronchiolitis in infancy
is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000; 161:


75. Sly PD, Hibbert ME. Childhood asthma following hospitalization with acute viral bronchiolitis in
infancy. Pediatr Pulmonol 1989; 7: 153158.
76. Kusel MMH, de Klerk N, Holt PG, et al. Role of respiratory viruses in acute upper and lower
respiratory tract illness in the first year of life: a birth cohort study. Pediatr Infect Dis J 2006; 25:
77. Jackson D, Gangnon R, Evans M, et al. Wheezing rhinovirus illnesses in early life predict asthma
development in high-risk children. Am J Respir Crit Care Med 2008; 178: 667672.
78. Ryan G, Knuiman MW, Divitini ML, et al. Decline in lung function and mortality: the Busselton
Health Study. J Epidemiol Community Health 1999; 53: 230234.
79. Bellia V, Scichilone N, Battaglia S. Asthma in the elderly. In: Bellia V, Antonelli Incalzi R, eds.
Respiratory Diseases in the Elderly. Eur Respir Mon 2009; 43: 5676.
80. Viegi G, Maio S, Simoni M, et al. The epidemiological link between ageing and respiratory
diseases. In: Bellia V, Antonelli Incalzi R, eds. Respiratory Diseases in the Elderly. Eur Respir
Mon 2009; 43: 117.
81. Kajekar R. Environmental factors and developmental outcomes in the lung. Pharmacol Ther
2007; 114: 129145.
82. Holt PG, Macaubas C, Prescott SL, et al. Microbial stimulation as an aetiologic factor in atopic
disease. Allergy 1999; 54: 1216.
83. Macaubas C, de Klerk NH, Holt BJ, et al. Association between antenatal cytokine production
and the development of atopy and asthma at age 6 years. Lancet 2003; 362: 11921197.
84. White GP, Hollams EM, Yerkovich ST, et al. CpG methylation patterns in the IFNc promoter in
naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics.
Pediatr Allergy Immunol 2006; 17: 557564.
85. Bousquet J, Jacot W, Yssel H, et al. Epigenetic inheritance of fetal genes in allergic asthma.
Allergy 2004; 59: 138147.