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CHAPTER 12
Tobacco smoke and respiratory disease
J. Behr*, D. Nowak
#
*Dept of Internal Medicine I, Section for Pulmonary Diseases and
#
Institute and outpatient Clinic for
Occupational and Environmental Medicine, University of Munich, Munich, Germany.
Correspondence: D. Nowak, Institut und Poliklinik fu¨r Arbeits und Umweltmedizin, Klinikum der
Universita¨t Mu¨nchen, Innenstadt, Ziemssenstrasse 1, 80336 Mu¨nchen, Germany.
Although tobacco has been used in Western culture for w400 yrs, inhalative cigarette
smoking is a relatively new development. It was during the 20th century that cigarette
smoking became a mass phenomenon. Interestingly, the evolution of the prevalence of
tobacco smoking in a given population strikingly resembles the evolution of an infective
epidemic [1]. Introduced by "trend-setters" into society, the "smoking epidemic" reached
its maximum in the 1950s in the male population, with considerable geographic variation
in time trends since then. However, the overall prevalence of smoking is determined
by such factors as sex, social status, and age [1]. Currently, the prevalence of smoking
around the world is estimated to be 47% amongst males and 12% amongst females, in
Europe y35% of males and 25% of females are active smokers [2, 3]. There are cross-
sectional and longitudinal studies demonstrating the deleterious effect of smoking on
respiratory health [4–6], but tobacco smoke is also a risk factor for cancer of the digestive
and urinary tract, coronary and vascular disease, as well as a number of nonfatal
conditions. Consequently, tobacco smoking is a major cause of premature death in
Europe. Moreover, throughout the European Union, 32% of deaths in males aged
35–69 yrs and 10% of deaths in females in the same age range are attributable to smoking
[7]. The proportion of deaths from respiratory diseases attributable to tobacco smoking
are even higher: 54% for males and 42% for females [7]. The economic impact of
smoking has been consistently estimated to be approximately 200–300 per capita in
the USA and Europe [8]. Furthermore, since the 1970s there is increasing evidence that
not only active smoking is a risk factor for respiratory diseases, but also environmental
tobacco smoke exposure in nonsmokers, especially in children [9]. Taken together, the
available data clearly demonstrate that active and passive smoking place a significant
burden on public health, especially with regard to respiratory diseases. Extrapolations
of the present data suggest that the proportion of tobacco-associated diseases will
increase in the coming decades with chronic obstructive pulmonary disease (COPD)
and lung cancer becoming the most prevalent causes of death in the year 2020 [10].
Trends in smoking prevalence
Time trends in cigarette consumption vary considerably between regions. During
the last 30 yrs, cigarette consumption per adult was rather stable in Europe, decreased
in America and increased in all other regions, particularly in the Western Pacific region.
The apparent stability of global per capita cigarette consumption, thus, results from
a decreasing consumption in developed countries counterbalanced by increasing
consumption in developing countries. The analysis of temporal trends in 111 countries
Eur Respir Mon, 2002, 21, 161–179. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2002; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-24-3.
161
[11] reveals that compared with the 1970s, cigarette consumption per adult increased
in 58 countries and was stable or declining in the other 53 (table 1). The rise in cigarette
consumption, however, includes the world’s most populous countries, such as China.
Reasons for smoking
Smoking status is believed to be largely a function of genetic and sociodemographic
factors, environmental determinants, behavioural factors and specific dimensions of
personality [12, 13].
Genetic factors
Twin studies show a substantial genetic determination of smoking [14]. This is not
surprising since genetic factors substantially contribute to major personality character-
istics as well as to psychiatric dimensions.
Sociodemographic factors
Age is an important determinant for smoking status, since the earlier in life smoking
is started the higher the likelihood of becoming a regular smoker. Moreover, the
likelihood of stopping smoking decreases the earlier the habit is taken up [15, 16]. Gender
differences show geographically and culturally different patterns. Higher smoking
rates in females are frequently found in countries with a "Western lifestyle". Ethnic
background is a major determinant of smoking status, with lower prevalences in Blacks
than in Hispanics [17] and lower relative frequencies of smoking in Northern than in
Southern Europe [11]. Across countries and rather consistently over time, growing up
in intact, two parent families has been demonstrated to be associated with a decreased
prevalence of smoking among children [18]. Parental socioeconomic status is generally
considered to be inversely related to smoking in adolescents [19].
Environmental factors
Children of parents who smoke generally have a higher risk of taking up the habit
themselves as compared to children of nonsmoker parents [20]. Likewise, an influence of
Table 1. – Number of countries and consumption of cigarettes per adult aged i15 yrs
WHO regions and countries
1970–1972 to 1990–1992
Increased Decreased Unchanged
WHO regions
African region 15 6 5
Region of the Americas 9 17 0
Eastern Mediterranean region 9 0 3
European region 11 14 1
South-East Asia region 6 2 0
Western Pacific region 8 5 0
More developed countries 12 18 1
Less developed countries 46 26 8
World 58 44 9
Number of countries where consumption of cigarettes per adult aged i15 yrs increased, decreased, or
remained unchanged in the period from 1970 – 1972 to 1990 – 1992 (according to the World Health
Organisation (WHO) [11]).
J. BEHR, D. NOWAK
162
sibling smoking on adolescent smoking behaviour has been reported, and the influence
of smoking by siblings may even be stronger than that of smoking by parents [21]. An
authoritative, positive parenting style, positively associated with child competencies
was inversely related to rates of smoking intention, initiation and experimentation in
adolescents [22]. In addition to smoking behaviour in the family, peer smoking is
sometimes even more of a consistent predictor of smoking [23]. Recently, Sargent et al.
[24] demonstrated a dose/response relationship between the number of cigarette
promotional items owned by an adolescent and the likelihood of smoking. The authors
interpreted their findings as support of a causal relationship between tobacco
promotional campaigns and smoking behaviour among adolescents, but they did not
adequately exclude the possibility that the tendency to start smoking may itself enhance
the chance of collecting promotional items.
Behavioural factors
Good academic performance in school is a major predictor for nonsmoking among
teenagers [25]. Risky behaviours such as carrying a weapon [26] and having a high
number of sexual partners [27] are positively associated with smoking statistically,
suggesting that smokers are generally more prone to potentially dangerous habits.
Personal factors
Perceived stress is associated with initiation and maintenance of smoking [28], and
nonsmokers may have healthier coping strategies. Markers of high self-esteem are
generally associated with lower smoking prevalence.
Of course, there are inconsistencies between some of the studies, and many markers
used in these studies may only be proxies for underlying mechanisms, however, the
majority of these findings can be translated into intervention programmes.
Composition of tobacco smoke
Cigarette smoke is a heterogenous aerosol produced by incomplete combustion of
the tobacco leaf. More than 4,000 substances have been identified in cigarette smoke,
including some that are pharmacologically active, antigenic, cytotoxic, mutagenic, and
carcinogenic (table 2).
In cigarette smoke particulate matter is dispersed in the gas phase. During puffing,
mainstream smoke emerges from the mouthpiece, whereas sidestream smoke is emitted
between the puffs at the burning cone and from the mouthpiece. Of the mainstream
smoke, 92–95% is in the gas phase and contains 0.3–3.3 billion particles?mL
-1
. The mean
particle size is 0.2–0.5 mm and therefore within the respirable range. Of special interest
is the fact that cigarette smoke contains a high concentration of reactive organic radicals
(RORs) and substances capable of producing RORs. Free radicals are formed in
high amounts at the tip of the cigarette due to the high temperatures of up to 900uC.
However, the lifetimes of these radicals are too short to allow inhalation by the smoker.
Consequently, fresh mainstream smoke contains only low concentrations of radicals,
whereas the concentration of RORs increases in the gas phase of cigarette smoke as it
ages, with maximal concentrations reached after 1–2 min [29]. This implies that highly
reactive free radicals are formed continuously within the smoke by chemical processes
during inhalation [30]. An important source for radical production is the relatively stable
nitric oxide (NO) radical that is found in cigarette smoke in high concentrations of
TOBACCO SMOKE AND RESPIRATORY DISEASE
163
up to 400 parts per million. NO is oxidised to the more reactive nitrogen dioxide radical
by dioxygen. This radical reacts with isoprene that has been demonstrated in high
concentrations in cigarette smoke to form various biologically active RORs [29].
Moreover, aqueous extracts of tar catalyse the formation of superoxide (O
2
?
-
), hydrogen
peroxide (H
2
O
2
), and the highly toxic hydroxyl radical (?OH) in the presence of oxygen.
These reactions are probably due to the presence of redox-cycling systems within
cigarette tar [29, 31]. Today, many of the adverse effects of cigarette smoke on respiratory
health are thought to be directly or indirectly associated with the high amount (1610
14
–
10
16
) of highly reactive free radicals inhaled by the smoker with each puff.
Mechanisms of tobacco smoke-induced lung disease
Among the effects that tobacco smoke exerts on the respiratory tract, two main
mechanisms can be differentiated: 1) induction of inflammation; and 2) mutagenic/
carcinogenic effects. The inflammatory reactions are composed of a variety of different
effects that include ciliotoxicity, increased mucous secretion, and accumulation of
activated inflammatory cells in the respiratory tract. Some of the constituents of tobacco
smoke are irritants, others exert toxic effects on the airway epithelium by virtue of their
chemical structure, e.g. acids, ammonia, aldehydes and, therefore, may cause cell damage
or death as well as local inflammation. Moreover, the normal clearance function of the
epithelium is impaired by ciliotoxic effects of these substances (table 2). Together with
goblet cell hyperplasia and increased mucous production, reduced clearance induces
mucous retention in the airways, a relevant predisposition for bacterial colonisation
and infection, ultimately causing inflammatory exacerbations. In addition to these
unspecific irritative and/or toxic effects caused by tobacco smoke constituents due to
their physicochemical properties, another more specific lesion is linked to the inhalation
of RORs. These RORs are either present in tobacco smoke or produced by tobacco
smoke constituents within the lungs after solution of tar constituents in the epithelial
lining fluid (ELF). Furthermore, oxidants in cigarette smoke have been shown to
induce sequestration of neutrophils and monocytes in the lungs that also penetrate the
endothelium and can be found in increased numbers in the bronchoalveolar lavage
(BAL) fluid [32]. These cells, predominantly neutrophilic granulocytes, are able to
produce large amounts of O
2
?
-
anions by the membrane bound reduced nicotinamide-
adenine dinucleotide phosphate-oxidase. O
2
?
-
anions are transformed into more
Table 2. – Selected constituents of cigarette smoke
Particulate phase Main effects Gas phase Main effects
Tar Mutagenic/carcinogenic Carbon monoxide Impairment of oxygen binding to
haemoglobin
Nicotine Dose-dependent stimulator
or depressor of
parasympathetic
N-cholinergic receptors
Oxides of nitrogen Irritant, pro-inflammatory, ciliotoxic
Aromatic
hydrocarbons
Mutagenic/carcinogenic Aldehydes Irritant, pro-inflammatory, ciliotoxic
Phenol Irritant, mutagenic/carcinogenic Hydrocyanic acid Irritant, pro-inflammatory, ciliotoxic
Cresol Irritant, mutagenic/carcinogenic Acrolein Irritant, pro-inflammatory, ciliotoxic
b-Naphthylamine Mutagenic/carcinogenic Ammonia Irritant, pro-inflammatory, ciliotoxic
Benzo(a)pyrene Mutagenic/carcinogenic Nitrosamines Mutagenic/carcinogenic
Catechol Mutagenic/carcinogenic Hydrazine Mutagenic/carcinogenic
Indole Tumour acceleration Vinyl chloride Mutagenic/carcinogenic
Carbazole Tumour acceleration
J. BEHR, D. NOWAK
164
aggressive oxidants like H
2
O
2
, ?OH and, in the presence of myeloperoxidase, hypohalides
are formed (fig. 1). These oxidants may cause oxidative damage to a variety of different
substrates (fig. 2) and will ultimately result in alterations or destruction of cells and
constituents of the extracellular matrix of the lungs.
A special relationship exists between oxidants and the protease/antiprotease balance
Oxidative tissue destruction
e
-
O
2
NADPH-
oxidase
O
2
·
-
NO·
ONOO
-
·OH
H
2
O
2
SOD
Fenton's
reaction
Fe
2+
Cu
2+
e
-
2H
+
2 Cl
-
MPO
2 HOCl
Fig. 1. – Overview of the metabolism of reactive organic radicals (ROR). NADPH: reduced nicotinamide-adenine
dinucleotide phosphate; O
2
?
-
: superoxide; SOD: superoxide dismutase; H
2
O
2
: hydrogen peroxide; MPO:
myeloperoxidase; NO?: nitrosyl; ? OH: hydroxyl radical; ONOO
-
: peroxynitrite.
Redox/signalling
Lipid mediators/
peroxidation
Cooperative effects
with proteases
Nonspecific
oxidative lesions
Proteins
Lipids
DNA
Injury/death,
of cells
Proteolysis
Tissue
destruction
Prostaglandins
Thromboxane
Leukotrienes
Vascular tone,
endothelial dysfunction
Transcription-
factors,
e.g
.
NF-
κ
B, AP-1
etc
.
Cytokines,
proliferation
apoptosis,
etc
.
ROR
Activated phagocytes
Cigarette smoke
mucus retention, infection
Fig. 2. – Mechanisms of cell injury and tissue destruction by reactive organic radicals (RORs). DNA:
deoxyribonucleic acid; NF: nuclear factor; AP: activator protein.
TOBACCO SMOKE AND RESPIRATORY DISEASE
165
within the lungs: oxidants may inactivate important antiproteases, such as a
1
-proteinase
inhibitor, and secretory leukoprotease inhibitor [33, 34]. Other proteases are activated
by oxidation. Taken together, these effects of oxidants result in a protease/antiprotease
imbalance in favour of proteolytic activity likewise inducing tissue damage and inflam-
mation. This interaction between oxidants and the protease/antiprotease system is
referred to as the "cooperative effect".
Another important aspect of oxidant injury induced by cigarette smoke is the
damage of the antioxidant screen of the lung. Physiologically, oxidants are completely
counterbalanced by antioxidants within the lungs. The highly active antioxidants in
the lungs include scavengers, enzymes, and enzyme systems (table 3), which prevent
oxidative damage.
Glutathione (GSH) is quantitatively the most important antioxidant of the lung in the
extracellular and intracellular compartment [35]. Moreover, GSH is a scavenger for most
biologically relevant oxidants and can be recycled intracellularly by the GSH redox cycle
or the c-glutamyl cycle, which allows for de novo biosynthesis of GSH using degraded
extracellular GSH or glutathione disulphide as a substrate [35, 36]. It has been
demonstrated that cigarette smoke leads to an acute intracellular drop of GSH but
after several hours GSH production is increased and elevated levels of GSH have
been measured in the ELF from smokers [37]. This may represent an effort of the lung
to counterbalance the increased oxidant burden from smoking. Moreover, antioxidant
enzymes such as catalase and O
2
?
-
dismutase, as well as the antioxidant vitamin C, have
been reported to be elevated in the lungs of smokers. However, due to the increased
amount of oxidation products and decreased plasma antioxidant capacity, a shift of
the oxidant/antioxidant balance towards a more oxidated milieu has been indicated
in smokers [38]. The causes and mechanisms of oxidant lung injury induced by tobacco
smoke are summarised in figure 3. Taken together, smoking poses an increased oxidative
burden on the lungs which is overall not adequately counterbalanced despite an elevated
antioxidant screen.
Chronic obstructive pulmonary disease
In this context, the term COPD is confined to those obstructive respiratory conditions
most closely associated with cigarette consumption, namely, chronic bronchitis and
emphysema. Murray and Lopez [10] predicted that COPD, being the sixth most
common cause of death in 1990, will advance to worldwide third place in 2020. The
population attributable fraction of smoking for the development of COPD has been
estimated to be 0.7–0.8 in males and 0.7 in females [39]. Despite a considerable healthy
smoker effect which tends to mask effects of smoking on spirometric indices [40, 41],
airflow obstruction is more common among smokers than nonsmokers. The increased
longitudinal decline in forced expiratory volume in one second in smokers might be
considerably lowered by smoking cessation even when mild-to-moderate COPD is
already present [42]. Beside cigarette smoking, other less important risk factors for the
development of COPD include those seen in table 4 [43].
Table 3. – Antioxidants of the lung
Scavengers Enzymes Enzyme systems
Serum proteins, albumin, transferrin,
coeruloplasmin, etc.
Superoxide dismutase c-Glutamyl cycle
Lactoferrin, taurin Catalase Glutathione redox cycle
Vitamin C and E
Glutathione
J. BEHR, D. NOWAK
166
The pathogenesis of smoking-related COPD includes the protease/antiprotease and
oxidant/antioxidant hypotheses and abnormal repair processes. In short, proteolytic
products from inflammatory cells, if not adequately counterbalanced by protective
antiprotease systems, lead to bronchial injury and destruction of alveolar architecture.
The protease/antiprotease hypothesis is based on the observation of premature
emphysema in patients with severe a
1
-proteinase inhibitor deficiency. Additionally,
the pathogenetic role of neutrophil elastase is compatible with the involvement of
neutrophils in the pathogenesis of COPD. Neutrophil elastase can damage the
respiratory epithelium and enhances mucous production by goblet cells [44]. It increases
interleukin-8 [45], which, in itself, is a potent chemoattractant for neutrophils.
In addition to neutrophils, alveolar macrophages and enzyme macrophage elastase,
a matrix metalloproteinase, play a role in the pathophysiology of emphysema [46].
However, the relative contribution of neutrophils and macrophages and their elastolytic
products for the development of COPD is not fully understood. The oxidant/antioxidant
hypothesis of COPD which has already been introduced in this article is based on a huge
amount of data indicating that oxidative stress contributes to COPD [47, 48]. In smokers
Cigarette smoke
Impaired ciliary
clearance
Oxidants
Aromatic hydrocarbons
Nitrosamines
etc.
Growth signals
Chromosomal damage
and DNA adducts
Oncogene expression
Carcinogenesis
Lung cancer
Infection
Mucus and toxin
retention
Oxidants
Aldehydes
Acids
Ammonia
etc.
Local irritation of
airway epithelium
Injury/death of cells
Influx of neutrophils
Inflammation
COPD & other inflammatory lung diseases
Fig. 3. – Mechanisms of cigarette smoke induced lung disease. DNA: deoxyribonucleic acid; COPD: chronic
obstructive pulmonary disease.
Table 4. – Risk factors (other than smoking) for the devlopment of chronic obstructive pulmonary disease
Genetic predisposition Host factors Environmental factors
a
1
-Proteinase inhibitor deficiency Female sex Childhood respiratory infections
Other familial predispositions Atopy and BHR Low socioeconomic status
Eosinophilia Alcohol consumption
Industrial exposures
Exposure to ETS
Air pollution
BHR: bronchial hyperresponsiveness; ETS: environmental tobacco smoke.
TOBACCO SMOKE AND RESPIRATORY DISEASE
167
and subjects with COPD, systemic increases in oxidants [49] and decreases in
antioxidants [38] have been demonstrated. Incomplete repair processes may cause
alterations in subepithelial structures leading to fibrosis of periobronchial tissue as well
as to inhibition of extracellular matrix remodelling [50–52].
Despite cigarette smoking being the most important risk factor for the development
of COPD, only a minority of smokers develop the disease. Therefore, research is
increasingly focusing on the question of which endogenous factors predispose smokers
to COPD [53–55].
Lung cancer
Since the beginning of the 20th century, from being a rare disease, lung cancer has
become the most common type of lethal cancer throughout the world [7]. In a recent
paper, Murray and Lopez [10] estimated lung cancer to be the 10th most common
cause of death today, accounting fory1 million deaths around the world annually. They
also predicted that by the year 2020 lung cancer will advance to the fourth most common
death cause in developed countries and to the fifth most common death cause worldwide
[10].
The causal relationship between lung cancer and cigarette smoking was first reported
in well conducted case-control studies in 1950 [56–59] and later confirmed in large
population-based, prospective, cohort studies [60, 61]. For most developed countries it
is currently estimated that 90% of lung cancer cases in males and 80% in females are
attributable to smoking. The critical risk factors are the early start of smoking during
teenage years and early adulthood, duration of smoking, number of cigarettes smoked
daily, and inhalation practices [62–64]. Amongst the established occupational respiratory
carcinogens, a multiplicative relationship with smoking has been shown for asbestos [65],
radon [66], nickel [67], as well as silica [68], and an overadditive but not multiplicative
relationship was demonstrated for arsenic [69].
As already stated, from a pathogenetic point of view, it is well established that cigarette
smoke contains a mixture of highly toxic compounds like irritants, mutagenic and
carcinogenic substances, including RORs that are fully capable of inducing alterations of
cell proliferation, chromosomal damage, deoxyribonucleic acid (DNA)-adduct forma-
tion, and activation of oncogenes. Recently, Denissenko et al. [70] reported selective
benzo(a)pyrene diol-epoxide adduct formation along exons of p53 in bronchial epithelial
cells, thus, providing a direct mechanistic link between tobacco smoke and lung cancer.
Therefore, toxin-induced injury or death of cells creates an environment of constant
generation of inflammatory and growth signals, including oxidants that finally results
in hyperplasia, metaplasia, mutagenic and carcinogenic transformation of resident cells
of the respiratory tract. Despite increased epidemiological and pathophysiological
knowledge about the links between smoking and lung cancer, it has to be kept in mind
that v20% of smokers develop lung cancer during their lifetime suggesting that host-
related factors are involved. Moreover, epidemiological studies revealed correlations
between familial risk of lung cancer and lung function level of relatives suggestive of the
existence of genetic susceptibility for the deleterious effects of cigarette smoke both as a
carcinogen and as a substance inducing airway obstruction [71, 72]. Genetic influence
may be mediated by various mechanisms like differences in carcinogen metabolism
[73–75], mucociliary clearance [76], efficiency of DNA repair [77], and regulation of
oncogene expression. A number of candidate genes for cancer suceptibility have already
been identified [78]. The new tools of molecular biology like microarray chip systems
may provide new insights into the genetic background of carcinogenesis in the near
J. BEHR, D. NOWAK
168
future. A better knowledge of individuals at risk might increase the efficacy of inter-
vention programmes due to the possibility of focusing on better defined high-risk groups.
Interstitial lung diseases
Interstitial lung diseases (ILDs) represent a heterogenous group of lung disorders,
generally characterised by dyspnoea, dry cough, diffuse interstitial infiltrates, restrictive
lung function pattern, and impaired gas exchange. The most common forms of ILDs
include sarcoidosis, idiopathic pulmonary fibrosis (IPF), pneumoconiosis, and those
ILDs associated with connective tissue diseases. It has recently been suggested that a
number of ILDs are positively linked to tobacco smoking whereas other forms are clearly
inversely related to cigarette smoking (table 5).
Idiopathic pulmonary fibrosis/usual interstitial pneumonia
Reclassification of the interstitial pneumonias by Katzenstein and Myers [79] has
defined usual interstitial pneumonia (UIP) as a clinical and pathological entity, and it is
solely this entity which should be referred to as IPF. The prevalence of IPF/UIP ranges
from 3–29 cases per 100,000 population, with this wide range being due to differences
in definition, study design, and populations [80]. Most importantly for the patient, IPF/
UIP has to be clearly differentiated from other interstitial pneumonias like respira-
tory bronchiolitis-associated (RB)-ILD or desquamative interstitial pneumonia (DIP)
because of its significantly worse median survival time of y3 yrs. The majority of cases
are sporadic with only a few familial forms; there is a slight male preponderance
(1–2:1; male:female), and most patients are w50 yrs of age [80–82]. The prevalence of
current or former smoking varied widely from 41–83% in series of IPF/UIP [83] and
was associated with an increased risk for developing the disease [84–86]. The role of
smoking in the pathogenesis of IPF/UIP is not well understood and there is no evidence
that smoking per se causes IPF/UIP. However, based on the pathogenetic mechanisms of
tobacco smoke already outlined, the underlying inflammatory process in IPF/UIP might
be enhanced by cigarette smoke.
Desquamative interstitial pneumonia
DIP is another form of the idiopathic interstitial pneumonias that is morphologically
characterised by a uniform picture showing accumulation of pigmented macrophages
within the alveolar spaces [79]. The clinical features of DIP are quite different from those
of IPF/UIP; an average age ofy40 yrs,y90% current or previous smokers, and ground-
glass appearance of lung tissue in high-resolution computed tomography (CT) are
characteristic [87, 88]. In contrast to IPF/UIP, most patients with DIP stabilise or
Table 5. – Association between interstitial lung diseases (ILD) and cigarette smoking
ILD positively associated with smoking ILD negatively associated with smoking
Usual interstitial pneumonia/idiopathic
pulmonary fibrosis
Exogenous allergic alveolitis
(hypersensitivity pneumonitis)
Desquamative interstitial pneumonia Sarcoidosis
Respiratory bronchiolitis-associated ILD
Connective tissue disease-associated ILD
Pulmonary Langerhans’ cell histiocytosis
TOBACCO SMOKE AND RESPIRATORY DISEASE
169
improve with corticosteroid therapy and complete remission is possible [89]. Overall,
the long-term prognosis of the disease is somewhat better (average survival is 12 yrs).
The role of smoking in the pathogenesis and for the treatment of DIP is unknown,
although smoking cessation is clearly advocated.
Respiratory bronchiolitis-associated interstitial lung disease
RBILD was first described as an incidental autopsy finding in young male smokers
[90]. Whereas respiratory bronchiolitis without accompanying ILD is a common
finding in smokers, usually without any significant clinical implications, some smokers
or exsmokers develop this symptomatic ILD [83, 90, 91]. Similarly to DIP, RBILD is
characterised by intra-alveolar accumulation of pigmented macrophages. In contrast
to DIP, these changes are less diffuse and clearly centred on respiratory bronchioles and
peribronchiolar alveoli, sparing peripheral airspaces. There are only mild interstitial
inflammatory changes in peribronchiolar parenchyma and frank fibrosis is absent.
Clinical presentation is dominated by cough and exertional dyspnoea, there may be
inspiratory cackles and occasionally clubbing is observed. Lung function tests reveal
a mixed restrictive and obstructive impairment of mild-to-moderate degree. On chest
radiographs reticular or reticulonodular changes are frequent, but normal chest
radiographs have been reported in approximately one-third of affected patients [91].
On high-resolution CT areas of ground-glass attenuation are the most common finding
whereas subpleural reticulations and honeycombing, typical findings in UIP, are
distinctly absent. Overall prognosis is good, especially with smoking cessation. In some
cases, corticosteroids have been employed with beneficial results. With respect to the
similarities between DIP and RBILD regarding epidemiology, positive association with
smoking and clinical as well as histopathological presentation, it has been suggested
to use the term "smoking-related ILD" for both disorders.
Pulmonary Langerhans’ cell histiocytosis
Pulmonary Langerhans’ cell histiocytosis (PLCH; also known as histiocytosis X) is
classified as a dendritic cell-related (Langerhans’ cell) disease of variable, nonmalignant
biological behaviour with a wide range of severity from spontaneous remission to
lethality [92]. Rarely, PLCH is observed in the context of a multifocal Langerhans’ cell
histiocytosis affecting multiple organs; most of these diseases occur in children and are
not related to smoking. By contrast, PLCH of the adult patient is observed almost
exclusively in smokers (w90%) and smoking has been demonstrated to be a strong risk
factor for PLCH in a case-control study [93]. Although the pathogenetic role of smoking
has not yet been elucidated, an increase of Langerhans’ cells on the surface of bronchial
epithelium from smokers has been observed [94]. The peribronchial distribution of the
lesions and the fact that Langerhans’ cells are potent antigen-presenting cells suggest
an inhaled antigen within cigarette smoke as the cause of PLCH.
Miscellaneous interstitial lung disease
Epidemiological associations between cigarette smoking and ILDs have been reported
for some disorders with potential pulmonary manifestations. For rheumatoid arthritis
(RA), most [95–100], but not all [101, 102], studies have reported a positive relationship
between cigarette smoking and pulmonary function or radiological abnormalities.
J. BEHR, D. NOWAK
170
Interestingly, in a study of 150 twin pairs discordant for RA, cigarette smoking was a
risk factor for RA itself [103].
Antiglomerular basement membrane antibodies may cause nephritis and/or pulmo-
nary haemorrhage by binding to glomerular and alveolar basement membranes. The
term "Goodpasture’s syndrome" refers to the subset of patients with both nephritis
and pulmonary haemorrhage. Pulmonary haemorrhage, as observed in 60–80% of
antibasal membrane antibody-associated disease, has been consistently found to be
linked to cigarette smoking [104, 105]. However, in none of the reported diseases
has the pathophysiological role of cigarette smoking within the disease process been
clarified beyond the level of speculation.
Diseases with decreased incidence or severity in smokers
Hypersensitivity pneumonitis
Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is a chronic
inflammatory lung disease caused by inhalation of organic dust including antigens
typically derived from animal proteins or microbes. Formation of precipitating
antibodies against these antigens is characteristic for patients with HP. Consequently,
a type-III immune response has been implicated in the pathogenesis of the disease but
endotoxin may also be involved [106]. A number of studies report a decreased prevalence
of precipitating antibodies among smokers within antigen-exposed populations [107–
110]. Moreover, smokers are clearly underrepresented among patients with manifest
HP [111–113]. In a prospective study by Arima et al. [114], HP was observed in 65.9%
of the nonsmokers and in only 27.3% of the smokers. Based on these findings, several
hypotheses have been proposed to explain the protective effect of smoking on the
development of HP. Most of them focus on immunomodulatory effects of smoking, e.g.
suppression of antibody production, reduction of T-helper cells in BAL, and impairment
of macrophage function [115–117]. More recently, it has been reported that down-
regulation of pulmonary GSH levels may be associated with disease manifestation
in farmers [118]. Although the reason for these differences has not yet been elucidated,
the observations are suggestive to assume that genetic predisposition may play a role
in disease manifestation.
Sarcoidosis
Sarcoidosis is a systemic granulomatous disease of unknown cause with y90%
pulmonary involvement. It is generally believed that sarcoidosis might be an immuno-
logical disorder. Initiated by a putative inhaled antigen that leads to T-cell activation,
sarcoidosis is characterised by a lymphocytic alveolitis with increased T-helper/
T-suppressor cell ratio and by formation of noncaseating granulomas. As in
hypersensitivity pneumonitis, smokers are underrepresented in patients with sarcoidosis
suggesting that cigarette smoke provides some kind of protection against this disease
[93, 119–121]. Although distinct differences in BAL differential cell counts and T-cell
subsets have been observed between nonsmokers and smokers affected by sarcoidosis,
there is no conclusive pathogenetic concept to explain the reduced incidence of
sarcoidosis in smokers [121]. Smoking-induced alterations of antigen presentation,
macrophage function, and lymphocyte proliferation may be involved.
TOBACCO SMOKE AND RESPIRATORY DISEASE
171
Smoking cessation
There is scientific consensus that cigarette smoking is an addiction to the drug nicotine.
As with any drug addiction, social, economic, personal and political influences play
an important part in determining patterns of smoking prevalence and cessation [122].
Seventy per cent of smokers report that they would like to quit [123]. However, in a USA
survey of exsmokers, respondents acknowledged little assistance in giving up smoking
[124]. Therefore, within the last 10 yrs, particularly in the USA, tremendous public
efforts have been undertaken to promote and spread plans for smoking cessation
[125, 126] (table 6).
Given that the progression of COPD can be slowed down by smoking cessation
[42] and that people who stop smoking even well into middle age avoid most of their
subsequent risk for lung cancer [127], smoking cessation should be a crucial issue in
Table 6. – A 5-day plan to quit smoking
The first step to quitting smoking is to decide to quit. Next, make an appointment with your healthcare provider,
or contact a smoking cessation clinic to discuss your options for treatment. Set a quit date.
Quit day minus 5: List all of your reasons for quitting and tell your friends and family about your plan.
Stop buying cartons of cigarettes.
Quit day minus 4: Pay attention to when and why you smoke. Think of new ways to relax or things to hold in your
hand instead of a cigarette. Think of habits or routines you may want to change. Make a list to use when you quit.
Quit day minus 3: Make a list of the things you could do with the extra money you will save by not buying cigarettes.
Think of who to reach out to when you need help, like a smoking support group.
Quit day minus 2: Buy the over-the-counter nicotine patch or nicotine gum, or get a prescription for the nicotine
inhaler, nasal spray, or the nonnicotine pill, bupropion SR. Clean your clothes to get rid of the smell of cigarette
smoke.
Quit day minus 1: Think of a reward you will get yourself after you quit. Make an appointment with your dentist to
have your teeth cleaned. At the end of the day, throw away all cigarettes and matches. Put away lighters
and ashtrays.
Quit day: Keep very busy. Change your routine when possible, and do things out of the ordinary that don’t r
emind you of smoking. Remind family, friends, and coworkers that this is your quit day, and ask them to help
and support you. Avoid alcohol. Buy yourself a treat, or do something to celebrate.
Quit day plus 1: Congratulate yourself. When cravings hit, do something else that isn’t connected with smoking,
like taking a walk, drinking a glass of water, or taking some deep breaths. Call your support network. Find things
to snack on, like carrots, sugarless gum, or air-popped popcorn.
Adapted from the Surgeon General [126].
Table 7. – Some of the smoking cessation methods available
Massmedia and community programmes
Self-help
Educational (books and other material, e.g. from the Internet)
Brief clinical interventions (physician advice and counselling)
Clinics and groups
Voluntary agencies
Commercial programmes
Pharmacotherapy
Nicotine replacement
Chewing gum
Transdermal systems
Nasal spray
Inhaler
Bupropion
Behavioural
Hypnosis?
Acupuncture?
Modified from Rennard and Daugton [128].
J. BEHR, D. NOWAK
172
evidence-based health promotion driven by pulmonologists. Available methods are listed
in table 7.
The "baseline rate" of successful quitting on a particular attempt ranges between
0.5–3.0% [128]. Brief clinical interventions can be provided by any clinician and reveal an
increase in the odds of quitting (odds ratio (OR), 1.7; 95% confidence interval: 1.5–2.0),
equal to an absolute difference in the cessation rate ofy2.5% [129]. Pharmacotherapeutic
first-line drugs are nicotine (gum, inhaler, nasal spray, patch) and sustained-release
bupropion hydrochloride [130]. A meta-analysis of 53 randomised controlled trials of
nicotine replacement therapy in individuals motivated to quit smoking showed ORs
for gum of 1.6, for transdermal patch of 2.1, for nasal spray of 2.9, and for inhaled
nicotine of 3.1. These ORs were nonsignificantly higher in subjects with higher levels
of nicotine dependence but were largely independent of the intensity of additional
support provided or the setting in which nicotine replacement therapy was offered [131].
In a recent, randomised controlled study comparing the efficacy of sustained-release
bupropion, a nicotine patch, or both for smoking cessation, the authors reported
12-month point (cumulative) prevalence abstinence rates of 15.6% (5.6%) in the placebo
group compared with 16.4% (9.8%) in the nicotine patch group, 30.3 (18.4%) in the
bupropion group, and 35.5 (22.5%) in the group given nicotine patches and bupropion
[132]. Thus, although smoking cessation is obviously the best strategy for eliminating
the health risks associated with smoking, the outlined strategies are effective only in a
minority of patients. Since smoke-free environments, advertising bans and price increases
have been demonstrated to be effective measures in many countries, primary prevention
and cessation strategies should be combined on a large-scale sociomedico-political scale
in order achieve better health.
Summary
During the 20th century, cigarette smoking has become a mass phenomenon. Within
the last 30 yrs, cigarette consumption per adult has remained stable in Europe,
decreased in America and increased in all other regions, particularly in the Western-
Pacific region. Smoking status is believed to be largely a function of genetic and
sociodemographic factors, environmental determinants, behavioural factors and
specific dimensions of personality.
Cigarette smoke is a heterogenous aerosol produced by incomplete combustion of the
tobacco leaf. More than 4,000 substances have been identified in cigarette smoke,
including some that are pharmacologically active, antigenic, cytotoxic, mutagenic, and
carcinogenic. Out of the different effects that tobacco smoke exerts on the respiratory
tract, this chapter focused on two main mechanisms: firstly, induction of inflamma-
tion; and secondly, mutagenic/carcinogenic effects.
The most relevant tobacco-associated diseases of the respiratory system are chronic
obstructive pulmonary disease (COPD) and lung cancer. COPD, being the sixth most
common cause of death in 1990, will advance to third place worldwide in 2020.
The pathogenesis of smoking-related COPD includes the protease-antiprotease and
oxidant-antioxidant hypotheses and abnormal repair processes. Lung cancer has
become the most common type of lethal cancer throughout the world. By 2020, it will
advance to the fourth most common cause of death in developed countries and to the
fifth most common worldwide. Additionally, it has recently been suggested that a
number of interstitial lung diseases are positively associated with tobacco smoking
(i.e. usual interstitial pneumonia, desquamative interstitial pneumonia, respiratory
TOBACCO SMOKE AND RESPIRATORY DISEASE
173
bronchiolitis-associated interstitial lung disease, connective tissue disease-associated
interstitial lung disease, and pulmonary Langerhans’ cell histiocytosis).
There is scientific consensus that cigarette smoking is an addiction to the drug
nicotine, with 70% of smokers reporting that they would like to quit. Thus, smoking
prevention and smoking cessation should be crucial issues in evidence-based health
promotion driven by pulmonologists. Brief clinical interventions can be provided by
any clinician and reveal an increase in the odds of quitting, and the efficacy of
pharmacotherapeutic intervention with nicotine and bupropion have been consistently
demonstrated. Furthermore, smoke-free environments, advertising bans and price
increases are effective measures in many countries.
Keywords: Chronic obstructive pulmonary disease, interstitial lung disease, lung
cancer, oxidants, smoking cessation, tobacco smoke.
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