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CURRENT TOPICS

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UDC: 612.017.1:616.24-007.272

The effect of tobacco smoke ingredients on immunity with special

reference to chronic obstructive pulmonary disease
Uticaj sastojaka duvanskog dima na imunski sistem sa posebnim osvrtom na
hroninu opstruktivnu bolest plua
Ljudmila Nagorni-Obradovi, Vesna kodri-Trifunovi,
Tanja Adi, Dragica Peut
Clinical Center of Serbia, Institute of Pulmonary Diseases and Tuberculosis,
Belgrade

Key words:
tobacco; immunity; immunologic factors; lung
diseases, obstructive.

Introduction
Tobacco smoke consists of several thousand toxic and
carcinogenic substances 1. Ingredients of tobacco smoke
have numerous extremely harmful effects on human health
and are related to the occurrence of various diseases such as
respiratory infections, chronic obstructive pulmonary disease
(COPD) and lung cancer 2. The insreased incidence of these
diseases in smokers is possibly caused by the effects of tobacco on the function disorder of the immune system.
Whereas the acute effect of smoking on the function of the
immune system is less known, chronic exposure to tobacco
ingredients causes a decreased function of T-lymphocytes 3.
Nowadays it is considered by the World Health Organization (WHO) that smoking cessation is the single most effective and cost effective way to reduce exposure to COPD
risk factors 4.
Tobacco smoke might affect the function of the immune system 5. Numerous studies in vitro and in vivo have
demonstrated so far that there is an immunosuppresive effect
of tobacco smoke on T and B-lymphocytes 6, 7.
During smoking, a smoker inhales both the smoke and
the particles. Among the particles inhaled, a thousand of ingredients are taken in the most important of which are nicotine, various carcinogenes, metals and others. Nicotine is the
main immunosuppressive ingredient of tobacco smoke 6.
Numerous investigations have demonstrated that tar and
nicotine have an extremely toxic effect on the immune system 6. The effect of tobacco smoke ingredients on immunity
depends on the doses of substances, as well as on the duration of exposure.

Kljune rei:
duvan; imunitet; imunski faktori; plua, opstruktivne
bolesti.

Investigations of effects of tobacco smoke on the

function of the immune system
Various experimental investigations have been carried
out warning that smoking imposes the occurrence of various
diseases due to an impaired function of the immune system 6, 8. Numerous investigations have also been carried out
to explain this phenomenon 6, 7.
Active smokers suffer from influenza more frequently
and have the lowest concentration of antibody titre against
influenza virus 9, 10. In order to recognize the difference in the
immune responses of smokers and non-smokers, their reactions in the production of antibodies after vaccination against
hepatitis B virus (VHB) have been studied 11. Active smokers have a significantly lowered immune response to the applied vaccine than non-smokers, because their production of
antibodies against VHB is significantly lower than in nonsmokers. A significant effect of the intensity of smoking on
the function of the immune system has been confirmed.
The first exposure to cigarette smoke might start in
utero, when a fetus is exposed to bloodborne metabolites
from a mother. Neonates and infants might be exposed passively to tobacco smoke at home if a sibling smokes. Children under 2 years, who are passively exposed to cigarette
smoke, have an increased prevalence of respiratory infections and are at a greater risk for developing chronic respiratory symptoms later in life 12.
By investigating concentrations of immunoglobuline in
the blood of children, the effect of smoking parents on the
immunity of children, exposed to tobacco smoke at home, is
studied at the same time 13. It has been proven that the chil-

Correspondence to: Ljudmila Nagorni-Obradovi, Clinical Center of Serbia, Institute of Pulmonary Diseases and Tuberculosis,
Viegradska 26/20, 11 000 Belgrade, Serbija. Tel. +381 11 363 5451.

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dren whose parents are smokers have a disbalance in the

function of the immune system with a significantly lowered
production of total immunoglobuline G (IgG) as compared
with those whose parents are non-smokers. Studies have not
confirmed, however, a significant effect of passive smoking
on the concentration of other immunoglobulins. The survey
of parents who were active smokers have shown that their
children have more frequent respiratory and alergic diseases
than the children who live in the environment without tobacco smoke 13.
Active smokers maight have the decreased values of serum immunoglobulins except for IgE which has an increased
concentration 14.
There is a higher risk of contracting infections with
human immunodeficiency virus (HIV) in active smokers
than in non-smokers 15.
The mechanism of the action of ingredients of tobacco
smoke on immunity has not been fully explained yet.
There is a close link between the functions of the neuroendocrine and immune systems because they both receive
signals through substances such as cytokines and hormons
which act as neurotransmitters and exert influence on the
receptors of both systems. Nicotine from the air ways is
quickly absorbed by the lung circulation and then passed
through the brain barrier and got into the central nervous
system (CNS). It is a classical sympathicoadrenal stimulant.
There are several explanations for the communicaton of
the immune and nervous systems, but the most acceptable
one is through the hypothalamus hypophysis adrenal axis
16
. Nicotine stimulates this axis tagether with the production
of corticotropic releasing hormone from the hypothalamus
which results in a faster secretion of adrenocorticotropic
hormone (ACTH). Tobacco smoke and nicotine increase the
concentration of norepinephrine and epinephrine in plasma.
ACTH together with kateholamines show an inhibitory influence on the immunological response of the organism. On
the other hand, activating nicotine receptors in the brain,
stimulates the function of the autonomic nervous system,
which then affects the function of visceral organs including
the lymph nodes, as well. Noradrenaline from the sympathetic part of the nervous system has influence on adrenoreceptors of T-lymphocytes. The effect of parasympathetic
nervous system on the function of T-lymphocytes is still not
explained well enough. Investigations showed that tobacco
smoke canses the disfunction of both T- and B-lymphocytes 6, 7.
The effect of tobacco smoke ingredients on
immunity in patients suffering from chronic
obstructive pulmonary disease
In recent years attention has been particularly focussed
on the appearance of immunosuppression of the organism
after active and passive smoking 11, 13.
Smoking is an important risk factor for the occurrence
of various lung diseases, the most serious among them being
COPD 2.

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Investigating bronchoalveolar lavate (BAL) in smokers suffering from COPD and asthma, has revealed that
there is an increased number of alveolar macrophages and
neutrophil leukocytes 17. Compared with non-smokers, alveolar macrophages of smokers seem to be active in terms
of showing the ability of secreting microsomal and lysosomal enzymes, an increased production of oxygen radicals
and activation of myeloperoxidase, as well as an increased
migration and haemotaxic response. However, in spite of
the cited functions, the alveolar macrophage of a smoker is
extremely deficient in phagocytosis and/or bactericidal
function which greatly affects the immune response of the
host 18.
Smoking stimulates aggregation of alveolar macrophages but significantly diminishes their function. Macrophages have an important role in immune response because
of their different activites, among which the most important
are phagocytosis, haemotaxis, preparation and presentation
of antigens for B- and T-lymphocytes. These cells can secrete hydrolytic enzymes, products of oxygen metabolism,
cytokines: interleukin 1 ( IL-1) and interleukin 6 ( IL-6),
metabolites of arachidonic acid, tumor necrosis factor alpha
( TNF- ) and others. A reduced degree of phagocytosis of
alveolar macrophages in smokers is connected with a decreased response of the immune system and inadequate defence against various respiratory infective agents 18. An increased number of alveolar macrophages and neutrophil leukocytosis in smokers causes inflammation in mucous walls
of the airways. The following products, collagenase and
elastase, are also released from these cells and they lead to
the destruction of alveolocapillary membranes which is
clinically manifested as pulmonary emphysema, or they can
cause chronic obstructive bronchitis because of the increased
production of mucus in the airways 16.
It has ben noted that in smokers there is an increased
level of CD8 T-lymphocytes in relation to non-smokers 1921.
Histopathological investigations of bronchial biopsy have
shown that the number of T-lymphocytes, especially CD8
cells (cytotoxic cells), is increased in smokers with
COPD 22, 23. The role of these cells in the occurrence of inflammation in this disease is not yet fully explained. These
cells can partly contribute to the development of COPD because of the release of perforins, granyme-B and TNF-,
which cause cytolysis and apoptosis of epithelial alveolar
cells, which is all responsible for continuation of inflammation.
The results of histopathological investigations of bronchial biopsy, BAL, and induced sputum have shown an increased number of alveolar macrophages in small and large
airways in smokers. These cells act as a conductor in the development of inflammation, on the basis of the release of
various mediators such as TNF-, interleukin 8 (IL-8), and
leukotrien B4 (LTB4), which provoke the development of
neutrophil inflammation 24. Tobacco activates macrophages
and epithelial cells to produce TNF- which stimulates gene
8 for IL-8, which leads to the accumulation and activation of
neutrophils. This process takes place by means of the activation of transcription factor-kB (NF-kB).
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Under the influence of tobacco inflammatory cells are

activated and they release various mediators. Among them are
powerful proteinases, oxydants and toxic peptides 25. These
mediators are capable of destructing the lung structure in patients with COPD and/or maintain neutrophil inflammation.
There is increasing evidence that an oxidant/antioxidant
inbalance, in favour of oxidants, occurs in COPD 24, 25. Tobacco smoke is one of the well-known risk factors for oxidative stress in smokers. Markers of oxidative stress have been
found in the epithelial lining fluid, breath and urine of cigarette
smokers and patients with COPD. Hydrogen peroxide (H2O2)
and nitric oxide (NO) are the direct measures of oxidants generated by cigarette smoking or released from inflammatory
leukocytes and epithelial cells. Oxidative stress contributes to
COPD in the variety of ways. Oxidants can react with, and
damage, a variety of biological molecules, including proteins,
lipids and nucleic acids and this can lead to cell dysfunction or
death, as well as to damage the lung extracellular matrix. Oxidative stress contributes to the proteinase-antiproteinase imbalance by inactivating antiproteinases, such as alpha-1 antitrypsin. Oxidants also promote inflammation.
Figure 1 shows the influence of tobacco smoke on activation of macrophages, neutrophils and epithelial cells which
produce mediators of inflammation 26.

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The presence of macrophages, neutrophils, eosinophils

and T-lymphocytes is different in healthy people, smokers or
sufferers from COPD and asthma 26. Therefore a significant
increase of neutrophils was noted in smokers in relation to
non-smokers, and the number of these cells is even greater in
smokers suffering from COPD (p < 0.05).
It has been noticed that the number of CD8 lymphocytes in smokers is in negative correlation with forced expiratory volume in the first second (FEV1) 22. We have already
said that in smokers the number of CD8 lymphocytes tends
to increase which is connected with the decrease of FEV1
value.
Conclusion
Various ingredients of tobacco smoke and nicotine in
particular, can influence immunity. Smoking leads to immunosuppression of T- and B-lymphocytes as well as to disturbed function of alveolar makrophages, in the form of decreased phagocytosis. Tobacco smoke stimulates alveolar
makrophages, neutrophils to release the mediators of inflammation which can damage the lung structure of smokers
suffering from COPD or asthma.

Fig. 1 Cigarette smoke activates macrophages in the respiratory tract that release neutrophil chemotactic factors, icluding IL-8 and LTB4 . These cells then release proteases
that break the down connective tissue in the lung parenchyma, resulting in emphysema,
and also stimulate mucus hypersecretion. These enzymes are normally counteracted by
protease inhibitors, including 1-antitrypsin (1-At ), secretory leucoprotease inhibitor
(SLPI), and tissue inhibitor of MMPs (TIMPs). Cytotoxic T cells (CD8=) may also be involved in the inflammatory cascade.

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