CME Article
Effects of early cigarette smoke exposure on early immune development and respiratory disease

https://doi.org/10.1016/j.prrv.2007.11.004Get rights and content

Summary

Exposure to tobacco constituents during early development remains a common but avoidable toxic exposure, which has been clearly linked with decreased lung growth and subsequent wheezing illness. There is also now emerging evidence that tobacco smoke can influence early immune function. This includes alterations in cytokine production by the fetoplacental unit, as detected ex vivo in cord blood, as well as in patterns of fetal mononuclear cell responses in vitro. Recent studies also suggest that the newborns of smoking mothers have altered signalling through Toll-like receptors (TLRs) that are essential for innate microbial responses. This may be implicated in the increased predisposition to infection in exposed infants. TLR-mediated innate response pathways are also believed to be important in promoting regulatory pathways that inhibit allergic immune responses. However, although a number of studies have documented associations between early cigarette smoke exposure and subsequent allergic disease, this remains controversial. This review explores the consequences of smoking on these important aspects of early development, including potential mechanisms, interactions with predisposing asthma genes and a potential role in epigenetic regulation. Although parental smoking may not be the primary factor in the changing prevalence of asthma and respiratory disease, we propose that it is an important contributor, with significant potential to interact with other genetic factors and environmental risk factors to influence disease propensity.

Section snippets

Effects of environmental tobacco smoke exposure on early development

A large body of literature now links both prenatal (maternal) smoking and environmental tobacco smoke (ETS) exposure in early childhood to decreased lung growth6, 7, 8 and increased rates of respiratory tract infections,9 otitis media10, 11, 12 and childhood asthma.13 Sudden infant death syndrome,14 behavioural problems15 and neurocognitive decrements16 are also associated with parental smoking in this early period. The effects of exposure to cigarette smoke on other aspects of health and

Effects of maternal smoking on infant respiratory disease

Both in utero and postnatal exposure to tobacco smoke have been identified as risk factors for subsequent altered lung function. The effects of maternal smoking in pregnancy, as well as postnatal ETS exposure, have been reviewed recently by DiFranza et al.17 especially in relation to chronic childhood respiratory problems. At this stage, the exact mechanisms for reduced lung function and increased respiratory pathology in children exposed to tobacco smoke early in life remain unclear.18

Evidence that maternal smoking affects immune function in the feto-placental unit

The placenta is the major source of cytokines and other immune mediators detected in the fetus32, 33 and therefore has enormous potential to influence fetal immune development. As the immunologically active interface between the fetus and the mother, the placenta is vulnerable to these and other maternal influences, and has significant capacity to modulate the effects of these on the fetus. Placental cells are also likely to be sensitive to adverse environmental exposures that may affect

Initial evidence that maternal smoking has effects on neonatal immune function

Early studies noted that parental smoking is associated with higher cord blood immunoglobulin E (IgE) levels.39 Because IgE does not cross the placenta, this provided preliminary evidence of a direct effect of maternal smoking on foetal immune function. More recently, Devereux and colleagues observed that maternal smoking is associated with stronger neonatal lymphoproliferation,40 but the effects on cytokine responses were not investigated. We also previously noted that maternal smoking in

Effects of maternal smoking on innate immune function

In our more recent studies, we explored the hypothesis that maternal smoking may also have effects on neonatal innate immune function, namely Toll-like receptor (TLR) function. These pathways are implicated in susceptibility to respiratory infection as well as in the potential regulation of allergic responses. To address this, we compared innate immune function in the neonates of women who smoked in pregnancy (n = 58) with that in the neonates of non-smokers (n = 59). Cotinine levels in maternal

Possible pathways of influence: immune effects of oxidative stress?

Cigarette smoke is a major source of free radicals and oxidative stress.49 Recent studies have identified the smoking-induced disruption of oxygen-related responses that are known to play a key role in placental cytotrophoblast proliferation and differentiation during critical early stages of placental development.34 Most notably, effects were also seen when women were passively exposed to tobacco smoke.34 Foreseeably, these disruptions in antioxidant systems could lead to further disruptions

Molecular targets: effects on transcription factors?

The production of inflammatory cytokines is mediated through transcription factors such as nuclear factor-kappaB (NF-kB) and activator protein-1 (AP-1).54, 55 In vitro studies demonstrate that cigarette smoke extracts reduce pro-inflammatory lipopolysaccharide (LPS)-induced TLR4 signalling by inhibiting transcription factors.31, 38 More recently, a major constituent of cigarette smoke (acrolein) has been shown to suppress the epithelial production of inflammatory chemokine IL-8 through a direct

Effects of postnatal tobacco smoke exposure on mucosal immune development

In the early postnatal period, passive smoking may also influence local immune development directly through pro-inflammatory effects at mucosal surfaces. As the main point of initial contact with the environment, the mucosal immune system has enormous potential to influence the development of systemic immune responses and disease expression.57 In addition to protection from infection, mucosal responses may influence local allergen processing and events at the regional lymph nodes.58

Foreseeably,

The relationship between early cigarette smoke exposure and the development of allergic disease

Although maternal smoking in pregnancy has been associated with an increased risk of early-onset wheezing and reduced lung function is well described,20, 63 the relationship with subsequent atopic risk has been more controversial. A number of studies have linked parental smoking with markers of atopy in children,64, 65 including serum IgE levels,66, 67, 68, 69, 70 eosinophilia69, 71 and positive skin-prick tests.72 Despite this, a systematic review by Strachan and Cook in 199873 did not find

The role of early smoke exposure in genetic predisposition to asthma

The adverse immunological (and other) effects of cigarette smoke are likely to depend on genetic susceptibility. Genetic studies on the effect of pollutants in asthma and allergic diseases have focused on genes that are likely to play a role in either inflammation or antioxidant protection. In humans, glutathione S-transferase (GST) antioxidant genes are the best studied in this context.76 Children with the GSTM1-null genotype born to mothers who smoked during pregnancy have an increased

The role of smoking in epigenetic predisposition to asthma

The epigenetic regulation of gene expression is a dynamic process, which confers the ability to change and adapt in response to developmental and/or environmental cues. This is mediated through the post-synthetic modification either of the DNA itself (e.g. by methylation)80 or of proteins that intimately associate with DNA (e.g. acetylation, methylation or phosphorylation of histones).81 In the context of allergic disease, two recent reviews have argued that epigenetic mechanisms responding to

Conclusion

There is good evidence that early exposure to cigarette smoke is a significant independent risk factor for subsequent respiratory disease. It is likely that in utero damage is compounded by increased susceptibility to the effects of continued postnatal smoke exposure. Genetic studies confirm that smoking interacts with asthma susceptibility genes as a critical factor determining disease risk. In addition to effects on developing airways, maternal smoking in pregnancy appears to have effects on

Research directions

  • Clarify the interactions between tobacco smoke exposure and genetic and epigenetic factors in the development of respiratory and immunological disorders

  • Study further the effects of tobacco smoke on dealing with oxidative stress

Key points

  • Effects of maternal smoking on immune development provide further evidence of effects on the fetus and newborn to promote avoidance of smoking

  • In utero exposure is compounded by continuing exposure after birth

Educational aims

  • To discuss how tobacco smoke can influence the maturation of both the adaptive and the innate immune system.

  • To highlight the fact that the role of exposure in the development of subsequent allergic disease is controversial.

  • To explain how exposure to tobacco smoke interacts with genetic susceptibility genes.

  • To examine how the effects on immunity are important contributors to respiratory disease.

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Acknowledgements

We wish to acknowledge the staff and patients who assisted in our studies. We are particularly grateful to the obstetricians and midwives at King Edward Memorial Hospital and St John of God Hospital, Subiaco, Western Australia. Professor Prescott is funded by National Health and Medical Council (of Australia).

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