Environmental Tobacco Smoke Exposure and ... - Ingenta Connect

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Inflammation & Allergy - Drug Targets, 2009, 8, 340-347

Environmental Tobacco Smoke Exposure and Airway Hyperresponsiveness Dale R. Bergren* Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska, USA Abstract: Environmental tobacco smoke (ETS) exposure is a common health concern despite legislation to limit its presence, especially in public environments. ETS exposure is associated with changes in lung development and morphology, airway hyperresponsiveness and obstruction and development of asthma and its increased severity. However these effects of ETS exposure are not universally supported. Clinical data as well as studies in laboratory animals report ETS exposure may even attenuate airway hyperresponsiveness (AHR). Therefore, we lack complete understanding of ETS effects on pulmonary function as well as its mechanism of action. Disparate clinical and laboratory reports likely result from variables of ETS exposure, degrees of atopy and mechanisms of sensitization. The present review addresses the effects of ETS on AHR reported in humans and animal models. ETS role as an adjuvant to AHR as well as it contribution to development of antigenic tolerance is also reviewed. Possible neurogenic, cellular and intracellular mechanisms of ETS-induced ARH are proposed based on the existing literature. Enhanced understanding of the effects and mechanism of ETS will enhance therapy strategies in treatment of ARH and related disease such as COPD as well as enhancing public presentation of convincing evidence to avoid ETS.

INTRODUCTION Over 4000 chemicals have been identified within tobacco smoke (TS). An analysis of ETS carcinogenic and respiratory toxin constituents is recently reviewed by Flouris et al. [1]. This complexity contributes to current issues involving ETS-induced airway hyperresponsiveness (AHR). Mainstream (MS), sidestream (SS), passive, active and environmental tobacco smoke (ETS) exposure further complicate interpretation of data from existing studies. Environmental TS contains both MS and SS TS. The composition and toxicity of MS and SS smoke differs. SS condensate more likely produces tumors than MS condensate assessed by dermal application [2]. SSTS toxicity increases with time as nitrosamines increase in room air. Therefore, methods of TS delivery contribute to disparities in the literature on the adjuvant, inflammatory and AHR properties of TS. Indeed ETS exposure with low versus high nicotine produces differing airway inflammation [3]. These issues, as well as length of exposure and individual responsiveness, have resulted in the divisiveness of the literature. This review will discuss the effects of ETS in both humans and animal models demonstrating AHR. Paramount to the present discussion is whether or not ETS acts as an adjuvant to allergens. Should ETS act as an adjuvant, what is its mechanism of action? Which inflammatory cells, cytokines or chemokines participate in the induction of AHR? Finally, is neurogenic inflammation important in ETS induced AHR? If this is so at what level(s) does the autonomic nervous system demonstrate plasticity, i.e. enhanced neuropeptide release, neuron responsiveness, central integration, efferent trafficking and/or the effector cell responsiveness such as airway smooth muscle? Further research in these areas will improve therapeutic strategies for diseases involving AHR induced by agents such as contained in ETS.

*Address correspondence to this author at the Department of Biomedical Sciences, School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA; E-mail: [email protected] 1871-5281/09 $55.00+.00

DOES AIRWAY HYPERRESPONSIVENESS RESULT FROM ENVIRONMENTAL TOBACCO EXPOSURE IN HUMANS? Despite intense research activity, links between ETS exposure and induction of AHR and asthma remain controversial. Nonetheless many studies establish an association between ETS exposure and increases serum immunogloubin E (IgE) and AHR [4-16]. ETS exposure is a likely adjuvant for antigenic sensitization [16]. Children exposed to ETS are at increased risk of developing asthma [9-14]. Similar results have been reported in adults [4, 15]. ETS exposure triggers acute asthmatic symptoms in some individuals. Mechanisms of induction and progression of ETS-induced AHR are however, poorly understood. Smokers with asthma experience more severe respiratory symptoms and are more likely to be admitted to hospital due to poorly controlled asthma than nonsmokers with asthma. A likely contributing factor is an impaired steroid efficacy that occurs with ETS exposure at least in some individuals. Cigarette smokers with asthma are less sensitive to either oral or inhaled corticosteroids than never-smokers with asthma as assessed by changes in lung function and asthma symptoms [17-25]. The mechanism of corticosteroid resistance in smokers with asthma is currently unexplained but could be due to alterations in airway inflammatory cell phenotypes or structural changes in glucocorticoid receptors such as a change in to receptor ratios [24]. Recent studies demonstrate that even limited ETS exposure of one hour alters pulmonary function in healthy young adults by decreasing the FEV1 and FEV1/FVC [26]. In addition serum analysis reveals increases in IL-5, IL-6 and INF-. Interestingly, IL-1, IL-4 and TNF- increased only in males. Furthermore sexual dimorphism occurs with regards to metabolism as well. ETS exposure increases free thyroxin in men and decreases T3/thyroxin [27, 28]. However, other studies fail to establish an association between ETS exposure and AHR or report that ETS exposure is not a risk factor for the development of AHR © 2009 Bentham Science Publishers Ltd.

Environmental Tobacco Smoke Exposure and Airway Hyperresponsiveness

Inflammation & Allergy - Drug Targets, 2009, Vol. 8, No. 5

though some of these studies concede that active smoking increases asthma severity [29-32]. In addition asthma-like symptoms have developed in asymptomatic individuals after smoking cessation [31]. Curiously, the incidence of asthmatic and non-asthmatic individuals who smoke cigarettes is similar [4, 25].

with carbachol aerosol challenge in this study. In recall experiments of OVA aerosol challenges for 30 minutes on 3 consecutive day conducted 3 weeks after treatments ceased, only serum IgE and goblet cells were elevated.

ANIMAL MODELS OF AIRWAY SENSITIZATION AND TS EXPOSURE To elucidate the effect of TS exposure on AHR numerous investigations have been conducted in dogs, rats, guinea pigs and mice. In animal models ETS exposure is reported to induce antigen sensitization, AHR, airway inflammation and remodeling [33-41]. However, TS-induced antigenic tolerance and depressed AHR are also reported and is discussed below. Regarding development of antigenic tolerance, possible etiological advantages of this effect to the individual are that immune mediated tolerance may circumvent unnecessary inflammation. Allergic immunotherapy utilizes the activation of immunesuppressive mechanisms to induce antigen tolerance and may share mechanisms of ETS induce-antigen tolerance. Variables such as methods of ETS exposure, species, strains and time of variable assessment have complicated the interpretation of the literature data in animal models of ETSinduced AHR. Recent studies conducted in mice concerning ETS as an adjuvant utilizing the availability of genetic manipulation is also not without data disparity. ETS AS AN ADJUVANT AND DELAYED ANTIGENIC TOLERANCE Certain TS constituents could be adjuvant to allergic sensitization. For example, lipopolysaachride (LPS) or endotoxin is a component of TS and is a potent adjuvant [42]. Due to the complexity of TS other constituents may also be an adjuvant to antigen sensitization of the airways. The possibilities require investigation as numerous studies support that TS is an adjuvant to antigenic sensitization. In adult BALB/c mice, MSTS induces airway inflammation that is clearly Th-2 driven with increases in IgE, IgG1, eosinophils, and Th2 cytokines [33]. Rumold et al. [34] demonstrated that the combination of ETS and OVA exposure in adult C57BL/6 mice, which are “low IgE responders,” induced increased serum OVA specific and total IgE and increased BALF eosinophils, neutrophils, IL-2, IL-5 and GM-CSF [33]. In BALB/C mice, which are “high IgE responses,” TS exposure alone transiently increased serum IgE and with prolonged OVA+TS exposure inducing elevated IgE levels. In neonatal BALB/c mice treated with OVA, ETS exposure increased eosinophils, IgE and IgG1 in serum with females being more sensitive [35]. Moerloose et al. [43] also report that in adult BALB/c mice, IgE and IgG1 in serum increased with OVA+TS treatment (4 exposures/day/3 weeks). In lung tissue OVA+TS increased eosinophils, lymphocytes, DCs and goblet cells. In BALF TRAC was increased, an important chemokine for eosinophilia, as was IFN- which is a TH1 cytokine. IFN- has been reported to be depressed by ETS exposure in other studies [33]. In the analysis of lymph node cell culture OVA+TS increased IL-5 and eosinophils compared to other treatments. However, no AHR occurred

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In 2008 Van Hove et al. [44] using male CB75BL/6 mice studied the effect of combined OVA and MSTS (5 2R4F cigarettes without filter/d/5d/wk) exposure on antigenic tolerance. After 4 weeks of exposure ETS delayed antigenic tolerance compared to OVA exposure alone. ETS alone increased BALF leukocytes, macrophages, neutrophils and lymphocytes. In OVA+TS exposed mice recall of Th-2 airway inflammation did not occur nor did eosinophilia after 8 weeks of combine OVA+ETS exposures. Neutrophilia, TARC and histological indices of airway inflammation were less in OVA-ETS exposed mice compared to 2 weeks ETS exposure. Additionally once antigenic tolerance developed to OVA with ETS exposure, no Th2 driven airway inflammation could be mounted to a secondary antigen sensitization. In summary OVA+ETS enhanced TH-2 induced inflammation and delayed antigenic tolerance. Trimble et al. [45] studied the adjuvant and inflammation effects of prolonged ETS exposure to OVA in BALB/c mice. The variables of the TS exposure were 12 2R4F cigarettes over 50 minutes (5d/wk for 2 weeks) with OVA challenge. In the first series variable analysis was conducted 72 hours after last TS exposure. TS exposure increased BALF eosinophilia and CD69+ T cells but decreased neutrophilia. No difference was observed in these variables with serum analysis among experimental groups. In a second series, 7 weeks of TS exposure preceded the simultaneous OVA+TS exposure. TS exposure increased DCs, CD69+ T cells, OVA-specific IgE and IgG1, eosinophila and goblet cell hyperplasia. With long term exposure (9 wks), BALF eosinophilia increased and neutrophilia decreased. Only OVA+TS exposure resulted in goblet cell hyperplasia. A mechanism for TS airway sensitization may involve GMCSF. Administration of anti-GM-CSF neutralizing antibody decreased variables of airway inflammation. These authors conclude that although TS acts as an adjuvant to allergic sensitization it also attenuates inflammation with time. This study also demonstrated robust antigen memory with eosinophilia and expression of OVA-specific IgE and IgG1 in OVA+TS exposed mice rested for 3 weeks prior to a week of combined OVA-TS exposure. Suppressed versus robust antigenic recall in above 2 studies [44, 45] are difficult to reconcile. However an explanation might be that in the studies of Van Hove et al. [44] the mice were male and CB75BL/6. Both variables could have suppressed a recall OVA response compared to the studies of Trimble et al. [45]. ETS contains chemicals that induce antigenic mechanisms. Dendritic cells (DCs) are believed to function as potent antigen presenting cells activating T-cell immunity. DCs also secrete chemotactic factors for macrophages, neutrophils and more DCs. In addition DCs induce and maintain eosinophilic inflammation that is necessary for maintaining the Th2 phenotype. Contiguous networks of DCs underlie the airway epithelial surface to process antigens and transport antigenic signals for presentation to T cells in bronchial lymph nodes. ETS likely affects DC function. Nicotine in tobacco smoke is believed to depress

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Dale R. Bergren

DC numbers and function in humans and mice [46-49]. Data suggest TS-exposed DCs induces over-expression of cytokines such as GM-CSF thereby delaying antigen tolerance [50]. These actions may then contribute to establishment of the Th-2 phenotype [51]. TS-exposed mice (2 cigarettes/d, 5 d/wk for 2-4 mo.) decreased DCs in lung tissue and CD4 and CD8 T cell expansion in mice inoculated with adenovirus [52] thereby enhancing successful opportunistic infection.

clinical observations. They also conclude that systemic biomarkers of inflammation do not necessarily predict pulmonary inflammatory responsiveness. In a study utilizing 3 different mice strains, nose only OVA exposure and ETS failed to induce sensitization [55]. A/J mice produced detectable levels of ovalbumin-specific immunoglobulin IgE, both A/J and BALB/c mice produced ovalbumin-specific IgG1 antibodies while C57Bl/6 mice did not produce detectable antibody levels. No mouse strain developed AHR in that study to ovalbumin challenge.

Indeed, chronic TS exposure can facilitate antigenic tolerance. Robbins et al. [53, 54] report attenuated antigenic reactivity in mice exposed to MSTS. Although spleenocyte cytokine production increased, certain variables of the pulmonary immunological reaction decreased compared to sensitized mice not exposed to ETS [53]. TS exposure decreased AHR to MCH and IgG2a, eosinophils, neutrophils, CD69+ Th2 cells levels in BALF. Dendritic and B cells and CD4, CD3/CD4+, T1ST2 TH2 associated makers also decreased that may explain suppressed leukocyte recruitment into the lungs with TS+OVA exposure [54]. On the other hand IL-4, 5 and 13 increased in these ETS+OVA treated mice. Robbins et al. conclude the results “echo” Table 1.

Melgert et al. [56, 57] report BALF eosinophils were decreased in response to ETS exposure in mice. AHR to carbachol challenge was not demonstrable in this study. As the authors suggest the method of immunization used may have been weaker than routinely used system antigenic presentations. Also retention of AHR to OVA aerosol challenge after a 3 week hiatus was lost. Only airways goblet cell numbers remained increased in the OVA+ETS group. A summary of the effects of ETS on variables of AHR and inflammation based upon the studies presented above is presented in Table 1.

Effects of TS on Pulmonary Variables in OA-Sensitized Mice*

Strain, Ref.

Method

Th2 Ag AHR DC CD8+ CD4+ CytoSensitivity kines

Bowles, 4 strains

ETS

Melgert, C57BL/6

MSTS

Moorloose 2005, BALB/c

MSTS

Moorloose 2006,

MSTS

Robbins 2005 BLAB/c

MSTS

Robbins 2008, BALB/c

MSTS

Seymour, BABLB/c

ETS

Trimble, BALB/c

MSTS

Van Hove 2008, C57BL/6

MSTS

Singh##, BALB/c

Maternal TS

Blacquière

Maternal TS

Wu, ICR

Maternal TS

No

Th1 Cytokines

Oa-Specific Igs** Eos IgE A/J

Neu

Chemokines

Recall Histology

IgG 1: A/J, BALB/c

A/J

IFN

No

IFN

No

2a

No

IFN

No

*Versus groups with TS exposure alone; **IL4, 5,13; # delays tolerance; ## and personal communication.

no

TACR

no

GM-CSF

yes

TRAC

no#

ASM C-fibers, ASM



INTRACELLULAR MECHANISM OF ETS-INDUCED AHR

Guinea pigs at a concentration as low as 1 ppm [69]. Acrolein as well as other aldehydes in ETS likely cause irritation of sensory nerves in the airway. Neurogenic inflammation in guinea pigs is quite strong even in naïve individuals and intensifies with airway sensitization or chronic irritant exposure [37, 38].

The intracellular pathways affected by ETS is poorly understood. Recent investigations have provided some insight. Histone deacetylase is active in signal transduction and gene expression. Histone deacetylase activity is altered by ETS-induced oxidant stress through its tyrosine nitration and may be involved in the development of glucocorticoid insensitivity. TS exposure in mice increases tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced glucocorticoid sensitivity. Histone deacetylase 2 activity and the anti-inflammatory effects of glucocorticoids were restored in PI3K kinase knock-in but not PI3K knock-out smoke-exposed mice compared with wild type mice [58]. Therefore, therapeutic inhibition of PI3K may restore glucocorticoid sensitivity resulting from TS exposure in asthmatic individuals. ETS EFFECTS ON AIRWAY SMOOTH MUSCLE: RAT RESPONSIVENESS AND INTRACELLULAR MECHANISMS Effects of ETS exposure in rats are similar to those in mice. ETS in rats is an adjuvant to IgE phenotype switching to an otherwise harmless substance [59]. ARH to MCh occurs in TS-exposed rats [60]. In addition ETS exposure induces in vitro airway remodeling in rats [61]. Few reports exist on the effect of ETS on airway smooth muscle contractility. In a recent study, isolated rat bronchial smooth muscle was exposed to dilute MSTS in vivo 2 hours per day every day for 2 weeks [62]. Variable assessment was conducted 24 hours after the final ETS exposure. ETS exposure increased Ca2+-dependant ACh smooth muscle contraction. Responsiveness to high K+ depolarization was unchanged however. Therefore mechanisms of AHR regarding airway smooth muscle may specifically involve calcium metabolism. RhoA is a binding protein on GTP molecule of the cell membrane. Its downstream target is Rho-kinase which may augment Ca2+ sensitization of ASM. RhoA expression is enhanced by ETS exposure in rats [63] and in sensitized mice as well as [64]. The evidence available suggests that RhoA-mediated Ca2+ sensitization of ASM is involved, at least in part, in AHR resulting from TS exposure. How this may occur is unknown although reactive oxygen species (ROS) may trigger up-regulation of RhoA expression. ETS exposure increases ROS in the lungs. These agents likely not only induce airway damage but also AHR. There are probable numerous pathways affected by ROS. Although not review here, antioxidants appear to attenuate the injurious effects of ETS exposure. NEUROGENIC INFLAMMATION VIA CENTRAL AND LOCAL REFLEXES: ETS EXPOSURE IN GUINEA PIGS Tobacco smoke exposure in guinea pigs induces enhanced airway and smooth muscle hyperresponsiveness, increases airway permeability and other variables of inflammation [65-67]. ETS exposure in guinea pigs is also a powerful adjuvant prolonging antigenic airway sensitization [68]. ETS contains numerous irritants including acrolein, an unsaturated aliphatic aldehyde, causing AHR to ACh in

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AIRWAY SENSORY NERVE ACTIVATION: C-FIBERS USING GUINEA PIGS AS A MODEL The sensory receptors in the airways mediating neurogenic inflammation are thought to be lung C-fibers. Activation of the sensory receptors increase afferent vagal tone to centers in the nucleus tractus solitarius (NTS) and local or so called axon reflexes [70]. Collateral tracks of the C-fibers once activated release neuropeptides contributing to local inflammation. ETS exposure may release neuropeptides locally by activating C-fibers that synthesize and release these potent agents. Other possible mechanisms included impaired neuropeptide metabolism and/or enhance neuropeptide release. Chronic ETS exposure can induce AHR mediated by Cfiber activation particularly with antigenic sensitization of the airways. AHR and increased secretions and plasma extravasation occur in asthmatic individuals exposed to ETS as well as other inhaled irritants. Defense reflexes attributed to lung C-fiber activation are bronchoconstriction, increased airway secretions, vasodilatation, and localized edema [70, 71]. Both centrally mediated and local axon reflexes are thought to induce these effects, with the latter involving release of neuropeptides such as substance P and neurokinin A from C-fibers. Daily ETS exposure enhances C-fiber and AHR to capsaicin and bradykinin in adult guinea pigs [39]. Therefore, C-fiber activation would be expected to enhance central and/or local “axon” reflexes. Mutoh et al. [72] reported that ETS exposure for 5 weeks duration enhances C-fiber responsiveness but not airway responsiveness to both capsaicin and bradykinin challenge in juvenile, nonsensitized guinea pigs exposed to SSTS. The differences in AHR between the two studies may be due to differences in the guinea pig ages and reflex maturation, airway sensitization, and duration of TS exposure (5 versus 22 weeks) or to dosages of irritant agents used. However, both studies support that TS exposure enhances C-fiber activation. Chronic ETS exposure may enhance transduction properties of the nerve endings. Possibilities include the number of ligand receptors in the cell membrane, changes in the resting membrane potential of the nerve cell or changes in the threshold of activation of the ion channels that lead to cell depolarization. Ligand receptors in C-fiber membranes include members of the transient receptor potential (TRP) ion channel family such as TRPV1 and TRPA1 ion channels. Recent experiment has identified TRPA1 activation by crotonaldehyde and acrolein, which are agents found in TS [73]. As does activation of TRPV1, TRPA1 activation mobilizes Ca2+ in cultured guinea pig jugular ganglia neurons and induces neuropeptide release and contraction of isolated guinea pig bronchi. A TRPA1-selective antagonist and aldehyde scavenger glutathione but not the TRPV1 antagonist capsazepine or by ROS scavengers block the actions of the ETS agents.

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A probable mechanism of enhanced action of neuropeptides after their release is the decrease in catabolism of the peptides. Dusser et al. [74] determined that ETS inhibits neutral endopeptidase. Therefore, the increased airway reactivity to capsaicin observed in this study may be the result of several factors. Daily TS exposure of OVAsensitized guinea pigs increases neuropeptide “overflow” into the lung perfusate during acute ETS challenge in groups pretreated with NEP inhibitors [38]. Since NEP is blocked these results imply enhanced C-fiber responsiveness in guinea pig lungs chronically exposed to TS. Therefore, AHR in OVA-ETS guinea pigs may result from enhanced tachykinin release from C-fibers as well as from impaired tachykinin metabolism. A possibility remains that airway hyperirritability induced by chronic ETS exposure may in part result from enhanced activation of eosinophils. Activated eosinophils secretory products may stimulate sensory neurons to release neuropeptides [75]. It is possible that chronic ETS exposure affects eosinophil activation or enhances mediator release. However, the effect of ETS exposure on eosinophil activation is unknown. RAPIDLY ADAPTING PULMONARY RECEPTORS (IRRITANT RECEPTORS)

STRETCH

Rapidly adapting receptors (RARs) are a second category of sensory receptor in the lungs that has been thought to contribute to reflex bronchoconstriction [76]. However, studies in guinea pigs suggest that activation of RARs to either histamine or capsaicin is secondary to changes in lung mechanics [77]. However, acute TS challenge activates RARs without apparent changes in airway mechanics [78] and SSTS exposure enhances RAR activation by substance P [79] also without demonstrable changes in lung mechanics. After exposing juvenile guinea pigs to 5 wk of SSTS, RAR responsiveness and peak insufflation pressure were examined in response to MSTS [80]. Increased RAR activity preceded increased tracheal pressure. However, RAR responsiveness was attenuated in animals with chronic SSTS exposure. The authors conclude that SSTS during development diminishes the responsiveness of RARs to acute inhalation of MSTS exposure. In adult guinea pigs chronic TS exposure did not alter base level RAR activity but did increase RAR and airway responsiveness to intravenous capsaicin challenge [39]. Again the enhanced RAR activity appears to be related to the enhance AHR. The disparaging results from the two studied may be due to the developmental stage of the animals in the studies. CNS INTEGRATION AND RESPONSIVENESS Few studies have focused on central processing of sensory input either during acute or chronic tobacco exposure. The limited data available has largely originated from one research group. Initial studies from this group provide evidence that chronic SSTS exposure enhances cough and ARH to substance P in the brainstem [81]. SSTS exposure increased NTS neuronal activity in response to intravascular capsaicin challenge [82]. Therefore, pulmonary C-fiber sensitization by chronic exposure to SSTS exposure is conceivably transmitted to the NTS enhancing efferent activity and reflex actions to the airways. SSTS exposure enhances evoked synaptic transmission between pulmonary

Dale R. Bergren

afferents and NTS neurons [83]. The mechanism appears depress evoked excitatory postsynaptic currents. This depression is reversed by a neurokinin-1-receptor antagonist. Furthermore these investigators report increased substance P-expressing lung afferent terminals synapsing with NTS neurons. TS EXPOSURE AND EFFERENT NERVE TONE Cholinergic tone to the airways is increased in asthma as well as COPD. Cholinergic antagonists such as atropine, ipatroprium and tiotropium bromide are effective in decreasing tone to airway smooth muscle and thereby reducing airways resistance [84, 85]. Enhanced vagal tone induced by TS may result from enhanced afferent vagal trafficking or possibly from agents carried in the blood acting on the parasympathetic centers of the CNS. Increased CNS activity would therefore increase efferent vagal tone to the airways. Matsumoto et al. [86] investigated efferent cholinergic mechanisms induced by exposure to TS in Guinea pigs. Acute exposure to TS increased bronchoconstriction and increased in thromboxane B2 in BALF. Pretreatment with a thromboxane synthase inhibitor and/or atropine attenuated changes in both variables. These results suggest that bronchoconstriction induced by TS is partially mediated by thromboxane A2, which is enhance by increased cholinergic tone. CONCLUSIONS The literature reports opposing immunological outcomes of the effects of ETS on airway sensitization and responsiveness. Most epidemiological studies support that ETS exposure exacerbates AHR and asthma although studies report negative findings. In reports involving both humans as well as experimental models ETS is an adjuvant for antigenic sensitization. More controversial is whether ETS exposure may induce AHR or asthma. The immunological responsiveness of the individual exposed to ETS may depend upon age as well as duration of exposure and presence of antigens. Both enhanced and attenuated airway inflammation have been report. The variant results may reflect variables in ETS exposure such as its composition, concentration, and length of daily exposure, exposure per week and the duration of the study. The impact of the relative and quantitative exposure of ETS and allergens or antigens on AHR is largely unknown. The role of neurogenic inflammation is human AHR is poorly understood in human airway disease. However certain asthmatic individuals are hyperreactive to inhalation of capsaicin suggesting a similarity to animal models of neurogenic inflammation [87]. Neuropeptides are proposed to play an important role in human AHR. Elucidating the integrative mechanism of ETS exposure and ARH from tissues to intracellular pathways is still in its early stages and is in need in further research as demonstrated in Fig. (1). ABBREVIATIONS ACHh

= Acetylcholine

MCh

= Methacholine

AHR

= Airway hyperresponsiveness



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Fig. (1). Summary of mechanism of ETS on AHR. Elements of ETS activate and penetrate the airway epithelium. Airway C-fibers are activated by acrolein and crotonaldehyde through TRPA1 rececptors. This activates central and local reflexes that cause neurogenic inflammation through the release of neuropeptides. DC act as APCs that migrate to lymph nodes to activate T cells which then travel to the airways. Agents from lymphocytes and other activated cells release cytokines that attract leukocytes from the circulation. These cells release mediators that enhance the inflammation and AHR. Target cells include ASM, endothelial cells and secretory cells. Increased inflammatory responses with these cells include activation of M3 and neuropeptide receptors and enhanced intracellular pathways involving histone deacetylase 2 and Rho-kinase (see text for details).

ASM

= Airway smooth muscle

DC

= Dendritic cell

EOS

= Eosinophils

ETS

= Environmental tobacco smoke

GM-CSF

= Granulocyte-macrophage colony-stimulating factor

IFN

= Interferon

Ig

= Immunoglobin

IL

= Interleukin

NEP

= Neuropeptide

NTS

= Nucleus tractus solitarius

Neu

= Neutrophils

OVA

= Ovalbumin

ROS

= Reactive oxygen species

TARC

= Thymus and activation-regulated chemokine

TRP

= Transient receptor potential

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Revised: September 21, 2009

Accepted: September 30, 2009