11 Oxidative Stress in Laboratory Animals Exposed to Cigarette Smoke, with Special Reference to Chronic Obstructive Pulmonary Disease

(1)

11.1 Introduction . . . 280

11.2 Cigarette Smoke . . . 280

11.3 Smoking Machines . . . 281

11.4 Markers of Oxidative Stress in Smoke-Exposed Animals . . . 282

11.5 COPD . . . 283

11.5.1 Epidemiology of COPD . . . 283

11.5.2 Basic Pathways Mediating Cigarette-Smoke-Induced COPD . . . 284

11.5.3 Animal Models of COPD . . . 285

11.6 Future Models . . . 286

References . . . 286

Contents Chapter

Oxidative Stress in Laboratory Animals Exposed to Cigarette Smoke, with Special Reference to Chronic Obstructive

Pulmonary Disease

Chris Coggins

11

(2)

11

11.1 Introduction

The historical concept of oxygen as a major air pollutant has already been well doc- umented (Halliwell and Gutteridge 1999), putting into balance the fact that virtually all life on Earth needs oxygen, with the fact that oxygen is biologically very reactive.

The two are in balance because of the evolutionary development of antioxidant-defense mechanisms. Organisms that have antioxidant defense mechanisms can use oxygen for the production of energy, mainly in the cellular mitochondria.

Oxidative stress comes about when organisms are exposed to excessive amounts of oxygen, as higher atmospheric concentrations, higher partial pressures in such activities as diving, disease and/or malnutrition, and in the case of higher species such as verte- brates, by alterations in the oxygen transport system. The lung is uniquely susceptible to oxidative stress, as several cell types are continuously exposed to oxygen at atmospheric concentrations, unlike virtually all other cells in the body. The major components of ambient air that contribute to oxidative damage in the lungs include cigarette smoke, exhaust from internal combustion engines (fueled by both diesel and gasoline), and gases such as ozone and nitrogen dioxide.

Antioxidant protective mechanisms in the lungs include the presence of surfactant (from serous and goblet cells), which in turn contains such compounds as reduced gluta- thione (GSH), α-tocopherol, and ascorbic acid (MacNee and Rahman 2004). The deeper, nonciliated parts of the lung contain free protective cells such as alveolar macrophages, neutrophils, and lymphocytes. Many of the antioxidant protective mechanisms can be upregulated in the presence of oxidative stress; pulmonary disease results when the normal balance between oxidants and antioxidants is lost. Many pulmonary diseases thought to result from such imbalances are hypothesized to do so through inflammatory processes (Reuben et al. 2004). This is especially thought to be the case for smoking-induced diseases, such as pulmonary neoplasia, cardiovascular disease, and chronic obstructive pulmonary disease (COPD).

11.2 Cigarette Smoke

The chemistry of smoke from reference cigarettes has been described in a number of publications (Hoffman and Hoffman 1997; Hoffmann et al. 2001; Rodgman and Green 2003; Roemer 2004; Stabbert 2003), including those that have concentrated in particular on radicals and the role radicals may play in disease (Pryor 1997; Pryor et al. 1998). An integral part of this chemistry is the complicated sequence of processes that occur dur- ing the combustion of tobacco. The conditions in the burning cone are highly reducing (temperatures up to 950 °C), as oxygen is consumed by carbonized tobacco to produce heat, carbon monoxide, carbon dioxide, and water (Baker 1999).

Immediately behind the combustion zone is a pyrolysis/distillation zone. Tempera- tures here are between 200° and 600 °C, still with low concentrations of oxygen (Baker 1999). Aerosol formation occurs as chemicals pass from the burning cone, through the unburned tobacco and (usually) through the cigarette filter.

The smoke that emerges from the cigarette filter is termed mainstream smoke. It is available to smokers, and to machines that mimic human smoking for analytical pur-

(3)

poses or for dilution and subsequent distribution to experimental animals. This mainstream smoke is arbitrarily divided into a particulate phase, which does not pass through a Cambridge pad, and a vapor or gas phase, which does. Additional complications include added ingredients (Baker et al. 2004), selective absorption (e.g., phenols by the cellulose acetate fibers used in most cigarette filters), and the use of ventilation holes and additional materials (e.g., activated charcoal) in the filter (Hoffman et al. 2001).

Both particulate and gas phases of cigarette smoke have been reported to contain large numbers (e.g., 10^15–16) of so-called free radicals (Pryor et al. 1998), low-molecu- lar-weight compounds, often carbon- or oxygen-centered radicals. The carbon-centered radicals can react with oxygen to produce other reactive oxygen species (ROS).

Although the concentrations of oxygen are reduced in the burning cone of the cigarette, it is unlikely that this would translate into reduced concentrations in the smoke inhaled by smokers. This is because the puffs taken from the cigarette (puffs usually with volumes of 20–100 ml) are diluted substantially with air at the point of inhalation into the respiratory tract (Bernstein 2004).

Nonsmokers may be exposed to a different kind of smoke, termed environmental tobacco smoke, or ETS (Baker and Proctor 1990). This is the aged and diluted mixture of exhaled smoke from the smoker, with smoke emitted from the burning tip of the cigarette between puffs (the latter being termed sidestream smoke). No filtration is involved in the formation of ETS; because of the dilution that takes place, ETS concentrations are very much smaller than are those of the mainstream smoke taken in by smokers (Jenkins et al. 2000). The free radicals mentioned above for mainstream smoke have also been reported to be present in large numbers in sidestream smoke (Pryor 1997); concentrations in ETS are likely to be very much lower.

11.3 Smoking Machines

A number of designs have been published for smoking machines to expose experimental animals (largely rodents) nose-only to diluted mainstream smoke. The designs have at- tempted to balance a short path length from the cigarette to the animal, with the ability to expose large numbers of animals. Long path lengths may prevent any short-lived components of the smoke from reaching the experimental animals. A typical range would be short path length, small number of animals (Guerin et al. 1979), medium path length, and medium-large number of animals (Baumgartner and Coggins 1980), and long path length, large number of animals (Henry et al. 1985). Designs involving whole-body exposures (Chen et al. 1992) would appear to have very long path lengths, along with other disadvantages. Long-term inhalation studies with a variety of different animal species have not resulted in useful animal models for human smoking-related disease (Coggins 2002).

Machines for exposing animals to surrogates of ETS (surrogates are required because of the logistical constraint in producing smoke exhaled by smokers) have in general used appropriate aging periods (Ayres et al. 1994; Haussmann et al. 1998a; Teague et al. 1994).

In general, responses noted in animals exposed to ETS surrogates have been restricted to localized hyperplasia in the nasal passages (Coggins et al. 1993; Haussmann et al. 1998b;

Stinn et al. 2005). By contrast, an inhalation study with mice exposed nose-only to sidestream smoke showed systemic inflammatory responses and accentuated systemic lipid

(4)

11

peroxidation (Zhang et al. 2003). This same group had earlier shown that antioxidant supplementation in healthy, old mice prevented inflammatory responses induced by exposure to sidestream smoke (Zhang et al. 2001). Unfortunately, neither of these two studies made measurements of the amounts of smoke presented—they were almost cer- tainly extremely high.

Although there are reports of measurements of radicals in mainstream smoke (Pryor 1997), there do not appear to any such measurements reported in mainstream smoke presented to experimental animals in smoking machines, or in similar studies using ETS surrogates as the test material.

11.4 Markers of Oxidative Stress in Smoke-Exposed Animals

The National Institute of Environmental Health Sciences (NIEHS) has “taken the lead in initiating the first comparative study for determining which of the available biomarkers of oxidative stress are most specific, sensitive, and selective,” using animals treated with carbon tetrachloride (Kadiiska et al. 2000). The original list of biomarkers was α-tocopherol, coenzyme Q, ascorbic acid and uric acid, GHS, and total oxidant capacity (Kadiiska et al. 2000). Very recently, an update was published (Kadiiska et al. 2005), giving a series of analytes for the oxidation products of lipids, proteins, and DNA in different body fluids. For oxidation products in lipids, the following assays are suggested: lipid hydroper- oxide, malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS), and 8- iso-PGF2α (free and esterified) (Kadiiska et al. 2005). For oxidation products of proteins, the list is protein carbonyls, methionine sulfoxidation, and tyrosine products. Finally, for oxidation products of DNA, the list is the Comet assay, leukocyte MDA–DNA adducts, and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Kadiiska et al. 2005). A variety of different assays is given for different body fluids (Kadiiska et al. 2005).

Very few of the NIEHS list (Kadiiska et al. 2005) have been measured in smoke-exposed animals. The subject of markers of oxidative stress in animals exposed to smoke was included as part of a recent review (van der Vaart et al. 2004), a review which also included studies in humans and which also assessed the effects of smoke on inflammation. A supplemental online report (van der Vaart et al. 2004) lists the various studies examined in the review and lists the various parameters that have been examined.

A total of six studies were included in the review (van der Vaart et al. 2004). The following parameters were reported: 8-OHdG, a DNA oxidation product (Evans et al.

2004) in both lung tissues and bronchoalveolar lavage fluid (BALF), GSH in lung homogenate, BALF and in blood, ascorbic acid in lung homogenate and in BALF, and cys- teine in blood and lung tissue (van der Vaart et al. 2004).

Other studies have concentrated on the 8-OHdG endpoint. In a study using whole- body exposures of rats to sidestream smoke, no effect was noted on 8-OHdG concentrations in lung tissue (Arif et al. 2001). This is in contrast to work with both mainstream smoke (Aoshiba et al. 2003a) and ETS (Izzotti et al. 1999), where increased concentrations were noted.

There are some studies that reported an impact of smoke exposure on GSH concentrations. Thus mainstream smoke increased total GSH in BALF (March et al. 2002), with no effect of concurrent treatment with ozone. Work has shown that it is the particulate phase of the smoke that is responsible for the oxidative damage, and that it can be

(5)

blocked by vitamin C (Panda et al. 2001). Various antioxidants have also been effective (D’Agostini 2001; De Flora 2003; Izzotti 2001; Sadowska 2005).

A study with only an indirect assessment of oxidative stress examined the effects after smoke exposure of an instilled catalytic antioxidant, manganese (III) meso-tetrakis(N,N'- diethyl-1,3-imidazolium-2-yl) porphyrin (Smith et al. 2002). The catalyst was given by intratracheal instillation to groups of rats exposed to filtered air or cigarette smoke, for up to 8 weeks (6 h/day, 3days/week). Smoke exposures were well characterized and were at conventional concentrations. The experimental treatment significantly reduced the number of cells recovered in BALF, specifically macrophages, neutrophils, and lymphocytes. The authors concluded that the catalysts decreased the adverse effects of smoke exposure. Metalloporphyrins are known to have multiple antioxidant properties, including scavenging superoxide, hydrogen peroxide, peroxynitrite, and lipid peroxyl radicals (Smith et al. 2002).

11.5 COPD

COPD is a disease state characterized by airflow limitation that is not fully reversible.

The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles and gases (Pauweis et al. 2001). The

“abnormal” or chronic inflammation leads to a narrowing of the small airways (bronchi- olitis) and to alveolar wall destruction (Hogg 2002; Snider 2003). The chronic inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, and cytotoxic T lymphocytes (Barnes and Cosio 2004), and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors) (Barnes 2003, 2004;

Rennard 1998). The abnormal inflammatory response may be the key to susceptibility (Agusti et al. 2003). Although many types of inflammatory cells and mediators have been identified in COPD patients, their role in the progression of the disease remains largely unknown (Barnes 2003).

The chronic obstructive bronchitis with mucus hypersecretion may contribute to, but is not necessarily associated with, airflow limitation (Barnes 2003; Cosio-Piqueras and Cosio 2001). Emphysema is defined as a condition of the lung characterized by abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of the lung parenchyma with or without obvious fibrosis and loss of lung elasticity (Cosio-Piqueras and Cosio 2001; Snider 1992a, b, 2003). Subjects with COPD do not often show emphysema without bronchitis and small airway disease (March et al. 2000).

11.5.1 Epidemiology of COPD

COPD is considered a major health concern, with an overall prevalence in adults esti- mated at between 4 and 10% in countries where it has been rigorously measured (Hal- bert et al. 2003). A recent estimate for the incidence of COPD in the United States was given as 16 million people (Mahadeva and Shapiro 2002). The major risk factors for COPD are considered to be cigarette smoking, use of biomass fuels, and air pollution

(6)

11

(Halbert et al. 2003); the population-attributable incidence for cigarette smoking and COPD is about 80–90% (Halbert et al. 2003).

Epidemiological studies have shown that it is mainly susceptible smokers that develop COPD (Siafakas and Tzortzaki 2002).

11.5.2 Basic Pathways Mediating Cigarette- Smoke-Induced COPD

Cigarette smoke exposure has been shown to cause severe oxidative stress in the lung (Aoshiba 2003; MacNee and Rahman 2001, 2004). The oxidants present in cigarette smoke, together with abundant infiltration and activation status of inflammatory cells in the smoker’s lung, releasing even more oxygen-based free radicals, may be involved in a proteolytic/antiproteolytic imbalance, leading to tissue destruction (Churg et al. 2003;

Seagrave 2000; Seagrave et al. 2004). The incidence of such an imbalance in human pop- ulations was the subject of a recent review (deSerres 2003).

A recent study characterized the inflammatory and mucus hypersecretory changes in the lungs of smoke-exposed rats, examining both the role of cytokine-induced neutrophil attractants (CINCs) and a possible mediator of the hypersecretion (Stevenson et al.

2005). The results showed that generation of a neutrophilic/mucus hypersecretory lung phenotype could be produced by just two exposures to smoke, 15 h apart (no details were given on smoke composition). There was a time-dependent increase in the number of CINCs in lung tissue and in lavage fluid over the 24-h period following exposure to smoke. These temporal changes in CINCs mirrored increases in neutrophil infiltration, indicative of a likely role in neutrophil influx, in turn thought to correlate well with matrix destruction (Churg and Wright 2005). The smoke-induced neutrophil infiltration could be inhibited in a dose-related manner (Stevenson et al. 2005).

Recent work has indicated that cigarette smoke is the main etiologic factor, through a mechanism that may involve enhanced proinflammatory gene transcription (Marwick et al. 2004). Other work has indicated that the oxidative stress produced by exposure to cigarette smoke (MacNee and Rahman 2001; Moodie et al. 2004) is a highly relevant factor. The responsiveness of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may act as a major determinant of the susceptibility to tobacco-smoke-induced airway disease, by upregulating antioxidant defenses and by decreasing inflammation and alveolar cell apoptosis (Rangasamy et al. 2004).

Oxidative stress has been shown to directly inactivate antiproteinases such as α1-antitrypsin (α1-AT) and secretory leukoprotease inhibitor (SLPI) (Betsuyaku et al. 2002;

Cavarra et al. 2001b; Hill et al. 2000), as well as activating matrix metalloproteinases (MMPs) (Belvisi 2003; Selman 2003). Moreover, oxidative stress induces the transcription of many proinflammatory genes controlled by transcription factors such as nuclear factor-κB (NF-κB) (Di Stefano 2002; Moodie et al. 2004). Oxidative stress is also thought to be involved in the accumulation of macrophages in the alveolar interstitial spaces, in- dependent of other proinflammatory stimuli (Kirkham et al. 2003). This latter group has hypothesized that the oxidative stress promotes the macrophage accumulation through the production of reactive carbonyls (particularly acrolein) (Kirkham et al. 2003).

(7)

11.5.3 Animal Models of COPD

A number of animal models have been reported that exhibit at least one of the features of the complicated pathology of COPD, such as chronic bronchitis (Nikula and Green 2000) and emphysema (Mahadeva and Shapiro 2002; March et al. 2000; Taraseviciene- Stewart 2004; Wright and Churg 2002). In these models, airspace enlargement has been demonstrated after chronic exposure to mainstream smoke, and also in shorter exposures to high concentrations of smoke. Ideally, such models need to represent the various patterns of alveolar wall destruction that have been reported in humans, as well as host factors that parallel the etiology of the pathological condition. Animal models with genetic predisposition (e.g., an inherent α1-AT deficiency or increased sensitivity to oxidative stress) to develop emphysema are probably the most relevant in mimicking the susceptible human population (deSerres 2003; Kodavanti et al. 1998, 2001). The application of genetic engineering strategies in mice offers a great potential to dissect the pathogenetic pathways of emphysema (Kodavanti 2001; Mahadeva et al. 2002). A few examples of susceptible and genetically engineered models are described below.

Promising susceptible animal models have been described that develop emphysema following whole body exposure to mainstream smoke (Caverra et al. 2001b; Takubo et al. 2002). C57Bl/6J mice, which have a mild deficiency in their antielastase screen, and DBA/2 mice, which are sensitive to oxidants, developed emphysema following 6 months of exposure to cigarette smoke, whereas the mouse strain with normal antielastase screen and nonsensitivity to oxidants (ICR-mouse) did not (Cavarra et al. 2001a). It appears that there are considerable strain differences in the extent of emphysema produced in smoke- exposed mice (Churg et al. 2004; Guerassimov et al. 2004; Obot et al. 2004; Shapiro et al.

2004; Valenca et al. 2004). The situation is complicated by large differences in the degree of detail in characterizing the smoke exposures used to produce emphysema.

The pallid mouse (C57Bl/6J, pa^+/+), with a severe α1-AT deficiency (DeSanti et al.

1995; Martorana et al. 1993), developed panlobular emphysema after only 4 months of whole-body exposure to cigarette smoke (Cavarra et al. 2001a; Takubo et al. 2002). The pallid mice exhibited features similar to the human situation, including a T-lymphocytic inflammatory response and increased lung compliance (after 6 months of exposure).

The development of spontaneous emphysema has been studied in various transgenic mouse models (Mahadeva and Shapiro 2002). Most of these models have contributed to the knowledge of certain aspects of the development of emphysema, but unfortunately, they have not been challenged by exogenous noxious agents.

Recently, a transgenic mouse model was established that expresses low levels of human α1-AT (Churg et al. 2003), as part of an effort to produce a treatment for cigarette smoke-induced emphysema. The transgenic mice were tolerant to exogenously applied human α1-AT. Mice were exposed to mainstream smoke for up to 6 months; some of them received human α1-AT repeatedly. The latter treatment abolished smoke-induced elevations of neutrophil counts in lavage fluide, as well as the elastin and collagen break- down products desmosine and hydroxyproline, respectively. Treatment also provided some protection against airspace size. It was concluded that α1-AT therapy reduced the inflammation and partially protects the animals against emphysema.

A murine model deficient for macrophage elastase (MME^–/–) has been used to shown to be protected against development of mainstream smoke-induced emphysema (Hauta- maki et al. 1997). The authors concluded that macrophage elastase is probably sufficient

(8)

11

for the development of emphysema that results from chronic inhalation of mainstream smoke. The role of the macrophage elastase in the smoke-induced inflammation and tissue destruction has been corroborated by elegant studies carried out by Ofulue and coworkers (1998).

Recent work has suggested that a further consideration should be taken when examining the role of inflammation and excessive proteolysis in the pulmonary tissue destruction (Aoshiba et al. 2003b). This work provided evidence that alveolar epithelial apoptosis causes emphysema in C57Bl/6J mice. The authors used a novel protein transfection agent (Chariot) to introduce active caspase-3 into bronchial epithelial cells in vivo. These findings indicate that inflammation, proteolysis, oxidative stress, apoptosis, or cell hemostasis in general are interrelated mechanisms contributing to cigarette smoke-induced emphysema (Tuder et al. 2003).

11.6 Future Models

In many of the studies described relatively minor attention was made to the abnormal inflammatory process mentioned earlier (Siafakas and Tzortzaki 2002; Rangasamy 2004). Future models should provide a tool to understand the exact role of inflammation on the etiology and progression of the disease (Adcock et al. 2005; Reuben et al. 2004;

Sadowska et al. 2005).

A prototypic chain of events might be as follows: cigarette smoke exposure → oxidative stress → proinflammatory mediators → inflammation → COPD. Support for this hypothesis is given from a recent paper that showed adverse effects of oxygen supplementation in COPD patients (Carpagnano et al. 2004), in conjunction with increased oxidative stress and with airway inflammation.

Novel designs for cigarette designs, and the potential use of antioxidants and other agents (Adcock et al. 2005; Xu et al. 2004), may be able to break this chain for those people unable to quit smoking.

References

Adcock IM, Cosio B, Tsaoprouni L, Barnes PJ, Ito K (2005) Redox regulation of histone deacety- lases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal 7:144–152

Agusti A, MacNee W, Donaldson K, Cosio MG (2003) Hypothesis: does COPD have an autoimmune component? Thorax 58:832–834

Aoshiba K, Koinuma M, Yokohori N, Nagai A (2003a) Immunohistochemical evaluation of oxidative stress in murine lungs after cigarette smoke exposure. Inhal Toxicol 15:1029–1038 Aoshiba K, Yokohori N, Nagai A (2003b) Alveolar wall apoptosis causes lung destruction and em-

physematous changes. Am J Respir Cell Mol Biol 28:555–562

Arif JM, Vadhanam MV, DeGroot AJL, VanZeeland AA, Gairola CG, Gupta RC (2001) Effect of cigarette smoke exposure on the modulation of 8-oxo-2'-deoxyguanosine in rat lungs as ana- lyzed by 32P postlabeling and HPLC-ECD. Int J Oncol 19:763–766

Ayres PH, Mosberg AT, Coggins CRE (1994) Design, construction and operation of an inhalation system for exposing laboratory animals to environmental tobacco smoke. Am Ind Hyg Assoc J 55:806–810

(9)

Baker RR (1999) Smoke chemistry. In: Davis DL, Nielsen MT (eds) Tobacco: production, chemistry, and technology. Blackwell, Oxford, pp 398–439

Baker RR, Proctor CJ (1990) The origins and properties of environmental tobacco smoke. Environ Int 16:231245

Baker RR, Massey ED, Smith G (2004) An overview of the effects of tobacco ingredients on smoke chemistry and toxicity. Food Chem Toxicol 42:S53–S83

Barnes PJ (2003) New concepts in chronic obstructive pulmonary disease. Ann Rev Med Selected Topics Clin Sci 54:113–129

Barnes PJ (2004) Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 56:515–548 Barnes PJ, Cosio MG (2004) Characterization of T lymphocytes in chronic obstructive pulmonary

disease. PLoS Med 1:25–27

Baumgartner H, Coggins CRE (1980) Description of a continuous-smoking inhalation machine for exposing small animals to tobacco smoke. Beitr Tabakforsch Int 10:169–174

Belvisi MG, Bottomley KM (2003) The role of matrix metalloproteinases (MMPs) in the patho- physiology of chronic obstructive pulmonary disease (COPD): a therapeutic role for inhibitors of MMPs? Inflamm Res 52:95–100

Bernstein DM (2004) A review of the influence of particle size, puff volume, and inhalation pattern on the deposition of cigarette smoke particles in the respiratory tract. Inhal Toxicol 16:675–689

Betsuyaku T, Takeyabu K, Tanino M, Nishimura M (2002) Role of secretory leukocyte protease inhibitor in the development of subclinical emphysema. Eur Respir J 19:1051–1057

Carpagnano GE, Kharitonov SA, Foschino-Barbaro MP, Resta O, Gramiccioni E, Barnes PJ (2004) Supplementary oxygen in healthy subjects and those with COPD increases oxidative stress and airway inflammation. Thorax 59:1016–1019

Cavarra E, Bartelesi B, Lucatelli M, Fineschi S, Lunghi B, Gambelli F, Ortiz LA, Martorana PA, Lungarella G (2001a) Effects of cigarette smoke in mice with different levels of alpha-1 protein- ase inhibitor and sensitivity to oxidants. Am J Respir Crit Care Med 164:886–890

Cavarra E, Lucatelli M, Gambelli F, Bartelesi B, Fineschi S, Szarka A, Giannerini F, Martorana PA, Lungarella G (2001b) Human SLPI inactivation after cigarette smoke exposure in a new in vivo model of pulmonary oxidative stress. Am J Physiol 281:L412–L417

Chen BT, Bechtold WE, Mauderly JL (1992) Description and evaluation of a cigarette smoke generation system for inhalation studies. J Aerosol Med 5:19–30

Churg A, Wright CW (2005) Proteases and emphysema. Curr Opin Pulm Med 11:153–159 Churg A, Wang RD, Xie CS, Wright JL (2003) Alpha-1-antitrypsin ameliorates cigarette smoke-

induced emphysema in the mouse. Am J Respir Crit Care Med 168:199–207

Churg A, Wang RD, Tai H, Wang X, Xie CS, Wright JL (2004) Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med 170:492–498

Coggins CRE (2002) A minireview of chronic animal inhalation studies with mainstream cigarette smoke. Inhal Toxicol 14:991–1002

Coggins CRE, Ayres PH, Mosberg AT, Sagartz JW, Hayes AW (1993) Subchronic inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette. Inhal Toxicol 5:77–96

Cosio-Piqueras MG, Cosio MG (2001) Disease of the airways in chronic obstructive pulmonary disease. Eur Respir J 18:S41–S49

D’Agostini F, Balansky RM, Izzotti A, Lubet RA, Kelloff GJ, DeFlora S (2001) Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats.

Carcinogenesis 22:375–380

De Flora S, D’Agostini F, Balansky R, Camoirano A, Bennicelli C, Bagnasco M, Cartiglia C, Tampa E, Longobardi MG, Lubet RA, Izzotti A (2003) Modulation of cigarette smoke-related end- points in mutagenesis and carcinogenesis. Mutat Res 523:237–252

(10)

11

DeSanti MM, Martorana PA, Cavarra E (1995) Pallid mice with genetic emphysema. Neutrophil elastase burden and elastin loss occur without alteration in the bronchoalveolar lavage cell population. Lab Invest 73:40–47

deSerres FTJ (2003) Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect 111:161851–161854

Di Stefano A, Caramori G, Oates T, Capelli A, Lusuardi M, Gnemmi I, Ioli F, Chung KF, Donner CF, Barnes PJ, Adcock IM (2002) Increased expression of nuclear factor-κB in bronchial biop- sies from smokers and patients with COPD. Eur Respir J 20:556–563

Evans MD, Dizdaroglu M, Cooke MS (2004) Oxidative DNA damage and disease: induction, re- pair and significance. Mutat Res 567:1–61

Guerassimov A, Hoshino Y, Takubo Y, Turcotte A, Yamamoto M, Ghezzo H, Triantafillopoulos A, Whittaker K, Hoidal JR, Cosio MG (2004) The development of emphysema in cigarette smoke- exposed mice is strain dependent. Am J Respir Crit Care Med 170:974–980

Guerin MR, Stokely JR, Higgins CE, Moneyhun JH, Holmberg RW (1979) Inhalation bioassay chemistry—Walton horizontal smoking machine for inhalation exposure of rodents to cigarette smoke. J Nat Cancer Inst 63:441–448

Halbert RJ, Isonaka S, George D, Iqbal A (2003) Interpreting COPD prevalence estimates: What is the true burden of disease? Chest 123:1684–1692

Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine, 3rd ed. Oxford Univer- sity Press, Oxford

Haussmann H-J, Anskeit E, Becker D, Kuhl P, Stinn W, Teredesai A, Voncken P, Walk R-A (1998a) Comparison of fresh and room-aged cigarette sidestream smoke in a subchronic inhalation study on rats. Toxicol Sci 41:100–116

Haussmann H-J, Gerstenberg B, Gocke W, Kuhl P, Schepers G, Stabbert R, Stinn W, Teredesai A, Tewes F, Anskeit E, Terpstra P (1998b) 12-Month inhalation study on room-aged cigarette sidestream smoke in rats. Inhal Toxicol 10:663–697

Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD (1997) Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277:2002–2004

Henry CJ, Dansie DR, Kanagalingam KK, Kouri RE, Gayle T, Guerin M, Holmberg R, Florant L, Greenspan J (1985) Chronic inhalation studies in mice. 1. Facilities and equipment for “nose- only” exposure to cigarette smoke. Beitr Tabakforsch Int 13:37–53

Hill AT, Bayley DL, Campbell EJ, Hill SL, Stockley RA (2000) Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency. Eur Respir J 15:886–890 Hoffmann D, Hoffmann I (1997) The changing cigarette, 1950–1995. J Toxicol Environ Health

50:307–364

Hoffmann D, Hoffmann I, El-Bayoumy K (2001) The less harmful cigarette: a controversial is- sue. A tribute to Ernst L. Wynder. Chem Res Toxicol 14:768–790

Hogg JC, Senior RM (2002) Chronic obstructive pulmonary disease center dot 2: pathology and biochemistry of emphysema. Thorax 57:830–834

Izzotti A, Bagnasco M, D’Agostini F, Cartiglia C, Lubet RA, Kelloff GJ, De Flora S (1999) Formation and persistence of nucleotide alterations in rats exposed whole-body to environmental cigarette smoke. Carcinogenesis 20:1499–1505

Izzotti A, Balansky RM, D’Agostini F, Bennicelli C, Myers SR, Grubbs CJ, Lubet RA, Kelloff GJ, DeFlora S (2001) Modulation of biomarkers by chemopreventive agents in smoke-exposed rats.

Cancer Res 61:2472–2479

Jenkins RA, Guerin MR, Tomkins BA (2000) Eisenberg M (ed) The chemistry of environmental tobacco smoke: composition and measurement, 2nd edn. Lewis, Boca Raton

Kadiiska MB, Gladen BC, Baird DD, Dikalova AE, Sohal RS, Hatch GA, Jones DP, Mason RP, Bar- rett JC (2000) Biomarkers of oxidative stress study: are plasma antioxidants markers of CCl4 poisoning? Free Radic Biol Med 28:838–845

(11)

Kadiiska MB, Gladen BC, Baird DD, Germolec D, Graham LB, Parker CE, Nyska A, Wachsman JT, Ames BN, Basu S, Brot N, Fitzgerald GA, Floyd RA, George M, Heinecke JW, Hatch GE, Hensley K, Lawson JA, Marnett LJ, Morrow JD, Murray DM, Plastaras J, Roberts LJ, Rokach J, Shigenaga MK, Sohal RS, Sun J, Tice RR, Van Thiel DH, Wellner D, Walter PB, Tomer KB, Mason RP, Barrett JC (2005) Biomarkers of oxidative stress study II. Are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning? Free Radic Biol Med 38:698–710 Kirkham PA, Spooner G, Ffoulkes-Jones C, Calvez R (2005) Cigarette smoke triggers macrophage

adhesion and activation: role of lipid peroxidation products and scavenger receptor. Free Radic Biol Med 35:697–710

Kodavanti UP, Costa DL (2005) Rodent models of susceptibility: what is their place in inhalation toxicology? Respir Physiol 128:57–70

Kodavanti UP, Costa DL, Bromberg PA (1998) Rodent models of cardiopulmonary disease:

their potential applicability in studies of air pollutant susceptibility. Environ Health Perspect 106:111–130

MacNee W, Rahman I (2001) Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease? Trends Mol Med 7:55–62

MacNee W, Rahman I (2004) Oxidative stress in chronic obstructive pulmonary disease. In: Val- lyathan V, Castranova V, Shi X (eds) Oxygen/nitrogen radicals: lung injury and disease. Marcel Dekker, New York, pp 317–360

Mahadeva R, Shapiro SD (2002) Chronic obstructive pulmonary disease center dot 3: experimental animal models of pulmonary emphysema. Thorax 57:908–914

March TH, Green FHY, Hahn FF, Nikula KJ (2000) Animal models of emphysema and their relevance to studies of particle-induced disease. Inhal Toxicol 12:155–187

March TH, Barr EB, Finch GL, Nikula KJ, Seagrave JC (2002) Effects of concurrent ozone exposure on the pathogenesis of cigarette smoke-exposed emphysema in B6C3F1 mice. Inhal Toxicol 14:1187–1213

Martorana PA, Brand T, Gardi C, vanEven P, deSanti MM, Calzoni P, Marcolongo P, Lungarella G (1993) The pallid mouse: a model of genetic alpha1-antitrypsin deficiency. Lab Invest 68:233–241

Marwick JA, Kirkham PA, Stevenson CS, Danahay H, Giddings J, Butler K, Donaldson K, MacNee W, Rahman I (2004) Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol 31:633–642

Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, Kilty I, Rahman I (2004) Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regu- late NF-κB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J 18:1897–1899

Nikula KJ, Green FHY (2000) Animal models of chronic bronchitis and their relevance to studies of particle-induced disease. Inhal Toxicol 12:123–153

Obot CJ, Lee KM, Fuciarelli AF, Renne RA, McKinney WJ (2004) Characterization of mainstream cigarette smoke (MS)-induced biomarker responses in ICR and C57BL/6 mice. Inhal Toxicol 16:701719

Ofulue AF, Ko M, Abboud RT (1998) Time course of neutrophil and macrophage elastinolytic activities in cigarette smoke-induced emphysema. Am J Physiol 19:L1134–L1144

Panda K, Chattopadhyay R, Chattopadhyay D, Chatterjee IB (2001) Cigarette smoke-induced protein oxidation and proteolysis is exclusively caused by its tar phase: prevention by vitamin C.

Toxicol Lett 123:21–32

Pauweis RA, Buist AS, Calverley PM (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 163:1256–1276

Pryor WA (1997) Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity.

Environ Health Perspect 105:S875–S882

(12)

11

Pryor WA, Stone K, Zang LY, Bermudez E (1998) Fractionation of aqueous cigarette tar extracts:

fractions that contain the tar radical cause DNA damage. Chem Res Toxicol 11:441–448 Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Pe-

trache I, Tuder RM, Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114:1248–1259

Rennard SI (1998) COPD: Overview of definitions, epidemiology, and factors influencing its development. Chest113:S235–S241

Reuben JS, Guo R-F, Ward PA (2004) Mediators of lung inflammation. Role of reactive oxygen and nitrogen species. In: Vallyathan V, Castranova V, Shi X (eds) Oxygen/nitrogen radicals: lung injury and disease. Marcel Dekker, New York, pp 91–110

Rodgman A, Green CR (2003) Toxic chemicals in cigarette mainstream smoke—hazard and hoopla. Beit Tabakforsch Int 20:481–545

Roemer E, Stabbert R, Rustemeier K, Veltel DJ, Meisgen TJ, Reininghaus W, Carchman RA, Ga- worski CL, Podraza KF (2004) Chemical composition, cytotoxicity and mutagenicity of smoke from US commercial and reference cigarettes smoked under two sets of machine smoking conditions. Toxicol 195:31–52

Sadowska AM, van Overveld FJ, Gorecka D, Zdral A, Filewska M, Demkow UA, Luyten C, Saenen E, Zielinski J, De Backer WA (2005) The interrelationship between markers of inflammation and oxidative stress in chronic obstructive pulmonary disease: modulation by inhaled steroids and antioxidant. Respir Med 99:241–249

Seagrave J (2000) Oxidative mechanisms in tobacco smoke-induced emphysema. J Toxicol Envi- ron Health 61:69–78

Seagrave J, Barr EB, March TH, Nikula KJ (2004) Effects of cigarette smoke exposure and cessation on inflammatory cells and matrix metalloproteinase activity in mice. Exp Lung Res 30:1–15 Selman M, Cisneros-Lira J, Gaxiola M, Ramirez R, Kudlacz EM, Mitchell PG, Pardo A (2003) Ma-

trix metalloproteinases inhibition attenuates tobacco smoke-induced emphysema in guinea pigs. Chest 123:1633–1641

Shapiro SD, DeMeo DL, Silverman EK (2004) Smoke and mirrors: mouse models as a reflection of human chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:929–931 Siafakas NM, Tzortzaki EG (2002) Few smokers develop COPD. Why? Respir Med 96:615–624 Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY, Pinkerton KE (2002) Inhibition

of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 33:1106–1114

Snider GL (1992a) Emphysema: the first two centuries—and beyond. A historical overview, with suggestions for future research: part 1. Am Rev Respir Dis 146:1334–1344

Snider GL (1992b) Emphysema: the first two centuries—and beyond. A historical overview, with suggestions for future research: part 2. Am Rev Respir Dis 146:1615–1622

Snider GL (2003) Nosology for our day—its application to chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 167:678–683

Stabbert R, Voncken P, Rustemeier K, Haussmann H-J, Roemer E, Schaffernicht H, Patskan G (2003) Toxicological evaluation of an electrically heated cigarette. Part 2. Chemical composition of mainstream smoke. J Appl Toxicol 23:329–339

Stevenson CS, Coote K, Webster R, Johnston H, Atherton HC, Nicholls A, Giddings J, Sugar R, Jackson A, Press NJ, Brown Z, Butler K, Danahay H (2005) Characterization of cigarette smoke- induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect. Am J Physiol 88:L514–L522

Stinn W, Teredesai A, Anskeit E, Rustemeier K, Schepers G, Schnell P, Haussmann H-J, Carchman RA, Coggins CRE, Reininghaus W (2005) Chronic nose-only inhalation study in rats, compar- ing room-aged sidestream smoke and diesel engine exhaust. Inhal Toxicol 17:549–576 Takubo Y, Guerassimov A, Ghezzo H, Triantafillopoulos A, Bates JHT, Hoidal JR, Cosio MG (2002)

α1-Antitrypsin determines the pattern of emphysema and function in tobacco smoke-exposed mice parallels with human disease. Am J Respir Crit Care Med 166:1596–1603

(13)

Taraseviciene-Stewart L, Scerbavicius R, Choe K-H, Moore M, Sullivan A, Nicolls MR, Fontenot AP, Tuder RM, Voelkel NF (2004) An animal model of autoimmune emphysema. Am J Respir Crit Care Med 171:734–742

Teague SV, Pinkerton KE, Goldsmith M, Gebremichael A, Chang S, Jenkins RA (1994) Sidestream cigarette smoke generation and exposure system for environmental tobacco smoke studies. In- hal Toxicol 6:79–93

Tuder RM, Petrache I, Elias JA, Voelkel NF, Henson PM (2003) Apoptosis and emphysema—the missing link. Am J Respir Cell Mol Biol 28:551–554

Valenca S, Da Hora K, Castro P, Moraes VG, Carvalho L, Porto LC (2004) Emphysema and metal- loelastase expresion in mouse lung induced by cigarette smoke. Toxicol Pathol 32:351–356 van der Vaart H, Postma DS, Timens W, Ten Hacken NHT (2004) Acute effects of cigarette smoke

on inflammation and oxidative stress: a review. Thorax 59:713–721

Wright JL, Churg A (2002) Animal models of cigarette smoke-induced COPD. Chest 122:

S301–S306

Xu L, Cai BQ, Zhu YJ (2004) Pathogenesis of cigarette smoke-induced chronic obstructive pulmo- nary disease and therapeutic effects of glucocorticoids and N-acetylcysteine in rats. Chin Med J 117:1611–1619

Zhang J, Jiang S, Watson RR (2001) Antioxidant supplementation prevents oxidation and inflammation responses induced by sidestream cigarette smoke in old mice. Environ Health Perspect 109:1007–1009

Zhang J, Liu YL, Shi JQ, Larson DF, Watson RR (2002) Side-stream cigarette smoke induces dose- response in systemic inflammatory cytokine production and oxidative stress. Exp Biol Med 227:823–829