Effects of Cigarette Smoke in Mice with Different Levels of α 1 -Proteinase Inhibitor and Sensitivity to Oxidants

Dipartimento di Fisiopatologia e Medicina Sperimentale, Università di Siena, Siena, Italy.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 10/2001; 164(5):886-90. DOI: 10.1164/ajrccm.164.5.2010032
Source: PubMed


The role of strain difference in the response to cigarette smoke was investigated in mice. Mice of the strains DBA/2 and C57BL/6J responded to acute cigarette smoke with a decrease of the antioxidant defenses of their bronchoalveolar lavage (BAL) fluids. On the other hand, under these conditions ICR mice increased their BAL antioxidant defenses. Mice of these three strains were then exposed to cigarette smoke (three cigarettes/d, 5 d/wk) for 7 mo. Lung elastin content was significantly decreased in C57BL/6J and DBA/2 but not in ICR mice. Also, emphysema, assessed morphometrically using three methods, was present in C57BL/6J and DBA/2 but not in ICR mice. In an additional study pallid mice, with a severe serum alpha(1)-proteinase inhibitor (alpha(1)-PI) deficiency and that develop spontaneous emphysema, were exposed to cigarette smoke for 4 mo. This resulted in an acceleration of the development of the spontaneous emphysema assessed with morphometrical and biochemical (lung elastin content) methods. All these results indicate that sensitivity to the effects of cigarette smoke is strain-dependent and cigarette smoke accelerates the effects of alpha(1)-PI deficiency.

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    • "smoke exposure protocols have also been used to explore genetic control of cigarette smoke-induced lung inflammation and emphysema (Guerassimov et al., 2004; Mahadeva and Shapiro, 2002). It has been shown that several inbred strains of mice develop emphysema spontaneously due to genetic abnormalities (Mahadeva and Shapiro, 2002) and genetic manipulation itself can result in emphysema either spontaneously or during development (Cavarra et al., 2001; Ernst et al., 2002; Mahadeva and Shapiro, 2002; Ruwanpura et al., 2011; Shapiro et al., 2004). Recent advances in lung function measurements and imaging have also been used to detect lung dysfunction in mice chronically exposed to cigarette smoke before CT detection of structural changes and can provide a non-invasive method for longitudinally studying lung dysfunction in preclinical models (Jobse et al., 2013). "
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    ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4(th) leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a "snapshot" at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.029 · 2.53 Impact Factor
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    • "The response of mice to cigarette smoke also varies considerably from strain to strain [34] and another possibility is that even though both our laboratory and Moriyama et al [8] were notionally using C57Bl/6 mice, mice sold as C57Bl/6 from different vendors may not really be genetically the same, as we have suggested elsewhere [13]. "
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    ABSTRACT: It has been proposed that the development of COPD is driven by premature aging/premature senescence of lung parenchyma cells. There are data suggesting that old mice develop a greater inflammatory and lower anti-oxidant response after cigarette smoke compared to young mice, but whether these differences actually translate into greater levels of disease is unknown. We exposed C57Bl/6 female mice to daily cigarette smoke for 6 months starting at age 3 months (Ayoung@) or age 12 months (Aold@), with air-exposed controls. There were no differences in measures of airspace size between the two control groups and cigarette smoke induced exactly the same amount of emphysema in young and old. The severity of smoke-induced small airway remodeling using various measures was identical in both groups. Smoke increased numbers of tissue macrophages and neutrophils and levels of 8-hydroxyguanosine, a marker of oxidant damage, but there were no differences between young and old. Gene expression studies using laser capture microdissected airways and parenchyma overall showed a trend to lower levels in older animals and a somewhat lesser response to cigarette smoke in both airways and parenchyma but the differences were usually not marked. Telomere length was greatest in young control mice and was decreased by both smoking and age. The senescence marker p21(Waf1) was equally upregulated by smoke in young and old, but p16(INK4a), another senescence marker, was not upregulated at all. We conclude, in this model, animal age does not affect the development of emphysema and small airway remodeling.
    PLoS ONE 08/2013; 8(8):e71410. DOI:10.1371/journal.pone.0071410 · 3.23 Impact Factor
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    • "Beyond being influenced by mouse strain (Guerassimov et al., 2004; Bartalesi et al., 2005; Foronjy et al., 2005), emphysema development is also dependent on the airspace content of antioxidants . This was demonstrated by comparing bronchoalveolar lavage (BAL) levels of endogenous anti-oxidants from the oxidant resistant mouse strain ICR with that from other strains (Cavarra et al., 2001; Richens et al., 2009). Successful antioxidant therapy is seen for mainstream (March et al., 2006; Suzuki et al., 2009; Churg et al., 2012) and side stream exposure models (Smith et al., 2002; Richens et al., 2009), as well as in a Rtp801 knockout model for side stream smoke (Yoshida et al., 2010). "
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    ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is one of the foremost causes of death worldwide. It is primarily caused by tobacco smoke, making it an easily preventable disease, but facilitated by genetic α-1 antitrypsin deficiency. In addition to active smokers, health problems also occur in people involuntarily exposed to second hand smoke (SHS). Currently, the relationship between SHS and COPD is not well established. Knowledge of pathogenic mechanisms is limited, thereby halting the advancement of new treatments for this socially and economically detrimental disease. Here, we attempt to summarize tobacco smoke studies undertaken in animal models, applying both mainstream (direct, nose only) and side stream (indirect, whole body) smoke exposures. This overview of 155 studies compares cellular and molecular mechanisms as well as proteolytic, inflammatory, and vasoreactive responses underlying COPD development. This is a difficult task, as listing of exposure parameters is limited for most experiments. We show that both mainstream and SHS studies largely present similar inflammatory cell populations dominated by macrophages as well as elevated chemokine/cytokine levels, such as TNF-α. Additionally, SHS, like mainstream smoke, has been shown to cause vascular remodeling and neutrophil elastase-mediated proteolytic matrix breakdown with failure to repair. Disease mechanisms and therapeutic interventions appear to coincide in both exposure scenarios. One of the more widely applied interventions, the anti-oxidant therapy, is successful for both mainstream and SHS. The comparison of direct with indirect smoke exposure studies in this review emphasizes that, even though there are many overlapping pathways, it is not conclusive that SHS is using exactly the same mechanisms as direct smoke in COPD pathogenesis, but should be considered a preventable health risk. Some characteristics and therapeutic alternatives uniquely exist in SHS-related COPD.
    Frontiers in Physiology 05/2013; 4:91. DOI:10.3389/fphys.2013.00091 · 3.53 Impact Factor
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