Cigarette Smoke Exposure in Mice using a Whole-Body Inhalation System

AbstractNumerous studies indicate that smoking during pregnancy exerts harmful effects on fetal brain development. The aim of this study was to determine the influence of maternal smoking during pregnancy on the early physical and neurobehavioral development of newborn rats. Wistar rats were subjected to whole-body smoke exposure for 2 × 40 min daily from the day of mating until day of delivery. For this treatment, a manual closed-chamber smoking system and 4 research cigarettes per occasion were used. After delivery the offspring were tested daily for somatic growth, maturation of facial characteristics and neurobehavioral development until three weeks of age. Motor coordination tests were performed at 3 and 4 weeks of age. We found that prenatal cigarette smoke exposure did not alter weight gain or motor coordination. Critical physical reflexes indicative of neurobehavioral development (eyelid reflex, ear unfolding) appeared significantly later in pups prenatally exposed to smoke as compared to the control group. Prenatal smoke exposure also resulted in a delayed appearance of reflexes indicating neural maturity, including hind limb grasping and forelimb placing reflexes. In conclusion, clinically relevant prenatal exposure to cigarette smoke results in slightly altered neurobehavioral development in rat pups. These findings suggest that chronic exposure of pregnant mothers to cigarette smoke (including passive smoking) results in persisting alterations in the developing brain, which may have long-lasting consequences supporting the concept of developmental origins of health and disease (DoHAD).

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Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00274.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. R1249-R1256 ◽

Cited By ~ 9

Author(s):

Robin E. Gandley ◽

Arun Jeyabalan ◽

Ketaki Desai ◽

Stacy McGonigal ◽

Jennifer Rohland ◽

...

Keyword(s):

Mouse Model ◽

Cigarette Smoke ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Smoke Exposure ◽

Renal Arteries ◽

Growth Restriction ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Pregnant Mice

Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day. Smoke particle exposure was increased from day 4 of gestation until late pregnancy ( day 16–19), with mean total suspended particle levels of 63 mg/m3, representative of moderate-to-heavy smoking in humans. Uterine, mesenteric, and renal arteries from late-pregnant and virgin mice were isolated and studied in a pressure-arteriograph system ( n = 23). Plasma cotinine was measured by ELISA. Fetal weights were significantly reduced in smoke-exposed compared with control fetuses (0.88 ± 0.1 vs. 1.0 ± 0.08 g, P < 0.02), while litter sizes were not different. Endothelium-mediated relaxation responses to methacholine were significantly impaired in both the uterine and mesenteric vasculature of pregnant mice exposed to cigarette smoke during gestation. This difference was not apparent in isolated renal arteries from pregnant mice exposed to cigarette smoke; however, relaxation was significantly reduced in renal arteries from smoke-exposed virgin mice. In conclusion, we found that passive cigarette smoke exposure is associated with impaired vascular relaxation of uterine and mesenteric arteries in pregnant mice. Functional maternal vascular perturbations during pregnancy, specifically impaired peripheral and uterine vasodilation, may contribute to a mechanism by which smoking results in fetal growth restriction.

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Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00304.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. L255-L265 ◽

Cited By ~ 52

Author(s):

Saskia Braber ◽

Pim J. Koelink ◽

Paul A. J. Henricks ◽

Patricia L. Jackson ◽

Frans P. Nijkamp ◽

...

Keyword(s):

Smoking Cessation ◽

Airway Inflammation ◽

Cigarette Smoke ◽

Lung Tissue ◽

Smoke Exposure ◽

Prolyl Endopeptidase ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Neutrophil Influx ◽

Lung Emphysema

There is increasing evidence that the neutrophil chemoattractant proline-glycine-proline (PGP), derived from the breakdown of the extracellular matrix, plays an important role in neutrophil recruitment to the lung. PGP formation is a multistep process involving neutrophils, metalloproteinases (MMPs), and prolyl endopeptidase (PE). This cascade of events is now investigated in the development of lung emphysema. A/J mice were whole body exposed to cigarette smoke for 20 wk. After 20 wk or 8 wk after smoking cessation, animals were killed, and bronchoalveolar lavage fluid and lung tissue were collected to analyze the neutrophilic airway inflammation, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels. Lung tissue degradation was assessed by measuring the mean linear intercept. Additionally, we investigated the effect of the peptide l-arginine-threonine-arginine (RTR), which binds to PGP sequences, on the smoke-induced neutrophil influx in the lung after 5 days of smoke exposure. Neutrophilic airway inflammation was induced by cigarette smoke exposure. MMP-8 and MMP-9 levels, PE activity, and PGP levels were elevated in the lungs of cigarette smoke-exposed mice. PE was highly expressed in epithelial and inflammatory cells (macrophages and neutrophils) in lung tissue of cigarette smoke-exposed mice. After smoking cessation, the neutrophil influx, the MMP-8 and MMP-9 levels, the PE activity, and the PGP levels were decreased or reduced to normal levels. Moreover, RTR inhibited the smoke-induced neutrophil influx in the lung after 5 days' smoke exposure. In the present murine model of cigarette smoke-induced lung emphysema, it is demonstrated for the first time that all relevant components (neutrophils, MMP-8, MMP-9, PE) involved in PGP formation from collagen are upregulated in the airways. Together with MMPs, PE may play an important role in the formation of PGP and thus in the pathophysiology of lung emphysema.

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Short-term whole body cigarette smoke exposure induces regional differences in cellular response in the mouse larynx

Toxicology Reports ◽

10.1016/j.toxrep.2021.04.007 ◽

2021 ◽

Author(s):

Meena Easwaran ◽

Joshua D. Martinez ◽

Daniel J. Ramirez ◽

Phillip A. Gall ◽

Elizabeth Erickson-DiRenzo

Keyword(s):

Cigarette Smoke ◽

Regional Differences ◽

Cellular Response ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Short Term

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Cigarette Smoke Exposure Impairs Pulmonary Bacterial Clearance and Alveolar Macrophage Complement-Mediated Phagocytosis of Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.00963-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 1214-1220 ◽

Cited By ~ 90

Author(s):

John C. Phipps ◽

David M. Aronoff ◽

Jeffrey L. Curtis ◽

Deepti Goel ◽

Edmund O'Brien ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Alveolar Macrophage ◽

Cigarette Smoke ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Necrosis Factor Alpha ◽

Macrophage Phagocytosis

ABSTRACT Cigarette smoke exposure increases the risk of pulmonary and invasive infections caused by Streptococcus pneumoniae, the most commonly isolated organism from patients with community-acquired pneumonia. Despite this association, the mechanisms by which cigarette smoke exposure diminishes host defense against S. pneumoniae infections are poorly understood. In this study, we compared the responses of BALB/c mice following an intratracheal challenge with S. pneumoniae after 5 weeks of exposure to room air or cigarette smoke in a whole-body exposure chamber in vivo and the effects of cigarette smoke on alveolar macrophage phagocytosis of S. pneumoniae in vitro. Bacterial burdens in cigarette smoke-exposed mice were increased at 24 and 48 h postinfection, and this was accompanied by a more pronounced clinical appearance of illness, hypothermia, and increased lung homogenate cytokines interleukin-1β (IL-1β), IL-6, IL-10, and tumor necrosis factor alpha (TNF-α). We also found greater numbers of neutrophils in bronchoalveolar lavage fluid recovered from cigarette smoke-exposed mice following a challenge with heat-killed S. pneumoniae. Interestingly, overnight culture of alveolar macrophages with 1% cigarette smoke extract, a level that did not affect alveolar macrophage viability, reduced complement-mediated phagocytosis of S. pneumoniae, while the ingestion of unopsonized bacteria or IgG-coated microspheres was not affected. This murine model provides robust additional support to the hypothesis that cigarette smoke exposure increases the risk of pneumococcal pneumonia and defines a novel cellular mechanism to help explain this immunosuppressive effect.

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Impact of whole‐body versus nose‐only inhalation exposure systems on systemic, respiratory, and cardiovascular endpoints in a 2‐month cigarette smoke exposure study in the ApoE −/− mouse model

Journal of Applied Toxicology ◽

10.1002/jat.4149 ◽

2021 ◽

Author(s):

Ulrike Kogel ◽

Ee Tsin Wong ◽

Justyna Szostak ◽

Wei Teck Tan ◽

Francesco Lucci ◽

...

Keyword(s):

Mouse Model ◽

Cigarette Smoke ◽

Inhalation Exposure ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Exposure Study ◽

Apoe Mouse

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Increased Monocyte-Derived CD11b+ Macrophage Subpopulations Following Cigarette Smoke Exposure Are Associated With Impaired Bleomycin-Induced Tissue Remodelling

Frontiers in Immunology ◽

10.3389/fimmu.2021.740330 ◽

2021 ◽

Vol 12 ◽

Author(s):

Steven P. Cass ◽

Olivia Mekhael ◽

Danya Thayaparan ◽

Joshua J. C. McGrath ◽

Spencer D. Revill ◽

...

Keyword(s):

Cigarette Smoke ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Tissue Remodelling ◽

Pulmonary Macrophage ◽

Pulmonary Macrophages ◽

Macrophage Subpopulations ◽

Compositional Changes ◽

The Impact

RationaleThe accumulation of macrophages in the airways and the pulmonary interstitium is a hallmark of cigarette smoke-associated inflammation. Notably, pulmonary macrophages are not a homogenous population but consist of several subpopulations. To date, the manner in which cigarette smoke exposure affects the relative composition and functional capacity of macrophage subpopulations has not been elucidated.MethodsUsing a whole-body cigarette smoke exposure system, we investigated the impact of cigarette smoke on macrophage subpopulations in C57BL/6 mice using flow cytometry-based approaches. Moreover, we used bromodeoxyuridine labelling plus Il1a-/- and Il1r1-/- mice to assess the relative contribution of local proliferation and monocyte recruitment to macrophage accumulation. To assess the functional consequences of altered macrophage subpopulations, we used a model of concurrent bleomycin-induced lung injury and cigarette smoke exposure to examine tissue remodelling processes.Main ResultsCigarette smoke exposure altered the composition of pulmonary macrophages increasing CD11b+ subpopulations including monocyte-derived alveolar macrophages (Mo-AM) as well as interstitial macrophages (IM)1, -2 and -3. The increase in CD11b+ subpopulations was observed at multiple cigarette smoke exposure timepoints. Bromodeoxyuridine labelling and studies in Il1a-/- mice demonstrated that increased Mo-AM and IM3 turnover in the lungs of cigarette smoke-exposed mice was IL-1α dependent. Compositional changes in macrophage subpopulations were associated with impaired induction of fibrogenesis including decreased α-smooth muscle actin positive cells following intratracheal bleomycin treatment. Mechanistically, in vivo and ex vivo assays demonstrated predominant macrophage M1 polarisation and reduced matrix metallopeptidase 9 activity in cigarette smoke-exposed mice.ConclusionCigarette smoke exposure modified the composition of pulmonary macrophage by expanding CD11b+ subpopulations. These compositional changes were associated with attenuated fibrogenesis, as well as predominant M1 polarisation and decreased fibrotic activity. Overall, these data suggest that cigarette smoke exposure altered the composition of pulmonary macrophage subpopulations contributing to impaired tissue remodelling.

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Comparison of the immune response in a mouse model of whole body and nose-only cigarette smoke-exposure

10.1183/1393003.congress-2017.oa4827 ◽

2017 ◽

Author(s):

Jef Serré ◽

Tom Tanjeko Ajimé ◽

Carolien Mathyssen ◽

Tobias Heigl ◽

Karen Maes ◽

...

Keyword(s):

Immune Response ◽

Mouse Model ◽

Cigarette Smoke ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure

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HIV infection model of chronic obstructive pulmonary disease in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00431.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. L500-L509 ◽

Cited By ~ 8

Author(s):

Patrick Geraghty ◽

Eran Hadas ◽

Boe-Hyun Kim ◽

Abdoulaye J. Dabo ◽

David J. Volsky ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Smoke Exposure ◽

Cathepsin G ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Stat3 Phosphorylation

Cigarette smoke usage is prevalent in human immunodeficiency virus (HIV)-positive patients, and, despite highly active antiretroviral therapy, these individuals develop an accelerated form of chronic obstructive pulmonary disease (COPD). Studies investigating the mechanisms of COPD development in HIV have been limited by the lack of suitable mouse models. Here we describe a model of HIV-induced COPD in wild-type mice using EcoHIV, a chimeric HIV capable of establishing chronic infection in immunocompetent mice. A/J mice were infected with EcoHIV and subjected to whole body cigarette smoke exposure. EcoHIV was detected in alveolar macrophages of mice. Compared with uninfected mice, concomitant EcoHIV infection significantly reduced forced expiratory flow 50%/forced vital capacity and enhanced distal airspace enlargement following cigarette smoke exposure. Lung IL-6, granulocyte-macrophage colony-stimulating factor, neutrophil elastase, cathepsin G, and matrix metalloproteinase-9 expression was significantly enhanced in smoke-exposed EcoHIV-infected mice. These changes coincided with enhanced IκBα, ERK1/2, p38, and STAT3 phosphorylation and lung cell apoptosis. Thus, the EcoHIV smoke exposure mouse model reproduces several of the pathophysiological features of HIV-related COPD in humans, indicating that this murine model can be used to determine key parameters of HIV-related COPD and to test future therapies for this disorder.

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