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

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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Prenatal cigarette smoke exposure slightly alters neurobehavioral development in neonatal rats: Implications for developmental origins of health and disease (DoHAD)

Physiology International ◽

10.1556/2060.2020.00007 ◽

2020 ◽

Vol 107 (1) ◽

pp. 55-66

Author(s):

B. Mammel ◽

T. Kvárik ◽

Zs. Szabó ◽

J. Gyarmati ◽

T. Ertl ◽

...

Keyword(s):

Cigarette Smoke ◽

Motor Coordination ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Control Group ◽

Developmental Origins ◽

Smoking During Pregnancy ◽

Neurobehavioral Development ◽

Health And Disease

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 Exposure in Mice using a Whole-Body Inhalation System

Journal of Visualized Experiments ◽

10.3791/61793 ◽

2020 ◽

Author(s):

Daniel E. Morales-Mantilla ◽

Xinyan Huang ◽

Philip Erice ◽

Paul Porter ◽

Yun Zhang ◽

...

Keyword(s):

Cigarette Smoke ◽

Smoke Exposure ◽

Whole Body ◽

Cigarette Smoke Exposure ◽

Whole Body Inhalation

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Differential expression and function of breast regression protein 39 (BRP-39) in murine models of subacute cigarette smoke exposure and allergic airway inflammation

Respiratory Research ◽

10.1186/1465-9921-12-39 ◽

2011 ◽

Vol 12 (1) ◽

Cited By ~ 14

Author(s):

Jake K Nikota ◽

Fernando M Botelho ◽

Carla MT Bauer ◽

Manel Jordana ◽

Anthony J Coyle ◽

...

Keyword(s):

Airway Inflammation ◽

Differential Expression ◽

Cigarette Smoke ◽

Allergic Airway Inflammation ◽

Smoke Exposure ◽

Cigarette Smoke Exposure ◽

Murine Models ◽

And Function

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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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