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Environ Pollut. 2017 Oct;229:746-759. doi: 10.1016/j.envpol.2017.04.098. Epub 2017 Jun 22.

Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model.

Author information

1
Department of Pharmacology and Pharmacotherapy, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; Department of Medical Biology, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary. Electronic address: agnes.kemeny@aok.pte.hu.
2
Department of Pharmacology and Pharmacotherapy, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary. Electronic address: cseko.kata@pte.hu.
3
Department of Pharmacology and Pharmacotherapy, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary. Electronic address: szitteristvan@gmail.com.
4
Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, H-1089 Budapest, Nagyvárad tér 4., Hungary. Electronic address: varga.zoltan@med.semmelweis-univ.hu.
5
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Faculty of Medicine, H-6720 Szeged, Dóm tér 9., Hungary; Pharmahungary Group, H-6722 Szeged, Hajnóczy u. 6., Hungary. Electronic address: peter.bencsik@pharmahungary.com.
6
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Faculty of Medicine, H-6720 Szeged, Dóm tér 9., Hungary. Electronic address: kiss.krisztina.1@med.u-szeged.hu.
7
Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary; I(st) Department of Internal Medicine, University of Pécs, Faculty of Medicine, H-7624 Pécs, Ifjúság útja 13., Hungary. Electronic address: halmosi.robert@pte.hu.
8
Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary; I(st) Department of Internal Medicine, University of Pécs, Faculty of Medicine, H-7624 Pécs, Ifjúság útja 13., Hungary. Electronic address: laszlo.deres@aok.pte.hu.
9
Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary; I(st) Department of Internal Medicine, University of Pécs, Faculty of Medicine, H-7624 Pécs, Ifjúság útja 13., Hungary; Department of Biochemistry and Medical Chemistry, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary. Electronic address: krisztian.eros@aok.pte.hu.
10
Department of Pharmacology and Pharmacotherapy, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary. Electronic address: aniko.perkecz@aok.pte.hu.
11
Department of Pathology, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary. Electronic address: kereskai.laszlo@pte.hu.
12
Department of Pathology, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary. Electronic address: laszlo.terezia@pte.hu.
13
Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary. Electronic address: tamas.kiss2@aok.pte.hu.
14
Cardiometabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, H-1089 Budapest, Nagyvárad tér 4., Hungary; Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Faculty of Medicine, H-6720 Szeged, Dóm tér 9., Hungary; Pharmahungary Group, H-6722 Szeged, Hajnóczy u. 6., Hungary. Electronic address: peter.ferdinandy@pharmahungary.com.
15
Department of Pharmacology and Pharmacotherapy, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Ifjúság útja 20., Hungary; MTA-PTE NAP B Chronic Pain Research Group, University of Pécs, Faculty of Medicine, H-7624 Pécs, Szigeti út 12., Hungary; PharmInVivo Ltd, H-7629 Pécs, Szondi György út 10., Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.

Abstract

Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model. Some respiratory alterations characteristic of emphysema (decreased airway resistance: Rl; end-expiratory work and pause: EEW, EEP; expiration time: Te; increased tidal mid-expiratory flow: EF50) were detected in anaesthetized C57BL/6 mice, unrestrained plethysmography did not show changes. Typical histopathological signs were peribronchial/perivascular (PB/PV) edema at month 1, neutrophil/macrophage infiltration at month 2, interstitial leukocyte accumulation at months 3-4, and emphysema/atelectasis at months 5-6 quantified by mean linear intercept measurement. Emphysema was proven by micro-CT quantification. Leukocyte number in the bronchoalveolar lavage at month 2 and lung matrix metalloproteinases-2 and 9 (MMP-2/MMP-9) activities in months 5-6 significantly increased. Smoking triggered complex cytokine profile change in the lung with one characteristic inflammatory peak of C5a, interleukin-1α and its receptor antagonist (IL-1α, IL-1ra), monokine induced by gamma interferon (MIG), macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) at months 2-3, and another peak of interferon-γ (IFN-γ), IL-4, 7, 13, 17, 27 related to tissue destruction. Transient systolic and diastolic ventricular dysfunction developed after 1-2 months shown by significantly decreased ejection fraction (EF%) and deceleration time, respectively. These parameters together with the tricuspid annular plane systolic excursion (TAPSE) decreased again after 5-6 months. Soluble intercellular adhesion molecule-1 (sICAM-1) significantly increased in the heart homogenates at month 6, while other inflammatory cytokines were undetectable. This is the first study demonstrating smoking duration-dependent, complex cardiopulmonary alterations characteristic to COPD, in which inflammatory cytokine cascades and MMP-2/9 might be responsible for pulmonary destruction and sICAM-1 for heart dysfunction.

KEYWORDS:

Echocardiography; Emphysema; Inflammatory cytokines; Pneumonitis; Whole-body plethysmography

PMID:
28648837
DOI:
10.1016/j.envpol.2017.04.098
[Indexed for MEDLINE]

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