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

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.

Altered protein turnover signaling and myogenesis during impaired recovery of inflammation-induced muscle atrophy in emphysematous mice

“…Histological analyses of lung sections post-LPS or –vc administration confirmed airspace enlargement in elastase-treated mice (Fig. 2g ) as shown previously in this model 14 , 16 , which based on the measured LAA% is expected to correspond with a mean linear intercept of 45–50 14 , and is similar to the extent of emphysema observed following chronic smoke exposure in mice 17 . Broncho-alveolar lavage (BAL)fluid protein content levels were increased following LPS, indicative of lung injury in control and emphysematous mice (Fig.…”

Gender‐biased kidney damage in mice following exposure to tobacco cigarette smoke: More protection in premenopausal females

“…IL‐4 is a pleiotropic cytokine engaged in several pathways that range from a classical anti‐inflammatory action with type 2 like effect to TGF‐β upregulation and fibrosis formation independently or in combination with multiple other processes (Luzina et al, ; Pardo & Selman, ; Sempowski, Beckmann, Derdak, & Phipps, ; Sime & O'Reilly, ; Striz et al, ). Interestingly, both experimental and clinical studies are in accordance with our findings and documented an increase in IL‐4 levels in serum and pulmonary tissue following CS exposure with a significance only seen in CS‐exposed men (Byron, Varigos, & Wootton, ; Flouris et al, ; Kemeny et al, ; Matsunaga et al, ; Nakamura et al, ; Sahlander, Larsson, & Palmberg, ; Zhu et al, ). TGF‐β1 is also a pleiotropic and multifunctional cytokine with profibrotic actions and is known to be upregulated in the kidneys of CS‐exposed subjects and plays a major role in the development of progressive glomerulosclerosis and interstitial fibrosis (Elliot et al, ; Mur et al, ).…”

Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models

“…CSE induced massive accumulations of granulocytes, macrophages and lymphocytes measured in the bronchoalveolar lavage fluid (BALF) of both Trpa1 +/+ and Trpa1 −/− mice. In agreement with our previous findings [63], the number of inflammatory cells reduced by the end of the 3rd month of CSE. There was no biologically relevant difference between the wildtype and gene-deficient mice in either inflammatory cell component (Figure 9).…”

“…The extent of perivascular/peribronchial oedema was the most severe after 1 month and gradually decreasing afterwards, and the inflammatory cell infiltration reached its maximum after 2 months of CSE in both groups, which is in agreement with our earlier findings in the same model [63]. TRPA1 deficiency did not result in significant changes of the cellular components of these chronic inflammatory processes, as shown by both the histopathological results and BALF analysis.…”

“…Chronic bronchitis was elicited by whole body cigarette smoke exposure for 4 months. Mice were exposed to cigarette smoke (3R4F Kentucky Research Cigarette; University of Kentucky, Lexington, KY, USA) twice daily, 10 times per week in a whole body smoke exposure chamber (Teague Enterprises, Woodland, CA, USA) for 30 min followed by a ventilation period of 30 min as described previously [63].…”