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. 2018 Feb 6:9:58.
doi: 10.3389/fphys.2018.00058. eCollection 2018.

Establishment and Evaluation of a Rat Model of Sidestream Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

Genfa Wang  1   2   3 , Nabijan Mohammadtursun  1   2   4 , Jing Sun  1   2 , Yubao Lv  1   2 , Hualiang Jin  1   2 , Jinpei Lin  1   2 , Lingwen Kong  1   2 , Zhengxiao Zhao  1   2 , Hongying Zhang  1   2 , Jingcheng Dong  1   2
Affiliations

Establishment and Evaluation of a Rat Model of Sidestream Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

Genfa Wang et al. Front Physiol. .

Abstract

Chronic obstructive pulmonary disease (COPD) is a common cause of mortality worldwide. The current lack of an animal model that can be established within a certain time frame and imitate the unique features of the disease is a major limiting factor in its study. The present study established and evaluated an animal model of COPD that represents the early and advanced stage features using short-, middle-, and long-term sidestream cigarette smoke (CS) exposure. One hundred and nine Sprague-Dawley rats were randomly divided into 10 groups for different periods of sidestream CS exposure or no exposure (i.e., normal groups). The rats were exposed to CS from 3R4F cigarettes in an exposure chamber. Histological analysis was performed to determine pathological changes. We also conducted open-field tests, lung function evaluations, and cytokine analysis of the blood serum, bronchoalveolar lavage fluid, and lung tissue. The lung tissue protein levels, blood gases, and were also analyzed. As the CS exposure time increased, the indicators associated with oxidative stress, inflammatory responses, and airway remodeling were greater in the CS exposure groups than in the normal group. At 24 and 36 weeks, the COPD model rats displayed the middle- and advanced-stage features of COPD, respectively. In the 8-week CS exposure group, after the CS exposure was stopped for 4 weeks, inflammatory responses and oxidative responses were ameliorated and lung function exacerbation was reduced compared with the 12-week CS exposure group. Therefore, we established a more adequate rat model of sidestream CS induced COPD, which will have great significance for a better understanding of the pathogenesis of COPD and drug effectiveness evaluation.

Keywords: airway remodeling; chronic obstructive pulmonary disease; cigarette smoke; passive smoking; rat model.

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Figures

Figure 1
Figure 1
Body weight changes in the cigarette smoke (CS) exposure groups and normal groups. (A) The 36-week cigarette smoke exposure group (M7) and normal group (N3). (B) The 12-week cigarette smoke exposure group (M4), the 8-week CS exposure + 4-week recovery group (M5), and the 12-week normal group (N1). The values are presented as the means ± the standard error of the mean (SEM). *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the control group.
Figure 2
Figure 2
Comparison of lung function indicators between the normal groups (N1, N2, and N3) and their respective cigarette smoke (CS) exposure group. (A) The FEV1/FVC ratio in each CS exposure group. (B) The FEV1/FVC ratio at weeks 12, 24, and 36 in the CS exposure group. (C) The vital capacity (VC) level at 12, 24, and 36 weeks in the CS exposure group. (D) The MMEF level at 12, 24, and 36 weeks in the CS exposure group. (E) The TLC level at 12, 24, and 36 weeks in the CS exposure group. (F) The FRC level at 12, 24, and 36 weeks in the CS exposure group. The data are shown as the mean ± the standard error of the mean (SEM). *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the control group. FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; MMEF, maximum mild expiratory flow; TLC, total lung capacity.
Figure 3
Figure 3
Comparison of lung function indicators between the normal group and the 12-week cigarette smoke (CS) exposure group and the 8-week CS exposure + 4-week CS exposure cessation group. (A) The FEV1/FVC ratio at 12 weeks in the normal group, M4 group, and M5 group. (B) The vital capacity (VC) at 12 weeks in the normal group, M4 group, and M5 group. (C) The FRC at 12 weeks in the normal group, M4 group, and M5 group. (D) The TLC at 12 weeks in the normal group, M4 group, and M5 group. (E) The MMEF at 12 weeks in the normal group, M4 group, and M5 group. The data are presented as the mean ± the standard error of the mean (SEM).*p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the control group N1.#p < 0.05 and ##p < 0.01 indicates a statistically significant difference compared to the M4 group. FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; MMEF, maximal mild expiratory flow; TLC, total lung capacity.
Figure 4
Figure 4
Photograph of HE-stained lung tissue under an optical microscope (×200). M1, 2-week cigarette smoke (CS) exposure group; M2, 4-week CS exposure group; M3, 8-week CS exposure group; M4, 12-week CS exposure group; M5, 8-week CS exposure + 4-week CS cessation group; M6, 24-week CS exposure group; M7, 36-week CS exposure group; N1, 12-week normal group; N2, 24-week normal group; N2, 36-week normal group. H&E, haematoxylin–eosin.
Figure 5
Figure 5
Comparison of lung tissue pathology findings between the model groups, based on semi-quantitative analysis of airway inflammation scores and emphysema indicators. (A) The airway inflammation score. (B) The destructive index (DI). (C) The mean linear intercept (MLI). (D) The mean alveolus area.
Figure 6
Figure 6
Comparison of HE-stained rat lung tissue of the model groups, based on semi-quantitative analysis. (A) Mean vessel area. (B) Bronchus smooth muscle thickness. (C) Vessel smooth muscle thickness. H&E, haematoxylin-eosin.
Figure 7
Figure 7
Open-field test results. (A) Residence time in the central grids. (B) Number of cross-links. (C) Upright grooming behavior. (D) Grooming Behavior. The data are presented as the mean ± the standard error of the mean (SEM). *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
Figure 8
Figure 8
Blood gas analysis after 36 weeks of cigarette smoke (CS) exposure. (A) Arterial PaO2 and PaCO2 levels. (B) Blood pH. PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen. The data are presented as the mean ± the standard error of the mean (SEM). *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group.
Figure 9
Figure 9
Comparison of inflammatory and anti-inflammatory factors in blood serum. (A) Interleukin (IL)-6. (B) IL-17. (C) IL-1β. (D) Tumor necrosis factor (TNF)-α. (E) IL-10. (F) surfactant protein D (SP-D), (G) Interleukin(IL)-10. The data are expressed as the mean ± standard deviation. *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
Figure 10
Figure 10
Comparison of oxidative and antioxidative factors in blood serum. (A) Malondialdehyde (MDA), (B) Reactive oxygen species (ROS), (C) Total antioxidant capacity (T-AOC), (D) Heme oxygenase-1 (HO-1), (E) Superoxide dismutase (SOD). The data are expressed as the mean ± standard deviation. *p < 0.05 and **p < 0.01 indicate a statistically significantly difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
Figure 11
Figure 11
Comparison of airway remodeling factors in blood serum. (A) Matrix metalloproteinase (MMP)-2. (B) MMP-9. (C) Tissue inhibitor of metalloproteinase 1 (TIMP-1). (D) Transforming growth factor beta-1 (TGFβ-1). (E) Vascular endothelial growth factor (VEGF). The data are expressed as the mean ± standard deviation. *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
Figure 12
Figure 12
Comparison of inflammatory and anti-inflammatory factors in bronchoalveolar lavage fluid (BALF). (A) Interleukin (IL)-6. (B) IL-8. (C) IL-17. (D) IL-1β. (E) Tumor necrosis factor (TNF)-α. (F) IL-10. The data are expressed as the mean ± standard deviation. *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
Figure 13
Figure 13
Comparison of inflammatory and anti-inflammatory factors in lung tissue. (A) Interleukin (IL)-6. (B) IL-8. (C) Tumor necrosis factor (TNF)-α. (D) IL-10. (E) Protein concentration. The data are expressed as the mean ± standard deviation. *p < 0.05 and **p < 0.01 indicate a statistically significant difference compared to the normal group. #p < 0.05 and ##p < 0.01 indicate a statistically significant difference between the M5 group and the M4 group.
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