A Rat Model for Stable Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke Inhalation and Repetitive Bacterial Infection

Abstract

To develop a stable chronic obstructive pulmonary disease (COPD) model in rats. Sprague-Dawley rats were treated with cigarette-smoke inhalation (CSI) for 12 weeks, repetitive bacterial infection (RBI) for 8 weeks, or the combination of the two (CCR) for 12 weeks and followed up for the additional 20 weeks. Tidal volume (V T ), peak expiratory flow (PEF) and 50% V T expiratory flow (EF 50 ), histological changes in the lungs, and levels of the cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-10 in serum and bronchial alveolar lavage fluid (BALF) were examined at intervals during the 32 week study period. The right ventricular hypertrophy index (RVHI) was also determined at the same times. V T , PEF, and EF 50 were decreased in rats with COPD compared to the control. The expression of TNF-α, IL-8 and IL-10 increased in both serum and BALF with a similar trend. Bronchiole and arteriole wall thickness and the degree of bronchiole stenosis and alveolar size increased in COPD rats. RVHI was reduced gradually following the treatment. All of these changes were more pronounced in the CCR-treatment group than in the other groups. Our results have shown that CSI or RBI alone can induce COPD in rats, but that the combination of CSI with RBI induces a stable COPD that has more similarity to complications seen in patients with COPD. This combination may therefore provide a more appropriate model for study of human COPD.Key words pulmonary disease; chronic obstructive; animal model; pulmonary function; histological change; right ventricular hypertrophy index Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable pathologic condition characterized by partially reversible airflow limitation, 1) and is a major cause of morbidity and mortality throughout the world.2) Its prevalence among the Chinese population aged 40 or older is 8.2%.3) Development of COPD is slow and progressive in humans, with occasional exacerbations caused by an inflammatory response to triggering substances such as noxious gases, 1) bacteria 4-6) or viruses. [7][8][9][10][11] Four abnormalities are present in chronic, stable COPD: emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis.Tobacco smoking and bacterial infection are the most common and important risk factors for COPD, 1,12,13) and they have each been used to establish animal COPD models. [14][15][16] Animal models have also used other noxious gases [17][18][19] and Pneumocystis carinii infection 20) in COPD induction. Short term induction protocols (days) 17,21) have resulted in a pulmonary inflammatory infiltrate, increased mucus production, and pulmonary edema. Long term induction protocols (weeks or months) 15,[17][18][19] have produced, in addition to the inflammatory infiltrate, emphysema and pulmonary remodeling characterized by fibrosis, and thickened bronchiole and arterial walls. Problems with animal models are that most of them are of short duration and the COPD produced does not correspond to the late...

A new experimental model of cigarette smoke-induced emphysema in Wistar rats

“…( 12 , 21 , 22 ) Li et al adopted a two-step exposure protocol whereby animals were initially exposed to smoke from 8 cigarettes twice a day for 2 weeks (weeks 1 and 2) and subsequently exposed to smoke from 15 cigarettes three times a day for another 10 weeks (weeks 3-12). ( 23 ) The animal model used in the present study simulates the pathophysiological conditions of active smoking, animals having been exposed to mainstream cigarette smoke daily (7 days a week) for 30 weeks.…”

“…( 12 , 21 , 22 ) Li et al adotaram um protocolo de exposição dividido em duas etapas: primeiramente, os animais foram expostos à fumaça de 8 cigarros duas vezes por dia durante 2 semanas (semanas 1 e 2) e, em seguida, foram expostos à fumaça de 15 cigarros três vezes por dia durante 10 semanas (semanas 3-12). ( 23 ) O modelo animal usado no presente estudo simula as condições fisiopatológicas do tabagismo ativo; os animais foram expostos à fumaça principal do cigarro diariamente (7 dias por semana) durante 30 semanas.…”

Experimental animal models for COPD: a methodological review

“…Tobacco smoking is the most important risk factor for COPD [2, 4] and the most common COPD-inducer employed in in vivo studies [12]. In addition, to mainstream cigarette smoke, environmental cigarette smoke may also contribute to respiratory symptoms and COPD [4].…”

“…Development of COPD is slow and progressive, with occasional exacerbations caused by inflammatory responses induced by triggering substances such as noxious gases, bacteria or viruses [2]. …”

An Evolutionary Medicine Approach to Understanding Factors That Contribute to Chronic Obstructive Pulmonary Disease

“…For example, it has been reported that airway inflammation induced by viral pathogen-associated molecular pattern stimulation is similar to that in COPD [39], and that cigarette smoke exacerbates airway inflammation induced by viral pathogen-associated molecular patterns [40]. In addition, it has been reported that latent adenoviral infection exacerbates airway inflammation and emphysematous lesions caused by cigarette smoke [41], and that simultaneous exposure to cigarette smoke and bacteria results in the formation of lesions similar to those in COPD [42]. Furthermore, it has been elucidated that CXCL13 is involved in lymphoid follicle formation in the airways of COPD patients as well as in response to viral infections [43,44].…”