Pulmonary Emphysema Induced by Cigarette Smoke Solution and Lipopolysaccharide in Guinea Pigs

Abstract

Chronic obstructive pulmonary disease (COPD) is a major global health problem that is predicted to become the third most common cause of death by 2020.1,2) Nearly 90% of COPD patients are smokers.3) COPD is a condition characterized by airway obstruction due to narrowing of the small airways that is not fully reversible, airway inflammation, and emphysema-related loss of the elastic recoil of the lung. [4][5][6] Pulmonary emphysema is a major component of COPD and is defined by a destructive change of the pulmonary alveoli and enlargement of the respiratory region of the lung distal to the terminal bronchioles. In addition, residual volume (RV) and functional residual capacity (FRC) are characteristically increased in COPD and are related to the degree of hyperinflation of the lungs, especially when there is predominately emphysema. 7,8) Still, the detailed sequence of events leading to the onset of pulmonary emphysema is not yet fully elucidated.On the other hand, it has been suggested that the morbidity and mortality of COPD are associated with acute exacerbations.9,10) Some exacerbations of COPD are undoubtedly related to respiratory bacteria, which infect the lower airways and increase overall airway inflammation. 11,12) In addition, meta-analyses of antibiotic therapy have indicated an advantage for the use of such interventions, which confirms that bacteria are responsible for the exacerbations in COPD. 13,14) In studies using guinea pigs and mice, it has been reported that repeated exposure of the animals to lipopolysaccharide (LPS) results in persistent chronic pulmonary inflammation observed in human subjects with COPD. 15,16) The use of appropriate experimental COPD animal models is indispensable for the development of new therapeutic drugs and for the analysis of the pathogenesis of the disease. By exposing animals to 3 or more months of cigarette smoke, various experimental COPD models have been developed in guinea pigs, rats and mice. [17][18][19][20][21][22][23][24] Although all of these models have emphysematous airspace enlargement, studies on the clinical pathogenesis of COPD would be much more efficient if the emphysematous condition could be experimentally reproduced within a much shorter time period.In order to shorten the period of development of an experimental COPD model, a more efficient delivery system of the constituents of cigarette smoke into the lung is required. To bypass the problem of using inhaled smoke, which is spontaneously exhaled, we attempted to intratracheally instill a cigarette smoke solution (CSS) over several weeks. Since respiratory infections are assumed to be the main risk factors for exacerbation of COPD, we decided to add LPS to the protocol of the multiple CSS administrations. Through the use of these multiple intratracheal administrations of CSS and LPS, we succeeded in inducing airway obstruction, bronchitis and emphysema over a considerably shorter term as compared to that seen for the other models that are currently in use. On the other hand, theophylline is ...

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

“…14) mice, 36,37) rats, 38) and dogs 39) by exposing the animals to sulfur dioxide (SO 2 ), 17) smoke from solid fuel, 19) cigarette smoke, 14,24,42) lipopolysaccharide, 39) proteases and their secretagogues, such as PAE, PPE, NE, proteinase 3, MMP, 44,48,49) and the factors used can enhance the effect of each other. 50,51) However, the rat model seems to be more economical and more feasible, and smoke and bacterial infections appear to be the most frequently used initiators. Although all of the factors used can induce COPD or emphysema-like pathophysiological pulmonary features, they are not similar to the disease occurring in patients with COPD.…”

Intratracheal Sensitization/Challenge-Induced Biphasic Asthmatic Response and Airway Hyperresponsiveness in Guinea Pigs

“…[15][16][17] Briefly, after the removal of any food struck to the inner surface of the oral cavity with cotton wool, the mucosal surface of the oral cavity and larynx was topically anesthetized by painting on a 1% lidocaine solution absorbed into cotton wool. Then, stainless steel tubing (external diameter: 3.40 mm; internal diameter: 2.84 mm; length: 70 mm), the tip of which was bent at an angle of 120°, was properly attached to the opening of the trachea at the larynx.…”

“…However, we recently developed a method for intratracheal administration in conscious guinea pigs. [15][16][17] In the present study, we attempted to develop a new model showing a biphasic asthmatic response, in which OVAϩAl(OH) 3 and OVA are delivered into the lung by intratracheal administrations over several weeks.…”

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

“…13) Briefly, 200 µL of CSE, which was made by bubbling the smoke of one cigarette (Hi Lite, Japan Tabaco) in 1 mL of saline, was intratracheally instilled into guinea pigs once daily on days 1-4, 6-9, 11-14, and [16][17][18][19], and 200 µL of LPS solution (500 µg/mL) was intratracheally instilled into the guinea pigs once daily on days 5, 10, and 15. On day 20, the guinea pigs were anesthetized with sodium pentobarbital (35 mg/kg, i.p.…”

“…), and lungs isolated were fixed with 10% neutral-buffered formalin solution under a pressure of 25 cm H 2 O for 4 h and then soaked for more than 24 h. Sections of the lungs were stained with Hematoxylin-Eosin, and histopathological changes, were evaluated under a microscope. 7,13) In order to evaluate the change in air space, mean linear intercept (MLI) was measured as an index according to the previous report. 7) GPD-1116 (1 mg/kg) was orally administered to guinea pigs once daily 1 h before CSE or LPS instillation on days 1-19.…”