Animal Model Of Chronic Obstructive Pulmonary Disease Research Articles

Can β2‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world. Inflammatory process progresses and contributes to irreversible airflow limitation. However, there is no available therapy to better control the inflammatory progression and therefore to reduce the exacerbations and mortality. Thus, the development of efficient anti-inflammatory therapies is a priority for patients with COPD. β(2) -Adrenoceptor agonists and anticholinergic agents are widely used as first line drugs in management of COPD because of their efficient bronchodilator properties. At present, many studies in vitro and some data obtained in laboratory animals reveal the potential anti-inflammatory effects of these bronchodilators but their protective role against chronic inflammation and the development of emphysema in patients with COPD remains to be investigated. The anti-inflammatory effects of theophylline at low doses have also been identified. Beneficial interactions between glucocorticoids and bronchodilators have been reported, and signaling pathways explaining these synergistic effects begin to be understood, especially for theophylline. Recent data demonstrating interactions between anticholinergics with β(2) -adrenoceptor agonists aiming to better control the pulmonary inflammation and the development of emphysema in animal models of COPD justify the priority to investigate the interactive effects of a tritherapy associating corticoids with the two main categories of bronchodilators.

Therapeutic Effect of Lecithinized Superoxide Dismutase on Pulmonary Emphysema

No medication exists that clearly improves the mortality of chronic obstructive pulmonary disease (COPD). Oxidative molecules, in particular superoxide anions, play important roles in the COPD-associated abnormal inflammatory response and pulmonary emphysema, which arises because of an imbalance in proteases and antiproteases and increased apoptosis. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anions. Lecithinized human Cu/Zn- SOD (PC-SOD) has overcome a number of the clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examine the effect of PC-SOD on elastase-induced pulmonary emphysema, an animal model of COPD. The severity of the pulmonary inflammatory response and emphysema in mice was assessed by various criteria, such as the number of leukocytes in the bronchoalveolar lavage fluid and the enlargement of airspace. Not only intravenous administration but also inhalation of PC-SOD suppressed elastase-induced pulmonary inflammation, emphysema, and dysfunction. Inhalation of PC-SOD suppressed the elastase-induced increase in the pulmonary level of superoxide anions and apoptosis. Inhalation of PC-SOD also suppressed elastase-induced activation of proteases and decreased in the level of antiproteases and expression of proinflammatory cytokines and chemokines. We also found that inhalation of PC-SOD suppressed cigarette smoke-induced pulmonary inflammation. The results suggest that PC-SOD protects against pulmonary emphysema by decreasing the pulmonary level of superoxide anions, resulting in the inhibition of inflammation and apoptosis and amelioration of the protease/antiprotease imbalance. We propose that inhalation of PC-SOD would be therapeutically beneficial for COPD.

New animal models of COPD

Aims: Cigarette smoke is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). The gram negative strain Haemophilus influnenzae (H.i.) plays a major role during exacerbations in patients with COPD. NF-κB plays a central role in inflammatory responses and the innate immune system.

Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.

CCR7 Modulates Pulmonary and Lymph Node Inflammatory Responses in Cigarette Smoke-Exposed Mice

Peribronchial lymphoid follicles have recently been identified as one of the hallmark features of (severe) chronic obstructive pulmonary disease (COPD). However, little is known about the relative contribution of peribronchial lymphoid follicles vs mediastinal lymph nodes in inflammatory responses in COPD patients and animal models. In a murine model of COPD, we studied inflammatory responses in airways, lungs, and mediastinal lymph nodes of wild-type (WT) vs CCR7 knockout (CCR7(-/-)) mice upon subacute or chronic exposure to cigarette smoke (CS). Although crucial for the organization of the secondary lymphoid organs, CCR7 was not required for the development of chronic CS-induced pulmonary lymphoid follicles. Moreover, T cell numbers were significantly increased in airways and lungs of air-exposed CCR7(-/-) mice, and they continued to increase upon chronic CS exposure. Unexpectedly, subacute CS-induced inflammation in airways and lungs, including airway neutrophilia and the recruitment of inflammatory-type CD11b(+) dendritic cells, depended greatly on CCR7. In the draining lymph nodes, chronic CS exposure induced CCR7-dependent recruitment of airway-derived dendritic cells, accompanied by increases in CD4(+) and CD8(+) T cells. Correspondingly, CS exposure up-regulated mRNA expression of CCR7 ligands CCL19 and CCL21-Ser in lymph nodes of WT mice, but not CCR7(-/-) mice. In the lungs of WT mice, chronic CS exposure significantly increased CCL19 mRNA and protein. Furthermore, double staining for CCL19 and pro-surfactant protein C showed that alveolar type II cells express high levels of CCL19. These data unveil a so far unappreciated role for CCR7 in modulating inflammatory responses in airways and lungs.

Inhibition of inducible nitric oxide synthase in respiratory diseases

Nitric oxide (NO) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases. A multitude of inhibitors of NOSs (nitric oxide synthases) have been developed, initially with low or even no selectivity against the constitutively expressed NOS isoforms, eNOS (endothelial NOS) and nNOS (neuronal NOS). In the meanwhile these efforts yielded potent and highly selective iNOS (inducible NOS) inhibitors. Moreover, iNOS inhibitors have been shown to exert beneficial anti-inflammatory effects in a wide variety of acute and chronic animal models of inflammation. In the present mini-review, we summarize some of our current knowledge of inhibitors of the iNOS isoenzyme, their biochemical properties and efficacy in animal models of pulmonary diseases and in human disease itself. Moreover, the potential benefit of iNOS inhibition in animal models of COPD (chronic obstructive pulmonary disease), such as cigarette smoke-induced pulmonary inflammation, has not been explicitly studied so far. In this context, we demonstrated recently that both a semi-selective iNOS inhibitor {L-NIL [N6-(1-iminoethyl)-L-lysine hydrochloride]} and highly selective iNOS inhibitors (GW274150 and BYK402750) potently diminished inflammation in a cigarette smoke mouse model mimicking certain aspects of human COPD. Therefore, despite the disappointing results from recent asthma trials, iNOS inhibition could still be of therapeutic utility in COPD, a concept which needs to be challenged and validated in human disease.

The role of animal models in the pharmacological evaluation of emerging anti-inflammatory agents for the treatment of COPD

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that has been relatively under researched compared to other inflammatory diseases. Indeed, thus far there have been no anti-inflammatory therapies specifically approved for COPD and the available anti-inflammatory therapies were originally developed for asthma. The challenges facing research in COPD are multi-faceted; the mechanisms underlying the complex and heterogeneous pathology of this disease require unravelling; the role of inflammation in disease progression needs to be confirmed and new drugs with potential to successfully treat COPD need to be identified. Many of the compounds in the clinic today have been identified through the work performed in a range of animal models of COPD. These models have provided us with an understanding of disease pathology and potential mechanistic pathways and have given us the means to prioritise new chemical entities before entry into the clinic. This review will summarise currently available models of COPD and highlight how they have been used to take a first generation of anti-inflammatory therapies for COPD into clinical development. The predictive nature of these animal models will become clear as these therapies are clinically evaluated. The recurring challenge will be to take emerging pre-clinical and clinical data and use it to continually improve animal models so that they remain a valuable tool in the drug discovery process.

Vulnerability of Gastric Mucosa to Prednisolone in Rats Chronically Exposed to Cigarette Smoke

We examined gastric mucosal vulnerability in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were exposed to cigarette smoke for 12 weeks (CSE rats), and on the last 4 days of exposure, prednisolone was given to induce gastric mucosal injury. Histopathology, pulmonary function, arterial blood gases, and levels of lipid peroxides (LPO), prostaglandin E2(PGE2), hypoxia-inducible factor 1 alpha subunit (HIF-1α ), and vascular endothelial growth factor (VEGF) in gastric mucosa were examined. We also tested the effect of rebamipide on prednisolone-induced gastric lesions. In CSE rats, although no gastric lesions were detected, LPO, PGE2, HIF-1α, and VEGF levels were higher than in control rats. Prednisolone induced gastric hemorrhagic lesions more readily in CSE rats than controls, with concomitant decrease in PaO2and increased levels of LPO, HIF-1α, and VEGF. Rebamipide reversed gastric lesions without affecting any parameters examined. CSE rats were found to be a useful animal model of COPD, and COPD appeared to render the gastric mucosa vulnerable to prednisolone.

Capsaicin‐induced mucus secretion in rat airways assessed in vivo and non‐invasively by magnetic resonance imaging

An up-regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non-invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI). Male Brown Norway rats were imaged prior to and 10, 30 and 60 min after intra-tracheal challenge with capsaicin (30 microg kg(-1)) or vehicle (0.5% ethanol solution). In subsequent studies, pre-treatment with the transient receptor potential vanilloid (TRPV)-1 antagonist, capsazepine; the dual neurokinin (NK) 1 and NK2 receptor antagonist, DNK333 and the mast cell stabilizer, di-sodium cromoglycate (DSCG) was used to modulate the effects of capsaicin. Diffuse fluid signals were detected by MRI in the lung as early as 10 min after capsaicin, remaining constant 30 and 60 min after treatment. Broncho-alveolar lavage (BAL) fluid analysis performed 60 min after capsaicin revealed increased mucin concentration. Capsazepine (3.5 mg kg(-1)), DNK333 (10 mg kg(-1)) but not DSCG (10 mg kg(-1)) administered prophylactically were able to block the effect of capsaicin in the airways. These observations suggest that the fluid signals detected by MRI after capsaicin administration reflected predominantly the release of mucus following activation of sensory nerves. They point to the opportunity of non-invasively assessing with MRI the influence of neuronal mechanisms in animal models of asthma and COPD.

25 Problems with animal models of COPD

Chronic obstructive pulmonary disease (COPD) is a slowly progressive lung disease that results in several complications, including cognitive dysfunction. Some evidences support that cognitive impairment is common and clinically important in COPD, but the exact mechanism is still unclear. It has been confirmed that chronic hypoxia-hypercapnia contributes a lot to the development in pathophysiology of COPD. Data from some pilot studies indicated that chronic hypoxia-hypercapnia influences cognitive functions both in patients and in animals, which includes some distinctive pattern of cognitive dysfunction in human being or impairment of spatial learning-memory in rat. Therefore, we propose that cognitive impairment is strongly related to combination of chronic hypoxia and hypercapnia, and chronic hypoxia-hypercapnia-induced animal models may mimic the cognitive dysfunction of COPD. Attempts to confirm this hypothesis may lead to new model of cognitive dysfunction in COPD.

Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD)

Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion.In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.

Cytokines in the pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality. The term is heterogenous and encompasses a number of distinct but often overlapping phenotypes including chronic bronchitis, small airways obstruction, emphysema and in some individuals, a systemic component. Although there have been significant advances in understanding the pathophysiology of COPD, understanding of the role of the inflammation in the pathogenesis of the condition remains in its infancy. Indeed, cytokines that are known to orchestrate the inflammatory response in asthma and other inflammatory diseases are only beginning to be reported in COPD. In this review, we highlight the potential role of cytokines in the development of mucus hypersecretion observed in chronic bronchitis and the morphological changes observed in the small airways and airspaces contributing to the development of airflow limitation and respiratory failure respectively. We report evidence that exacerbations are linked to increased expression of pro-inflammatory cytokines and that the wasting and skeletal muscle dysfunction observed in some patients is most probably related to the presence of a systemic inflammatory response. In addition transgenic and gene therapy technology has been used to explore the temporal and co-ordinated role of cytokines in the development of COPD animal models. Enhanced understanding of the events involved in the pathogenesis of COPD will lead to the development of therapy with potential to modify the observed progressive decline in lung function and impact on the development of the illness.