Two New Robust Models Available to Evaluate COPD or Asthma
May 14, 2012 - By combining long-standing expertise with new research solutions, Charles River facilitates drug development in these important disease areas. Our recently validated rodent models provide rapid, cost-effective methods for evaluating the potential efficacy of novel anti-inflammatory agents targeting COPD or asthma conditions.
Polymorphonuclear neutrophils are thought to play a critical role in the pathogenesis of respiratory conditions in diseases such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis. In these diseases, the recruitment and activation of neutrophils is known to contribute to observed dysfunctional symptoms, which include increased airway reactivity, presence of pulmonary fibrosis and hypersecretion of mucus. These symptoms are exacerbated by increases in pulmonary cytokines, including tumor necrosis factor-alpha (TNF-α) and cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-3).
Charles River Discovery Research Services (DRS) offers an acute rodent model of pulmonary neutrophilia, the rat lipopolysaccharide (LPS) model, which has been extensively characterized and used as a preclinical surrogate tool to examine pulmonary neutrophilia in small animals. In this model, acute lung neutrophilia was induced by exposing the animals to a pulmonary airway challenge of LPS, which is known to be a significant and active component of cigarette smoke, the leading cause of COPD. Sprague Dawley rats were exposed to a single inhaled LPS challenge resulting in an acute pulmonary neutrophilia, which attained significance within 4 hours, peaking around 8 hours, and remaining elevated for up to hours. Pretreatment with glucocorticoids, such as betamethasone, has demonstrated a dose-dependent decrease in neutrophil count. Orally administered betamethasone, at 0.03, 0.3 and 3 mg/kg 2 hours prior to LPS challenge, resulted in a dose-dependent inhibition of neutrophils, attaining >80% inhibition at 3.0 mg/kg at both 4 and 24 hours after challenge compared to animals that received saline alone.
Neutrophil Inflammation Time Course
Effects of Bethamethasone on NeutrophilAccumulation
Asthma is an allergic reaction where a chronic inflammation of the airways develops following exposure to a known allergen. Traditionally this response is driven by a type 2 immune response and is characterized by a variable degree of airflow obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The airway inflammation is caused by tissue infiltration of activated inflammatory cells (e.g., eosinophils, lymphocytes and degranulated mast cells), which release proinflammatory cytokines (interleukin [IL]-4, IL-5 and IL-13) and chemical mediators (leukotrienes, prostaglandin D2 [PGD2] and histamine) resulting in airway epithelium damage, occlusion of the bronchial lumen by mucus, hyperplasia of the goblet cells and hypertrophy of the smooth muscle.
Several animal models of human asthma have been developed in an attempt to induce the pathology and pathophysiology seen in human conditions. The Brown Norway lung inflammation model is an established allergen-dependent, pharmacokinetic/pharmacodynamic model that can be used to investigate the basic pathology of asthma disease and assess the in vivo efficacy of antiasthma drugs. This model features many similarities to human allergic asthma, including the presence of eosinophilic lung inflammation, damage to the airway epithelium, thickening of the basement membrane, acute and late phase airflow obstruction and the presence of airway hyperresponsiveness after the antigen challenge.
In these recent studies, Charles River evaluated the time course of inflammation following antigen sensitization and challenge in the Brown Norway rat and evaluated the effect of glucocorticoids in this model. Animals were sensitized on Days 1 and 8 to ovalbumin. On Day 15, animals were pretreated with saline or a glucocorticoid and then challenged to inhaled ovalbumin. Total and differential cell counts of inflammatory cells in the lung were performed on the bronchoalveolar lavage (BAL) fluid at various time points to observe the time course of inflammation and evaluate the effects of compounds at 24 or 48 hours post challenge. Ovalbumin sensitization and challenge resulted in an acute pulmonary neutrophilia and later-phase eosinophilia. Significant increases in pulmonary neutrophils were observed at 6 hours following airway challenge, and levels remained significantly elevated until approximately 48 hours post challenge. Significant increases in eosinophils were observed at 24 hours following challenge, peaked at 48 hours and remained elevated to at least 72 hours post challenge. Pretreatment with betamethasone, at 0.03, 0.3 and 3 mg/kg 2 hours prior to ovalbumin challenge, resulted in a dose-dependent decrease in neutrophils at 24 hours following dosing attaining >80% inhibition at 3.0 mg/kg, while a single dose of betamethasone, at 3 mg/kg, resulted in >80% inhibition of eosinophil accumulation at 48 hours following challenge.
Neutrophil and Eosinophil Inflammation Time Course
Effects of Bethamethasone on Neutrophil and Eosinophil Accumulation at 24 Hours Post Ovalbumin Challenge
Effects of Bethamethasone on Neutrophil and Eosinophil Accumulation at 48 Hours Post Ovalbumin Challenge
Additional services that can be combined with these models include cytokine profiling, histopathologic evaluations and assessments of airway hyperresponsiveness (e.g., Penh assessments in conscious animals or anesthetized assessments of resistance and compliance).
For more information about the COPD or Asthma Discovery Research Models, please contact us at email@example.com.
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May 28–Jun 01
The International Bone and Mineral Society (IBMS) and the Japanese Society for Bone and Mineral Research (JSBMR) are excited to sponsor the second joint scientific meeting by the two organizations.
May 23–May 23
This full-day seminar encompasses selected topics from our Charles River Short Course on Laboratory Animal Science. We would like to acknowledge Michigan State University for hosting this event and extend our heartfelt thanks to guest speaker Dr. Danielle Ferguson.
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