Tobacco smoke induces inflammation in smokers’ lungs, and chronic exposure results in lung tissue damage and destruction. The inflammation associated with COPD in humans is characterized as steroid insensitive. Viral and bacterial infection can cause acute exacerbation of COPD, which often results in hospitalization and increased health care costs. These exacerbation events are routinely treated with high-dose oral steroid therapy.
Charles River has developed models of COPD in mice and guinea pigs that allow examination of compounds (both small molecule and biologics) against three key translatable features relating to the disease seen in humans: inflammation, exacerbation and airspace enlargement.
Lung Inflammation Model
Exposure to tobacco smoke for 11 days induces inflammation in the lungs of mice and guinea pigs. As in humans, tobacco smoke-induced inflammation is characterized by an increase in inflammatory cells (particularly neutrophils) in the bronchoalveolar lavage fluid (BALF) and insensitivity to both oral and inhaled steroid treatments.
Steroid administration throughout the 11 days of tobacco smoke exposure via oral or inhaled routes at doses known to be effective in other models of COPD (e.g., LPS challenge) has no impact upon the tobacco smoke-induced inflammatory response in either the guinea pig or the mouse, even at supramaximal dose levels.
Compounds can be administered daily during the exposure period (“prophylactic dosing”) via a variety of routes, including intranasal, oral or implanted minipumps. Alternatively, compounds can be dosed once the inflammation has been established in a “therapeutic” manner from day 6 onward.
Combined with cytokine profiling, histopathologic evaluations and assessments of lung function, we can help you build a comprehensive data package on the efficacy of your compound towards steroid-insensitive COPD.
Following a sustained, steroid-insensitive inflammatory response brought on by tobacco smoke exposure, mice are challenged with the viral mimetic polyinosinic:polycytidylic acid (poly I:C) to elicit a further increase in the inflammatory response in the lungs above the tobacco smoke-induced baseline. This exacerbation is characterized by an increase in neutrophils, macrophages and lymphocytes but it is sensitive to steroid treatment, thus mimicking human disease.
Airspace Enlargement Model
Long-term exposure to tobacco smoke (6 months) induces airspace enlargement in the lungs, as determined by measurements of mean linear intercept across the airways. This model has been established in the mouse (6 months exposure required) and the guinea pig (3 months exposure required). The guinea pig model of airspace enlargement is steroid insensitive.