A ferret model of COPD-related chronic bronchitis

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. The majority of COPD patients have symptoms of chronic bronchitis, which lacks specific therapies. A major impediment to therapeutic development has been the absence of animal models that recapitulate key clinical and pathologic features of human disease. Ferrets are well suited for the investigation of the significance of respiratory diseases, given prior data indicating similarities to human airway physiology and submucosal gland distribution. Here, we exposed ferrets to chronic cigarette smoke and found them to approximate complex clinical features of human COPD. Unlike mice, which develop solely emphysema, smoke-exposed ferrets exhibited markedly higher numbers of early-morning spontaneous coughs and sporadic infectious exacerbations as well as a higher level of airway obstruction accompanied by goblet cell metaplasia/hyperplasia and increased mucus expression in small airways, indicative of chronic bronchitis and bronchiolitis. Overall, we demonstrate the first COPD animal model exhibiting clinical and pathologic features of chronic bronchitis to our knowledge, providing a key advance that will greatly facilitate the preclinical development of novel treatments for this disease.

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

“…Nonetheless, these findings emphasize the importance of airway clearance as a means of improving health of the CF lung. We propose that the pathogenesis of CF lung disease shares mucoinflammatory components (55) with other forms of COPD, such as chronic bronchitis (31,32,56,57) and severe asthma (52,58) and thus strengthens the case for developing new therapeutics targeting these aberrant responses. n Author disclosures are available with the text of this article at www.atsjournals.org.…”

Animal Models of Chronic Obstructive Pulmonary Disease

“…All three of these exposure models were utilized in several species of animals but are rarely utilized in current studies of COPD. A recent NHO chronic CS exposure model in ferrets demonstrated clinical features close to human bronchitis [79] and suggests that the animal species may be a deciding factor in bronchitis research. Overall, new approaches are needed to access bronchitis in animal models of COPD.…”

“…To prevent contrasting results when doing CS studies, Kentucky reference cigarettes (from the Center for Tobacco Reference Products) are used by many research groups throughout the world to aid in the standardization of the CS exposure model. Other species are very susceptible to CS-induced COPD, such as guinea pigs [78] and ferrets [79]. They develop COPD-like lesions and emphysema-like airspace enlargement within a few months of active CS exposure.…”

“…Ferrets have several similarities to human airway physiology and submucosal gland distribution. In a recent NHO chronic CS exposure model, ferrets demonstrated clinical features close to human COPD, such as early-morning spontaneous coughs, sporadic infectious exacerbations, airway obstruction, goblet cell metaplasia/hyperplasia and increased mucus expression in small airways [79]. Despite larger animals displaying a lung morphology closer to human, the mouse model is the favored model of NHO CS exposure induced COPD.…”

Optimising experimental research in respiratory diseases: an ERS statement

“…However, significant differences between human and mouse lungs question the appropriateness of murine lungs as valid surrogates of human lungs [26, 27,139]. Large animal models, using ferret, pig and sheep have been described with phenotypes that appear more congruent with human pulmonary fibrosis [140][141][142][143][144]. Further, naturally occurring pulmonary fibrosis models exist [37,38,[145][146][147][148][149][150][151][152], which may offer insights into pathogenesis and systems to test therapeutic agents.…”