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. 2016 Sep 22;1(15):e87536.
doi: 10.1172/jci.insight.87536.

A ferret model of COPD-related chronic bronchitis

S Vamsee Raju  1 , Hyunki Kim  2 , Stephen A Byzek  1 , Li Ping Tang  1 , John E Trombley  1 , Patricia Jackson  1   3 , Lawrence Rasmussen  1 , J Michael Wells  1   3   4 , Emily Falk Libby  1   4 , Erik Dohm  5 , Lindy Winter  6 , Sharon L Samuel  2 , Kurt R Zinn  2 , J Edwin Blalock  1   3   4 , Trenton R Schoeb  4   7 , Mark T Dransfield  1   3   4 , Steven M Rowe  1   3   4   6   8
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A ferret model of COPD-related chronic bronchitis (V体育2025版)

VSports最新版本 - S Vamsee Raju et al. JCI Insight. .

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 VSports手机版. 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. .

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Figures

Figure 1
Figure 1. Evidence of chronic cough in a ferret model of COPD.
(A) Representative plethysmograph (blue) and audio (green) tracings of a ferret inside an integrated cough monitor. The typical change in respiratory cycle and audio recording during a cough event is designated by the red arrows. See Supplemental Video 1 for a representative video. (B) Summary of verified early-morning, unstimulated coughs in ferrets exposed to 6 months of either cigarette smoke or room air. n = 4–6/group. *P < 0.05.
Figure 2
Figure 2. Histopathologic evidence of chronic mucus hypersecretion and goblet cell hyperplasia in a ferret model of COPD.
(A) Mucus-expressing goblet cells and submucosal glands (yellow arrows) were stained with PAS (magenta) in tracheal sections of ferrets exposed to room air or cigarette smoke for 6 months. Scale bar: 34 μm. (B) Similarly, lung sections from the same ferrets were stained with AB-PAS to highlight mucus-expressing cells (deep blue). Scale bar: 110 μm. (C) The same staining as in B demonstrating goblet cell hyperplasia and increased epithelial cell height. Scale bar: 17 μm. (D and E) Quantitative analyses demonstrating epithelial hyperplasia, as measured by increased epithelial cell height (D) controlled for luminal area (E). (F) Goblet cell area controlled for luminal area in cigarette smoke–exposed ferrets. (G) Goblet cell area controlled for luminal area expressed as a function of the airway luminal (inner) diameter quintile (diameter; quintile 1: 116–293 μm, quintile 2: 294–415 μm, quintile 3: 424–535 μm, quintile 4: 537–793 μm, and quintile 5: 810–2,651 μm). n = 8/group. *P < 0.05, **P < 0.01, ****P < 0.0001.
Figure 3
Figure 3. Chronic bronchitis exacerbations in cigarette smoke-exposed ferrets.
(A) Kaplan-Meier survival curve of ferrets exposed to cigarette smoke or room air for 6 months. (B) Body weight changes observed in cigarette smoke–exposed ferrets compared with air controls over 6 months of exposure. (C) Image (original magnification, ×2) capturing evidence of mucus obstruction in a large airway shown in a smoke-exposed ferret that suffered from spontaneous lung infection with Staphylococcus xylosus and Staphylococcus schleiferi. (D and E) Histopathologic examination confirmed mucus accumulation in the trachea by PAS staining (D, yellow arrow; scale bar: 135 μm) and inflammatory foci (E; scale bar: 135 μm) in lung highlighted by H&E staining. n = 8/group. **P < 0.01, ****P < 0.0001.
Figure 4
Figure 4. Lung function analyses in a ferret model of COPD.
Functional estimate of airway obstruction in ferrets exposed to cigarette smoke or their corresponding air controls was carried out using a forced oscillometry-based system. (A) Compared with control ferrets, ferrets that underwent chronic smoke exposure for 6 months exhibited significantly diminished inspiratory capacity, a sensitive marker of airway obstruction. (B) Newtonian resistance, a measure of airway resistance of the conducting airways, was elevated in COPD ferrets. (C and D) Tissue damping (C), a measure of tissue elastance, and quasistatic compliance (D) were not significantly affected by smoking. n = 9–12/group. *P < 0.05.
Figure 5
Figure 5. Emphysema and neutrophilic inflammation in smoke-exposed ferrets.
(A and B) Histopathologic evidence of emphysematous airspace enlargement shown in representative lung sections of ferrets exposed to cigarette smoke and their corresponding air controls. Scale bar: 220 μm. (C and D) H&E-stained section of respiratory bronchioles, indicating an influx of neutrophils (black arrows) in ferrets exposed to cigarette smoke for 6 months compared with air controls. Scale bar: 34 μm. (E) Summary of mean linear intercept (MLI), a marker of alveolar enlargement, in ferrets exposed to cigarette smoke or air controls for 6 months. (F) Summary of mean neutrophil counts observed in bronchoalveolar lavage fluids in cigarette smoke–exposed ferrets and their air control counterparts. n = 8–12/group. **P < 0.01.
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References

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