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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.

SUBMITTER: Raju SV

PROVIDER: S-EPMC5033751 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A ferret model of COPD-related chronic bronchitis.

Raju S Vamsee SV Kim Hyunki H Byzek Stephen A SA Tang Li Ping LP Trombley John E JE Jackson Patricia P Rasmussen Lawrence L Wells J Michael JM Libby Emily Falk EF Dohm Erik E Winter Lindy L Samuel Sharon L SL Zinn Kurt R KR Blalock J Edwin JE Schoeb Trenton R TR Dransfield Mark T MT Rowe Steven M SM

JCI insight 20160922 15

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 phys ...[more]

PMID: 27699245

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Project description:BackgroundNo currently approved intervention counteracts airway metaplasia and mucus hypersecretion of chronic bronchitis in COPD. However, metered cryospray (MCS) delivering liquid nitrogen to the tracheobronchial airways ablates abnormal epithelium and facilitates healthy mucosal regeneration. The objective of this study was to evaluate the feasibility, efficacy and safety of MCS in chronic bronchitis.MethodsPatients with a forced expiratory volume in 1 s of 30-80% predicted who were taking optimal medication were recruited. Primary outcomes were feasibility (completion of treatments), efficacy (3-month change in St George's Respiratory Questionnaire (SGRQ)) and safety (incidence of adverse events). Secondary outcomes were lung function, exercise capacity and additional patient-reported outcomes.Results35 patients, 19 male/16 female, aged 47-76 years, Global Initiative for Chronic Obstructive Lung Disease grade I (n=3), II (n=10) and III (n=22), underwent staggered liquid nitrogen treatments to the tracheobronchial tree. 34 patients completed three treatments, each lasting 34.3±12.1 min, separated by 4-6 weeks; one withdrew after the first treatment. ∼1800 doses of MCS were delivered. Clinically meaningful improvements in patient-reported outcomes were observed at 3 months: change in SGRQ -6.4 (95% CI -11.4 to -1.3; p=0.01), COPD Assessment Test (CAT) -3.8 (95% CI -6.4 to -1.3; p<0.01) and Leicester Cough Questionnaire (LCQ) 21.6 (95% CI 7.3 to 35.9; p<0.01). Changes in CAT were durable to 6 months (-3.4, 95% CI -5.9 to -0.9; p=0.01); changes in SGRQ and LCQ were durable to 9 months (-6.9, 95% CI -13.0 to -0.9; p=0.03 and 13.4, 95% CI 2.1 to 24.6; p=0.02, respectively. At 12 months, 14 serious adverse events were recorded in 11 (31.4%) subjects; six (43%) moderate and eight (57%) severe. Nine were respiratory-related: six exacerbations of COPD, two pneumonias and one case of increased coughing; all recovered without sequelae. None were serious device- or procedure-related adverse events.ConclusionMCS is safe, feasible and associated with clinically meaningful improvements in multidimensional patient-reported outcomes.

Project description:BackgroundSmoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices.MethodsBased on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.ResultsOf 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking.ConclusionsThe results confirm and quantify the causal relationships with smoking.

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A ferret model of COPD-related chronic bronchitis.

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A ferret model of COPD-related chronic bronchitis.

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