COPD Heterogeneity: What This Will Mean in Practice

Rennard, Stephen I.

doi:10.4187/respcare.01419

Cited by 16 publications

(10 citation statements)

References 58 publications

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“…This complexity is so profound that the National Institutes of Health is sponsoring ongoing studies of subpopulations and intermediate outcome measures in the disorder (65). To account for this heterogeneity, some have proposed that these differences are the result of disparate disease causes (67). Only time and study will determine if this is true.…”

Section: Discussionmentioning

confidence: 99%

IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13

Kang

Choi²,

Kim³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, alveolar destruction, and airway and vascular remodeling. However, the mechanisms that lead to these diverse alterations have not been defined. Objectives: We hypothesized that IL-18 plays a central role in the pathogenesis of these lesions. Methods: We generated and characterized lung-specific, inducible IL-18 transgenic mice. Measurements and Main Results: Here we demonstrate that the expression of IL-18 in the mature murine lung induces inflammation that is associated with the accumulation of CD4 1 , CD8 1 , CD19 1 , and NK1.1 1 cells; emphysema; mucus metaplasia; airway fibrosis; vascular remodeling; and right ventricle cardiac hypertrophy. We also demonstrate that IL-18 induces type 1, type 2, and type 17 cytokines with IFN-g-inhibiting macrophage, lymphocyte, and eosinophil accumulation while stimulating alveolar destruction and genes associated with cell cytotoxicity and IL-13 and IL-17A inducing mucus metaplasia, airway fibrosis, and vascular remodeling. We also highlight interactions between these responses with IL-18 inducing IL-13 via an IL-17A-dependent mechanism and the type 1 and type17/ type 2 responses counterregulating each another. Conclusions: These studies define the spectrum of inflammatory, parenchymal, airway, and vascular alterations that are induced by pulmonary IL-18; highlight the similarities between these responses and the lesions in COPD; and define the selective roles that type 1, type 2, and type 17 responses play in the generation of IL-18-induced pathologies.Keywords: IL-18; chronic obstructive pulmonary disease; airway fibrosis; mucus metaplasia; vascular remodeling Chronic obstructive pulmonary disease (COPD) encompasses several clinical syndromes, most notably emphysema and chronic bronchitis (1, 2). It is a major unmet medical need in the United States and worldwide where it is the fourth and fifth leading cause of morbidity and mortality, respectively (3, 4). This is caused partly by our limited ability to treat people with COPD and a distinct lack of disease-modifying therapies (4, 5). Tissues from patients with COPD are characterized pathologically by chronic inflammation and varying degrees of emphysematous alveolar destruction, airway remodeling with tissue fibrosis and mucus metaplasia (6, 7), vascular remodeling with intimal hyperplasia, smooth muscle proliferation, and collagen deposition (8, 9). Importantly, a mechanistic construct that adequately accounts for the simultaneous existence of these varied tissue pathologic responses has not been put forth and animal models that simultaneously elicit these varied responses have not been commonly used. In particular, a mechanism that allows tissue destruction (emphysema) to coexist millimeters away from airway and vascular fibrotic responses has not been described (7).Inflammation with infiltrating macrophages, neutrophils, lymphocytes, and occasionally eosinophils is seen throughout the bronchial tree and parenchyma of lung...

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Section: Discussionmentioning

confidence: 99%

IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13

Kang

Choi²,

Kim³

et al. 2012

Am J Respir Crit Care Med

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“…These therapeutic options are therefore recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for effective disease management [5] Aclidinium is a novel inhaled long-acting muscarinic antagonist (LAMA) indicated for maintenance treatment of COPD. Due to the heterogeneity of COPD [6] and prevalence of polypharmacy among COPD patients [7,8], the availability of aclidinium as an additional effective therapeutic option with a good safety profile and reduced potential for drug interactions would be valuable for this patient population.…”

Section: Introductionmentioning

confidence: 99%

Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD

Gelb¹,

Tashkin

Make

et al. 2013

Respiratory Medicine

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“…Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition comprising multiple pulmonary and extra-pulmonary manifestations. 1 , 2 The disease has a variable natural history and significant heterogeneity exists with respect to clinical presentation, response to therapy, and survival. 1 – 3 As a result, there is consensus that spirometry alone does not adequately reflect the complexity of the disease and is an incomplete marker of the severity of symptoms, exercise limitation and health status.…”

Section: Introductionmentioning

confidence: 99%

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials

D’Urzo

Bader

Shen

et al. 2018

npj Prim Care Resp Med

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Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George’s Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p < 0.001). No statistically significant differences were found between the glycopyrronium and tiotropium treatment groups in time to CID or sustained CID. Glycopyrronium is effective in delaying time to clinically important deteriorations, with similar efficacy to tiotropium.

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COPD Heterogeneity: What This Will Mean in Practice

Cited by 16 publications

References 58 publications

IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13

IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13

Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD

Comparison of glycopyrronium versus tiotropium on the time to clinically important deteriorations in patients with COPD: a post-hoc analysis of randomized trials

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