Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma

Berge, van den Maarten; Hacken, ten Nicolaas; Wiel, Erica van der; Postma, Dirkje S.

doi:10.1111/all.12062

Cited by 74 publications

(55 citation statements)

References 80 publications

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“…Thus, surfactant is an interesting source of potential biomarkers. Currently, there is large interest in understanding the involvement of the distal airways in the development and progression of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (14,15 ). For a long time the distal airways were not accessible and therefore were often referred to as the "silent zone" of the lungs.…”

Section: Surfactantmentioning

confidence: 99%

Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath

2016

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BACKGROUND:Exhaled breath contains nonvolatile substances that are part of aerosol particles of submicrometer size. These particles are formed and exhaled as a result of normal breathing and contain material from distal airways of the respiratory system. Exhaled breath can be used to monitor biomarkers of both endogenous and exogenous origin and constitutes an attractive specimen for medical investigations.CONTENT: This review summarizes the present status regarding potential biomarkers of nonvolatile compounds in exhaled breath. The field of exhaled breath condensate is briefly reviewed, together with more recent work on more selective collection procedures for exhaled particles. The relation of these particles to the surfactant in the terminal parts of the respiratory system is described. The literature on potential endogenous low molecular weight compounds as well as protein biomarkers is reviewed. The possibility to measure exposure to therapeutic and abused drugs is demonstrated. Finally, the potential future role and importance of mass spectrometry is discussed.

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Section: Surfactantmentioning

confidence: 99%

Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath

2016

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“…[1–3] An advantage of small-particle instead of large-particle inhaled treatment could be a higher total lung deposition in addition to better deposition in the small airways. [4,5] Yet, we are currently not able to select asthma patients with small airway dysfunction, i.e. those who will probably benefit most from the inhaled small-particle medication.…”

Section: Introductionmentioning

confidence: 99%

Targeting the small airways with dry powder adenosine: a challenging concept

Wiel

Lexmond

Berge

et al. 2017

European Clinical Respiratory Journal

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Background: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective: We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design: In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min–1) and once with a high flow rate (60 l min–1). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV1 reflects the large airways, and FEF25–75%, R5-R20 and X5 reflect the small airways. Results: The four adenosine tests were not significantly different with respect to the threshold values of FEV1 (p = 0.12), FEF25–75% (p = 0.37), R5-R20 (p = 0.60) or X5 (p = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions: In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

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“…A number of clinical studies have shown that small particle ICS therapies, with aerosol MMAD values of approximately 1 μm, reduce airway hyperresponsiveness and improve asthma symptoms as well as quality of life (5, 7, 12). The small particle ICS products are expected to improve drug mass delivery to the small airways, which is consistent with multiple in vivo (75–79) and recent complete-airway CFD predictions (80, 81).…”

Section: Discussionmentioning

confidence: 99%

“…The small airways can be classified as having an internal diameter < 2 mm, do not contain cartilage, and generally start with the 8th airway generation together with the alveolar region (7, 12). The small tracheobronchial (TB) airways can be considered to start at approximately bifurcation B8 and continue through the terminal bronchioles at approximately B15, which then lead to the alveolar airways (13).…”

Section: Introductionmentioning

confidence: 99%

“…It has widely been reported that increasing small airway dose of ICS in asthma reduces hyperresponsiveness and improves both symptom control and quality of life (12, 19–22). Furthermore, ICS therapies are topical medications acting on the surface of the lungs, and response is proportional to dose per surface area until the dose-response curve plateaus.…”

Section: Introductionmentioning

confidence: 99%

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Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Longest

Hindle

2017

Pharm Res

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Purpose To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. Methods A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. Results Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and uniform drug delivery to all cells. Conclusions Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.

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Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma

Abstract: To cite this article: van den Berge M, ten Hacken NHT, van der Wiel E, Postma DS. Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma. Allergy 2013; 68: 16-26.

Cited by 74 publications

References 80 publications

Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath

Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath

Targeting the small airways with dry powder adenosine: a challenging concept

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

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