Cystic Fibrosis and Other Respiratory Diseases of Impaired Mucus Clearance

Cystic Fibrosis/Pulmonary Research and Treatment Center, Department of Medicine, The University of North Carolina at Chapel Hill, 27599, USA.
Toxicologic Pathology (Impact Factor: 1.92). 02/2007; 35(1):116-29. DOI: 10.1080/01926230601060025
Source: PubMed

ABSTRACT Exposed to a diverse array of potentially noxious agents, the respiratory tract is protected by a highly developed innate defense system. Physiologically regulated epithelial ion and water transport coordinated with mucin secretion, beating cilia, and cough results in continuous flow of fluid and mucus over airway surfaces toward the larynx. This cleansing action is the initial and perhaps most quantitatively important innate defense mechanism. Repeated lung infections and eventual respiratory insufficiency characteristic of human cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) illustrate the consequences of impaired mucus clearance. Altered mucus clearance likely contributes to the initiation, progression, and chronicity of other airway diseases characterized by inflammation and mucous secretory cell hyper/metaplasia that afflict millions worldwide, including chronic obstructive pulmonary disease (COPD). This review concisely discusses the pathophysiology of human diseases characterized by genetic defects that impair mucus clearance. It then explores animal models in which components of the mucus clearance system have been disrupted. These models firmly establish the importance of mucus clearance for respiratory health, and will help elucidate disease mechanisms and therapeutic strategies in CF, PCD and COPD.

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    ABSTRACT: The embryonic skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the skin epithelium. This effect was mediated by serotonin type 3 receptor (Htr3), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic skin as a model system for human MCEs, which have been known for serotonin-dependent regulation of ciliary beat frequency.
    Development 03/2014; 141(7). DOI:10.1242/dev.102343 · 6.27 Impact Factor
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    ABSTRACT: Mucociliary clearance has long been known to be a significant innate defence mechanism against inhaled microbes and irritants. Important knowledge has been gathered regarding the anatomy and physiology of this system, and in recent years, extensive studies of the pathophysiology related to lung diseases characterized by defective mucus clearance have resulted in a variety of therapies, which might be able to enhance clearance from the lungs. In addition, ways to study in vivo mucociliary clearance in humans have been developed. This can be used as a means to assess the effect of different pharmacological interventions on clearance rate, to study the importance of defective mucus clearance in different lung diseases or as a diagnostic tool in the work-up of patients with recurrent airway diseases. The aim of this review is to provide an overview of the anatomy, physiology, pathophysiology, and clinical aspects of mucociliary clearance and to present a clinically applicable test that can be used for in vivo assessment of mucociliary clearance in patients. In addition, the reader will be presented with a protocol for this test, which has been validated and used as a diagnostic routine tool in the work-up of patients suspected for primary ciliary dyskinesia at Rigshospitalet, Denmark for over a decade.
    Clinical Physiology and Functional Imaging 09/2013; DOI:10.1111/cpf.12085 · 1.33 Impact Factor
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    ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by mucus hyper-production. This pathology, together with other inflammatory contributions, leads to airway obstruction and breathing complications. Newer therapeutic approaches are of increased interest, including the use of HMG-CoA reductase inhibitors. Retrospective studies have shown that statins are effective in reducing patient mortality, and blood cytokines levels. These findings suggest statins may also provide a new therapeutic approach in COPD treatment. PURPOSE: The aim of the present work was to study the transport of SV across Calu-3 epithelial cells and to investigate its pharmacological action with respect to reduction in mucus production. METHODS: Calu-3 cells were grown under liquid covered culture (LCC) conditions for transport studies in order to demonstrate the ability of SV to transport across the monolayer. For mucus detection, cells were grown under air interface culture (AIC) conditions. Samples collected for microscope analysis, were stained with alcian blue; images of the stained cell surface were acquired and the mucus was quantified as the RGBB ratio. RESULTS: SV was transported through the cell monolayer and 'retained' inside the Calu-3 cells. Colour analysis of stained Calu-3 monolayers microscope-images, showed that chronic administration of SV for 14 days caused a significant inhibition in mucus production. CONCLUSION: These findings suggest that local delivery of SV directly to the lungs may provide a promising treatment and potential disease management approach of COPD, with significant effects on mucus reduction.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 03/2013; 84(3). DOI:10.1016/j.ejpb.2013.01.021 · 4.25 Impact Factor


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