Chest
Volume 146, Issue 2, August 2014, Pages 496-507
Journal home page for Chest

Translating Basic Research Into Clinical Practice
Secretory Hyperresponsiveness and Pulmonary Mucus Hypersecretion

https://doi.org/10.1378/chest.13-2609Get rights and content

The term bronchial hyperresponsiveness is generally used to describe a heightened airway smooth muscle bronchoconstrictor response measured by bronchoprovocation testing. However, the airway also responds to inflammation or bronchoprovocation with increased mucus secretion. We use the term “secretory hyperresponsiveness” to mean increased mucus secretion either intrinsically or in response to bronchoprovocation. This is not the same as retained phlegm or sputum. Unlike smooth muscle contraction, which is rapidly reversible using a bronchodilator, mucus hypersecretion produces airflow limitation that reverses more slowly and depends upon secretion clearance from the airway. Certain groups of patients appear to have greater mucus secretory response, including those with middle lobe syndrome, cough-dominant (“cough-variant”) asthma, and severe asthma. Secretory hyperresponsiveness also is a component of forms of lung cancer associated with bronchorrhea. An extreme form of secretory hyperresponsiveness may lead to plastic bronchitis, a disease characterized by rigid branching mucus casts that obstruct the airway. Secretory hyperresponsiveness and mucus hypersecretion appear to be related to activation of the extracellular-regulated kinase 1/2, signaling through the epidermal growth factor receptor, or secretory phospholipases A2. Recognizing secretory hyperresponsiveness as a distinct clinical entity may lead to more effective and targeted therapy for these diseases.

Section snippets

Physiology of Mucus Hypersecretion

In health, mucus is secreted to coat the airway, prevent water loss, and trap inhaled material, which is removed by mucociliary clearance. Normal mucus is a mixture of mucin glycoproteins, electrolytes, water, and secreted lipids and peptides. Mucins are linearly linked core proteins encoded by mucin (MUC) genes. These core mucin proteins are heavily glycosylated. Of the identified human MUC genes, 11 are expressed in the airway at the messenger RNA or protein level. The principal airway

IL-13 and Mucus Hypersecretion in Asthma

Patients with asthma who have chronic cough and sputum production have worse clinical control as measured by the Asthma Control Questionnaire (ACQ) and more frequent exacerbations19; additionally, there is dramatic mucus obstruction in the airways of patients with asthma who are dying.20, 21 Helper T-cell type 2 cytokines, including IL-13, are implicated in mucus production and goblet cell hyperplasia in asthma,22 and IL-13 induces goblet cell hyperplasia with mucus hypersecretion in the mouse

Allergic Bronchopulmonary Aspergillosis

Fungi in the genus Aspergillus are ubiquitous. They can be found wherever there is decomposing organic matter and on surfaces that get wet. Spores from some species in this genus, particularly Aspergillus fumigatus, can cause human disease. The spores are 2 to 3 μm in diameter, small enough to reach the alveoli in humans. Host defenses are normally able to clear Aspergillus spores without disease but hosts with propensity for airway mucus plugging, such as patients with asthma, are susceptible

Summary

Mucus hypersecretion is a distinct component of many airway diseases including inflammatory diseases and some forms of airway cancer. Although mucus secretion is an effective airway defense, secretory hyperresponsiveness can lead to airway obstruction and poor clearance. Therapy targeted at inflammation may be less effective in decreasing pathologic hypersecretion. There is a need for effective mucoregulatory medications to treat secretory hyperresponsiveness.

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts: Dr Rubin holds patents for the use of aerosol surfactant as mucokinetic medications and aerosolized Dapsone as a mucoregulatory therapy in airway hyperinflation. VCU has licensed this to InspiRx. Dr Rubin also holds research grants from the Cystic Fibrosis Foundation and the Denny Hamlin Foundation for studying mucus clearance as well as research grants from Fisher & Paykel, GlaxoSmithKline, and

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      The main reasons are the overproduction of biomolecules and the decrease of mucociliary clearance. In the mucus of CF patients, although the content of water and mucins is reduced by the serine proteases degradation, increase of the content of DNA and actin with high MW induces mucus accumulation in the airway [73,74]. The pore size of mucus mesh also reduces to 140 ± 50 nm in CF [75].

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    Dr Henke is currently at Asklepios Fachkliniken München-Gauting, Comprehensive Pneumology Center, Member of the German Center for Lung Research (Gauting, Germany)

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