What Causes Increased Mucus Production in Asthma?

Overview

Have you experienced shortness of breath, tightness in your chest, coughing or wheezing?  These are common symptoms of asthma, a condition in which one has difficulty breathing, particularly during expiration.¹ It is a common chronic obstructive lung disease in which the bronchi and smaller bronchioles are hypersensitive to allergens.² This triggers chronic inflammation with excess production of mucus and smooth muscle spasms, which narrows the airways leading to difficulty breathing.² 

Common triggers include cold air, dust, pollen, pollution, air particles, smoke, and sometimes exercise or stress.¹ Respiratory infection or a family history of asthma can also increase the risk of developing asthma. It affects 1 in every 12 adults and 1 in every 11 children, influencing people of all ages, with symptoms often emerging during childhood.³

During an asthma attack, one may find it more difficult to exhale than inhale. When we exhale, lung and airway volume decreases, narrowing the airway slightly. During an asthma attack, smooth muscle contraction and inflamed airways further narrow the airways, increasing resistance. This increases the duration of exhalation, and breathing becomes more difficult. Asthma patients often find they struggle to inhale, but this is because the time available for inhalation has been reduced.² During an asthma attack, inhalation does not cause a problem since the bronchi widen due to the expansion of the lungs.²

Resistance is a measure of ‘difficulty’ of flow. It results from friction between gas particles and friction between the gas and tube wall. It is affected by the dimensions of the airway. During an asthma episode, the airways narrow and excess mucus is produced, which increases resistance and decreases airflow through them.² This is why you may find it hard to breathe during an asthma attack.

What is overproduction of mucus?

Mucus secretion forms the first line of defence against foreign particles in our body. It occurs at a highly regulated and extremely rapid pace, approximately a tenth of a millisecond, forming a thin film on the airway surface.⁴ The primary function of mucus involves the transportation and removal of trapped inhaled particles, debris, senescent cells, cell products, bacteria, viruses, and chemicals.⁵ Mucus glycoproteins give it a characteristic adhesiveness, viscosity and elasticity, allowing mucus to trap and clear exogenous material.⁵ During infection, allergic reaction, smoking, pathogenic factors, and oxidative stress, the lining cells secrete numerous prosecretory factors initiating secretory cell hypertrophy and goblet cell hyperplasia leading to overproduction of mucus.⁵ Chronic obstructive pulmonary disease (COPD), asthma, and bronchiectasis entail airway mucus hypersecretion and ciliary malfunctioning.⁵ 

Causes

The amount of mucus secreted varies according to different stimuli, including bacteria, viruses, particles and chemical irritants.⁵ In COPD, inflammatory responses caused by cigarette smoking and other various stimulators, along with oxidative stress, damage epithelial cells, which stimulate mucus secretion.⁵ In bronchial asthma, upregulation of MUC5AC and MUC5B in the airways leads to damage of the epithelium, causing ciliated cell exfoliation, submucosal gland hypertrophy and hyperplasia of goblet cells.⁵ In bronchiectasis, an irreversible expansion of the bronchial lumen allows the colonisation of bacteria by compromising the mucus.⁵ The toxins released by the bacteria increase inflammation, stimulating goblet cell hyperplasia and metaplasia, and hence mucus hypersecretion.⁵

Stimulations such as cigarette smoking generate abundant production of proteases and reactive oxygen species, which in turn activate certain receptors, including Toll receptor, growth factor receptor etc., which trigger signalling pathways. These signalling pathways induce goblet cell metaplasia and hyperplasia, leading to overproduction of mucus.⁵ 

Similarly, inflammation, oxidative stress, cholinergic nerve disfunction, imbalance of proteases, genetic susceptibility factors, and other pathological mechanisms can affect mucus secretion.⁵

Overproduction of mucus in asthma

The mucociliary system consists of mucus-secreting goblet cells and hair-like projecting ciliated cells. These cells produce a continual overturning layer of mucus, providing a protective covering to our airway epithelium cells and preventing foreign particles from entering our lungs.² Mucus is a viscoelastic substance with anti-microbial properties which traps and inactivates infectious agents essential for mucociliary clearance. These properties of mucus, coupled with the coordinated beating of cilia, provide the force to eliminate potentially harmful materials from our airways before entry into our lungs. Mucociliary clearance is the body's first line of defence against infection, essential for normal body function. Under normal circumstances, the mucus protects the epithelium lining of the airway by entrapping various bacteria, viruses, and foreign particles and then clearing them out. However, during clinical conditions like asthma, mucus shifts from a protective role to one that generates a respiratory disease by increased production of mucus referred to as hypersecretion, which may cause difficulty breathing or infection.^2,6 This is observed pathologically by mucus metaplasia (increase in intracellular goblet cell number caused by differentiation of proximal airway epithelium leading to an increased rate of mucus production) or mucus in the airway lumen.⁶ Excessive luminal mucus may become impacted, progressing to airway closure.^5,6 Mucus plugging of airways is fatal, comprising of plasma proteins, cells, DNA, and proteoglycans, with mucins forming the major gel component.⁷ Significantly increased amounts of mucus can be found throughout the airways of chronic asthma patients, which is fatal. This is linked to an elevated presence of mucus markers in the sputum. Increased luminal mucus is associated with sputum production, reflecting an increased airway secretion, specifically during or following an asthma attack. 

What causes the overproduction of mucus in asthma?

Mucins are a group of proteins forming the most important component of mucus, with MUC5AC and MUC5B forming the majority.⁵ MUC5AC is the gel-forming mucin from the goblet cells or surface mucus, while the latter from the submucosal glands are the primary secretory polymeric protein.⁵ In bronchial asthma, upregulation of  MUC5AC and MUC5B in our airway and damage to epithelium causes hyperplasia of goblet cells, ciliated cell exfoliation and submucosal gland hypertrophy, all of which lead to hypersecretion of airway mucus. ^5,6 This facilitates bacterial colonisation of the airway, airflow limitation and compromised ventilation.⁶

The initial phase is activated by interactions between the foreign particle and IgE antibodies. IgE antibodies are produced by the immune system in response to an allergen, initiating an allergic reaction by a chemical release. IgE is present on mast cells of the pulmonary columnar epithelium found along the lining of the respiratory tract. Once activated, the mast cells begin to secrete inflammatory mediators, which include histamine and leukotrienes.² These mediators cause spasms in the smooth muscle of the bronchi and increase mucus secretion into the airways.² 

Airway goblet cell hyperplasia is a distinctive pathological feature of asthma where new goblet cells are produced by differentiation.⁴ The basal serous and Clara cells are referred to as the primary progenitor cells, which can then undergo differentiation into mature goblet or ciliated cells.⁴ As the number of goblet cells increases during an asthma attack, the amount of serous and Clara cells decreases.⁴ Serous and Clara cells produce a number of anti-inflammatory, antibacterial and immunomodulatory substances, which are crucial for host immunity and defence.⁴ Hence, the absence of these cells leads to inflammation and narrowing of the airway with increased mucus production.

Consequences of mucus hypersecretion

There are two main consequences of overproduction of mucus: airway obstruction and increased airway responsiveness.

Airway obstruction is a consequence of reduced mucociliary clearance, epithelial shedding and damage, goblet cell hyperplasia and mucus plugging. This causes ventilation/perfusion mismatch. The uneven mucus obstruction diverts ventilation from one alveolar region to others leading to an imbalance of gas exchange and difficulty breathing.

Airway wall thickening, air-liquid interface surface tension, increased luminal mucus, and reduced cross-section area amplifies an increase in resistance - bronchoconstriction. 

Asthma can also cause excess mucus build-up in the lungs initiating chest congestion and pain along with a long-term decline in lung function.²

Does overproduction of mucus mean my asthma is getting worse?

Coughing up more phlegm than usual could be a sign that your airways are getting more inflamed, leading to common asthma symptoms.⁸ In bronchial asthma, chronic mucus overproduction was found to be a significant marker of rapid decline in the FEV1 value (forced expiratory volume in one second) and increased severity of the disease.⁸ In addition, mucus plugs, characteristic of asthmatic patients, easily adhere to the surface epithelium and are difficult to displace from the airways.⁸ This leads to a decrease in protease release, a substance which cleaves the mucins attached to goblet cell surfaces. Mucus plugs are fatal and dangerous.⁸

Does inhibition of mucus overproduction lead to clinical improvement in asthma?

Airway mucus is essential for our bodies' natural defence system, but excessive mucus production in asthma is dangerous and could be fatal. Hence, inhibition of mucus should lead to clinical improvements and benefit the patient.²

Managing mucus with asthma

Airway mucus gives rise to morbidity and mortality in many asthmatic patients; therefore, effectively managing mucus levels is essential.

Remedies

• Exogenous inhalants such as irritants, pollutants, or certain allergens should be identified and avoided as much as possible.
• Bronchodilators dilate the bronchus, thereby reducing mucus secretion. An asthma inhaler relaxes the smooth muscle, increasing the airway radius, thereby allowing more airflow and mucus clearance.
• Anti-inflammatory steroid drugs reduce inflammation. (Eg. Glucocorticosteroids)
• Mucolytic drugs (Eg. N-acetylcysteine, nacystelyn) target the mucus and reduce thickening.
• Use a humidifier, this will loosen the mucus, relieve wheezing and improve breathing and airflow.
• Gargle with salt water to ease throat pain and clear mucus. A sterile nasal saline spray may help thin the mucus and reduce secretion from the nose. The saline present helps to remove any pollen, dust, debris, pollen or other allergens along with loosening thick mucus. Hot drinks can help to break and thin out mucus providing relief.

When to consult a doctor

When you experience symptoms such as fever, persistent cough, chest tightness, shortness of breath, change in mucus colour and wheezing for more than 10 days, it is important to consult a doctor to get the best treatment to effectively manage your symptoms.⁹ 

Summary

Mucus airway secretion is an essential homeostatic mechanism which protects the respiratory tract and lungs. Mucus has to have accurate and proportionate components, viscosity and elasticity for optimum cilia interaction enabling effective mucociliary clearance. During an asthma attack, the protective function of airway mucus secretion is lost; thus, goblet cell hyperplasia and mucus hypersecretion occurs, which leads to accumulation and obstruction in the small airways. This could be dangerous, and therefore great care should be taken to manage your symptoms and improve your health.