What is the function of goblet cells in the lungs, particularly in patients with and without pre-existing respiratory conditions such as Chronic Obstructive Pulmonary Disease (COPD) or asthma?

Function of Goblet Cells in the Lungs

Goblet cells produce mucus that is essential for normal mucociliary clearance in healthy airways, but their hyperplasia and metaplasia in diseased states—particularly in COPD and chronic bronchitis—leads to excessive mucus production, airway obstruction, impaired bacterial clearance, and contributes directly to morbidity through chronic cough and recurrent infections. 1

Normal Physiological Function

In healthy individuals, goblet cells serve a protective role:

• Mucus production for mucociliary clearance: Goblet cells secrete gel-like mucus onto airway surfaces that traps particles, toxicants, and microbial pathogens, which are then eliminated by ciliary action to the hypopharynx where the mucus is swallowed 1, 2
• Normal mucus volume: Approximately 500 mL of sputum is produced daily in healthy airways and goes unnoticed 1
• Anatomical distribution: In normal airways, goblet cells are present in large central airways but are normally absent in small airways (bronchioles <2 mm) 1

Pathological Changes in Respiratory Disease

COPD and Chronic Bronchitis

The pathological hallmark of chronic bronchitis involves dramatic alterations in goblet cell populations:

• Goblet cell hyperplasia: There is an increase in both the size and number of goblet cells on the surface epithelium of large airways, along with mucous gland enlargement in submucosal glands 1
• Mucous metaplasia: Goblet cells appear in small peripheral airways where they are normally absent—this metaplastic change is particularly important to the development of COPD and contributes to small airway obstruction 1
• Excessive mucus production: Smokers with chronic bronchitis produce up to 100 mL/day more sputum than normal individuals, resulting in chronic cough and sputum production 1

Mechanisms of Airway Obstruction

Goblet cell hyperplasia contributes to airflow limitation through multiple mechanisms:

• Direct lumen obstruction: Increased intraluminal mucus physically narrows airways 1
• Continuous mucus blanket formation: Instead of discrete mucus deposits seen in normal airways, diseased airways develop a continuous sheet of mucus lining the airways with pooling of secretions 1
• Impaired mucociliary clearance: The combination of excessive mucus, ciliary dysfunction (decreased number and length of cilia), and ineffective cough creates a vicious cycle of secretion retention 1
• Bacterial colonization: Pooled secretions provide a nidus for bacterial growth, which releases toxins that further damage cilia and epithelial cells, stimulate additional mucus production, and slow ciliary beating 1

Inflammatory Pathways

The development of goblet cell hyperplasia is mediated by specific inflammatory mechanisms:

• Cytokine-driven: Th2 cytokines (particularly IL-9 and IL-13), IL-1β, TNF-α, and COX-2 upregulate mucin synthesis and drive goblet cell hyperplasia 3
• Signaling pathways: IL-13 acts via STAT-6 and FOXA2, TNF-α via NF-κB, and epidermal growth factor receptor (EGF-R) appears to be a convergent pathway for multiple inflammatory mediators 3
• WNT/β-catenin signaling: Reduced RYK expression (a WNT coreceptor) is associated with goblet cell metaplasia in COPD patients, suggesting that defects in this pathway contribute to disease pathogenesis 4

Clinical Implications by Disease State

Asthma

• Neutrophilic asthma association: Goblet cell hyperplasia correlates with neutrophilic inflammatory patterns on BAL analysis (P = 0.002), not eosinophilic inflammation 5
• Disconnection from symptoms: Interestingly, goblet cell hyperplasia itself is disconnected from chronic cough and sputum symptoms when assessed by validated questionnaires; symptoms are more related to airway eosinophilia 5

COPD

• Progressive pathology: Goblet cell changes worsen progressively when comparing smokers with mild versus severe COPD 1
• Persistent inflammation: Inflammatory changes and goblet cell alterations persist even in former smokers, suggesting that once established, the pathological process continues 1
• Reduced antimicrobial defenses: In larger airways with chronic bronchitis, there is reduction in serous acini of submucosal glands, which normally produce antimicrobial deterrents (lactoferrin, antiproteases, lysozyme), further compromising local bacterial defenses 1

Important Clinical Caveats

• Small airway disease is critical: The appearance of goblet cells in small airways (mucous metaplasia) where they are normally absent is a key pathological feature distinguishing disease from health and is central to COPD development 1
• Multifactorial cough mechanism: The cough in chronic bronchitis results from airway inflammation, excessive secretions activating cough receptors, heightened cough receptor sensitivity (demonstrated by increased capsaicin-induced cough), and ineffective cough from airflow obstruction 1
• Vicious cycle: The combination of goblet cell hyperplasia, impaired mucociliary clearance, bacterial colonization, and ongoing inflammation creates a self-perpetuating cycle that worsens with acute viral and bacterial infections 1