What is the pathophysiology of asthma?

Pathophysiology of Asthma

Asthma is fundamentally a chronic inflammatory disorder of the airways where inflammation drives three interconnected pathophysiologic processes: bronchoconstriction, bronchial hyperresponsiveness, and progressive airway remodeling that together produce the variable and reversible airflow obstruction characteristic of the disease. 1

Core Inflammatory Process

The underlying inflammation involves multiple cellular players working in concert 1:

• Mast cells, eosinophils, T lymphocytes, macrophages, and epithelial cells orchestrate the inflammatory cascade, with neutrophils playing a particularly important role in sudden-onset fatal exacerbations, occupational asthma, and in patients who smoke 1
• Inflammatory cells release potent mediators including cysteinyl leukotrienes that directly cause bronchoconstriction and are responsible for allergen-induced, exercise-induced, and aspirin-induced asthma 2
• TH2 lymphocytes maintain the inflammatory cascade through cytokine production, while proinflammatory cytokines like GM-CSF, IL-3, and IL-5 promote survival and activation of eosinophils and mast cells 2

Three Mechanisms of Airflow Limitation

The inflammation produces airflow obstruction through distinct but overlapping mechanisms 1:

1. Bronchoconstriction

• Bronchial smooth muscle contracts rapidly in response to allergens, irritants, and other stimuli, quickly narrowing the airways 1
• This represents the most immediately reversible component of airflow obstruction 1

2. Airway Hyperresponsiveness

• Airways develop an exaggerated bronchoconstrictor response to stimuli that would not affect normal airways 1
• This hyperresponsiveness results from both the inflammatory process and structural airway changes 2
• Bronchial hyperreactivity can be demonstrated through methacholine or mannitol challenge testing 3, 4

3. Airway Edema and Mucus Obstruction

• As inflammation becomes more persistent, edema, mucus hypersecretion, and formation of inspissated mucus plugs further limit airflow 1
• These changes are less immediately reversible than bronchoconstriction alone 1

Airway Remodeling: The Structural Consequence

Persistent inflammation leads to permanent structural changes in the airway architecture 1:

• Sub-basement membrane fibrosis develops beneath the epithelial layer 1
• Smooth muscle hypertrophy increases the mass of contractile tissue 1
• Epithelial cell injury and shedding disrupts the protective airway lining 1
• Angiogenesis creates new blood vessels that perpetuate inflammation 1
• Mucus gland hyperplasia leads to chronic mucus hypersecretion 1

These structural changes explain why airflow limitation may become incompletely reversible in some patients despite aggressive treatment 1. The remodeling process can occur even in patients with mild asthma who have few symptoms 1.

Genetic and Environmental Interplay

The development of asthma requires both genetic susceptibility and environmental triggers 1, 5, 6:

• Strong genetic component: 80% of children with two asthmatic parents develop asthma, compared to 40% with one asthmatic parent and 10% with neither parent affected 5, 6
• Gene-environment interactions are critical, with environmental exposures during immune system development being essential 5, 6
• In utero exposures such as maternal smoking increase childhood asthma risk in a dose-dependent pattern 5, 6
• The hygiene hypothesis suggests that early-life infections and exposures (older siblings, early childcare enrollment, country living, less antibiotic use) promote TH1 immune responses that protect against asthma, while absence of these factors allows TH2-dominated responses that lead to allergic diseases and asthma 1

Phenotypic Variation

Different asthma phenotypes exist with varying patterns of inflammation, cellular mediators, and therapeutic responses 1:

• Allergic (IgE-mediated) asthma 3, 4
• Nonallergic asthma (often viral-triggered) 3, 4
• Occupational asthma with prominent neutrophilic inflammation 1
• Aspirin-exacerbated respiratory disease 3, 4
• Exercise-induced asthma 3, 4

Understanding these phenotypes is increasingly important as treatment approaches may eventually be directed to specific patient phenotypes and genotypes 1, 5.

Clinical Manifestations

The pathophysiologic changes produce characteristic symptoms 1:

• Recurrent episodes of coughing (particularly at night or early morning), wheezing, breathlessness, and chest tightness 1
• Variable airflow obstruction that is often reversible either spontaneously or with treatment 1
• Symptoms triggered by specific stimuli including allergens, irritants, exercise, cold air, and viral infections 5

A critical clinical pitfall: These pathologic changes—including inflammatory cell infiltration, plasma exudation, edema, smooth muscle hypertrophy, and mucus plugging—can be present even in patients with mild asthma when they have few symptoms 1. This underscores why anti-inflammatory treatment is necessary even in apparently mild disease.