Asthma Pathophysiology: Airway Inflammation, Hyperresponsiveness, and Remodeling

Asthma is a chronic inflammatory disorder of the airways characterized by variable airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation. Understanding these mechanisms clarifies treatment targets.

Core Pathophysiological Processes

1. Airway Inflammation (The Foundation)

• Cells: Eosinophils (Type 2), neutrophils (non-Type 2), mast cells, T-lymphocytes (Th2), ILC2s.
• Mediators: Histamine, leukotrienes (C4/D4/E4), IL-4, IL-5, IL-13, IgE, prostaglandins.
• Effects: Mucosal edema, mucus hypersecretion, epithelial shedding, smooth muscle hypertrophy, angiogenesis.

2. Airway Hyperresponsiveness (AHR)

• Exaggerated bronchoconstriction to triggers (allergens, cold air, exercise, irritants) at doses harmless to healthy airways.
• Mechanisms: Inflammation-induced neural dysregulation, smooth muscle hypercontractility, epithelial loss exposing nerves.

3. Bronchospasm (Acute Narrowing)

• Rapid contraction of airway smooth muscle (ASM) via cholinergic, histamine, and leukotriene pathways.
• Reversible (spontaneously or with bronchodilators).

4. Airway Remodeling (Chronic Structural Changes)

• Subepithelial fibrosis, ASM hyperplasia/hypertrophy, gland hyperplasia, neovascularization.
• Contributes to fixed airflow obstruction and reduced bronchodilator response over time.
• Early anti-inflammatory therapy may prevent remodeling.

5. Mucus Hypersecretion & Plugging

• Goblet cell metaplasia + submucosal gland hypertrophy → thick, tenacious mucus.
• Forms casts (Curschmann's spirals) obstructing small airways.

Clinical Phenotypes & Endotypes

• Type 2 High (Allergic/Eosinophilic): IgE-mediated, FeNO↑, blood eosinophils↑ → responds to ICS, biologics (anti-IgE, anti-IL5/5R, anti-IL4Rα).
• Type 2 Low (Non-eosinophilic): Neutrophilic, paucigranulocytic → less ICS-responsive; macrolides, bronchial thermoplasty considered.

Treatment Targets

• ICS (inhaled corticosteroids): Suppress inflammation (core controller).
• LABA/LAMA: Bronchodilation (symptom control).
• Biologics: Target specific inflammatory pathways (severe asthma).
• SABA: Reliever (as-needed); MART (ICS-formoterol) preferred for mild asthma.

Asthma control = minimizing inflammation + managing hyperresponsiveness + preventing remodeling.