The triple-hit hypothesis: exploring pulmonary e-cigarette, PM_2.5 and viral polyexposure

Exposure to e-cigarette aerosols, particulate matter with aerodynamic diameter ≤2.5 µm (PM_2.5) and respiratory viruses rarely occurs in isolation, but rather in complex polyexposure contexts during daily life. On a cellular and molecular level, vaping induces a distinct lipid-laden macrophage phenotype, alters pulmonary neutrophilic infiltration and impairs epithelial differentiation and ciliary function. In contrast, PM_2.5 alters the macrophage polarisation equilibrium, temporally favouring an acute pro-inflammatory phenotype and a subsequent chronic tissue-remodelling phenotype, while also driving an oxidative inflammatory epithelial milieu. Both exposures thus impair antiviral defences and enhance susceptibility to respiratory viral infections such as influenza A, rhinovirus and severe acute respiratory syndrome coronavirus 2. The triple-hit hypothesis proposes that concurrent exposure to vaping aerosols, PM_2.5 and respiratory viruses may exert additive or synergistic effects on chronic airway inflammation. PM_2.5 may amplify vaping-induced macrophage lipid accumulation, thereby reducing the macrophage clearance capacity. Decreased efferocytosis and autophagy may further exacerbate inflammation by increasing secondary necrosis from apoptotic cells and debris. This persistent inflammatory state coupled with epithelial injury and impaired antiviral responses may increase the risk of infection and accelerate the development or progression of chronic respiratory diseases such as asthma and COPD. These insights highlight the crucial need for polyexposure models to accurately reflect real-world environmental and behavioural exposures and evaluate their impact on respiratory health and disease exacerbations. Understanding this exposure triad is also crucial for refining exposure guidelines, updating risk assessments and implementing preventive strategies.