Electronic cigarette (E-cig) usage has surged in recent years, often marketed as a safer alternative to traditional tobacco smoking. However, exposure to E-cigarette liquid has the potential to exacerbate respiratory diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma which are conditions characterized by airway mucin hypersecretion and increased mucus viscosity [1-3]. While airway inflammation is often emphasized in these conditions, it does not fully capture the multifaceted pathological changes that limit therapeutic progress. The impact of E-cig liquids on mucus rheology and calcium signaling pathways remains poorly understood, particularly concerning their role in promoting mucus stasis and hypersecretion. This dissertation focuses on two key E-cig liquid components: vegetable glycerin (VG) and propylene glycol (PG). Although widely used for their co-solvent, humectant, and plasticizing properties in gel formulations, their direct interaction with airway mucus has not been fully characterized. The first aim of this work was to investigate how VG and PG alter the swelling kinetics and diffusivity of mucus. Using polymer swelling kinetics and imaging-based diffusivity analyses, it was found that VG and PG significantly impair mucin hydration, likely through dehydration and altered crosslinking, producing denser and less transportable mucus gels. These findings suggest a physicochemical mechanism by which E-cig solvents may impede mucociliary clearance. The second aim was to determine whether VG and PG initiate calcium-induced calcium release (CICR) and thereby stimulate mucin secretion in airway epithelial cells. Live-cell calcium imaging in BEAS-2B cells revealed that VG and PG induce sustained elevations in cytosolic calcium concentration [Ca²⁺]c, mediated by a combination of voltage-gated calcium channels, store-operated calcium entry (SOCE) through Orai1-STIM1 interactions, and TRP channels. Pharmacological inhibition using thapsigargin, ryanodine, nifedipine, and 2-APB, attenuated the calcium response. Among these, only thapsigargin, ryanodine, and nifedipine were tested and found to significantly reduce mucin exocytosis, along with calcium chelation by BAPTA-AM. This confirms that VG/PG-induced mucin secretion is calcium-dependent and CICR-amplified. Together, these findings reveal that VG and PG not only compromise the physical properties of mucus but also modulate intracellular calcium dynamics, resulting in enhanced mucin secretion. This dual impact raises serious concerns about the long-term inhalation of E-cigarette solvents, especially for individuals with pre-existing pulmonary conditions. By identifying specific molecular pathways involved in VG/PG-induced mucus dysfunction, this work not only advances scientific understanding but also highlights an urgent need for regulatory oversight and informed public health policies to address the underestimated risks associated with E-cig use.