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E‐Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin Secretion

Rationale: E‐cigarettes have become increasingly popular and little is known about their potential adverse health effects. Objectives: To determine the effects of e‐cigarette use on the airways. Methods: Induced sputum samples from cigarette smokers, e‐cigarette users, and nonsmokers were analyzed by quantitative proteomics, and the total and individual concentrations of mucins MUC5AC and MUC5B were determined by light scattering/refractometry and labeled mass spectrometry, respectively. Neutrophil extracellular trap (NET) formation rates were also determined for the same groups. Measurements and Main Results: E‐cigarette users exhibited significant increases in aldehyde‐detoxification and oxidative stress‐related proteins associated with cigarette smoke compared with nonsmokers. The levels of innate defense proteins associated with chronic obstructive pulmonary disease, such as elastase and matrix metalloproteinase‐9, were significantly elevated in e‐cigarette users as well. E‐cigarette users' sputum also uniquely exhibited significant increases in neutrophil granulocyte‐related and NET‐related proteins, such as myeloperoxidase, azurocidin, and protein‐arginine deiminase 4, despite no significant elevation in neutrophil cell counts. Peripheral neutrophils from e‐cigarette users showed increased susceptibility to phorbol 12‐myristate 13‐acetate‐induced NETosis. Finally, a compositional change in the gel‐forming building blocks of airway mucus (i.e., an elevated concentration of mucin MUC5AC) was observed in both cigarette smokers and e‐cigarette users. Conclusions: Together, our results indicate that e‐cigarette use alters the profile of innate defense proteins in airway secretions, inducing similar and unique changes relative to cigarette smoking. These data challenge the concept that e‐cigarettes are a healthier alternative to cigarettes.