Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine
Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.
The electronic nicotine delivery system (ENDS), or e-cigarette, entered the US market in the mid-2000s and rapidly gained popularity among tobacco smokers and never-smokers (1). Currently, an estimated 10 million US adults and over 3 million high school age adolescents are active ENDS users (2, 3). Notably, ENDS have become the most commonly consumed tobacco substitute in the adolescent population, fueling concerns over the health-related consequences of ENDS exposure (4). A large contributor to the public appeal of ENDS among both adults and adolescents is the effective delivery of nicotine in the form of a vapor composed of the vehicle solvents propylene glycol (PG) and vegetable glycerin (VG), thereby circumventing the need for tobacco combustion. The popularity of ENDS has been further augmented by the additional flavorings that can be added to ENDS solutions. Over 7,000 flavors are available to accompany ENDS devices currently, which add essences of fruit or candy to enhance the experience of “vaping” (5).
ENDS-related studies often examine their addictive properties and the enticing advertising campaigns used by e-cigarette companies, which target impressionable youth (6). Specifically, studies have found that early ENDS use in teenagers may increase the risk for tobacco smoking later in life as they exhibit increased intention to smoke traditional cigarettes compared with those who have never used ENDS (7, 8). Moreover, toxicological studies have highlighted the potential health concerns of ENDS by revealing detectable levels of both heavy metals and carbonyls, such as formaldehyde and acrolein, in the vapor produced by some of the devices (9–11). Further, terms such as “popcorn lung” have become synonymous with ENDS among their opponents for the deleterious diacetyls detected in ENDS-associated flavorings (12). In contrast, other reports have advocated the safety of the products over traditional tobacco cigarettes (13, 14), thus emphasizing the unmet need to better understand the health-related consequences of exposure to e-cigarette components.
Multiple case reports have described atypical types of pneumonia in ENDS users (15, 16). A shared feature in these reports is the presence of lipid-laden macrophages found in the bronchoalveolar lavage (BAL) fluid from individuals with ENDS-associated pneumonia (15, 16). Despite this commonality, the physiological importance of lipid accumulation and whether this phenomenon can be recapitulated in experimental systems remain unknown. Lipid metabolism is critical for proper cellular function in all tissues. Pulmonary surfactant and lipid homeostasis in the distal airways are essential for adequate gas exchange and innate immune function (17). Pulmonary surfactant, a complex mixture of lipids and proteins produced exclusively by alveolar type II pneumocytes (ATIIs), forms a critical part of the alveolar-lining fluid (18). Surfactant reduces alveolar surface tension, thereby preventing lung atelectasis, ventilation perfusion mismatch, and hypoxemia (19). Surfactant protein A (SP-A) and surfactant protein D (SP-D), 2 components of the surfactant complex, play essential roles in innate immune defense by facilitating microbial opsonization and clearance (20). To maintain the integrity of the surfactant complex, alveolar macrophages catabolize altered or oxidized surfactant in the distal liquid-air interface, which is critical for responses to inhaled pathogens (21). Impairment of macrophage metabolism of pulmonary surfactant leads to accumulation of intracellular lipid and deposition of excess lipid in the alveolar space (22).