Pulmonary diseases present a significant burden worldwide and lead to severe morbidity and mortality. Lung inflammation caused by interactions with either viruses, bacteria or fungi is a prominent characteristic of many pulmonary diseases. Tobacco smoke and E-cig use (“vaping”) are considered major risk factors in the development of pulmonary disease as well as worsening disease prognosis. However, at present, relatively little is known about the mechanistic actions by which smoking and vaping may worsen the disease. One theory suggests that long-term vaping leads to Ca²⁺ signaling dysregulation. Ca²⁺ is an important secondary messenger in signal transduction. Cellular Ca²⁺ concentrations are mediated by a complex series of pumps, channels, transporters and exchangers that are responsible for triggering various intracellular processes such as cell death, proliferation and secretion. In this review, we provide a detailed understating of the complex series of components that mediate Ca²⁺ signaling and how their dysfunction may result in pulmonary disease. Furthermore, we summarize the recent literature investigating the negative effects of smoking and vaping on pulmonary disease, cell toxicity and Ca²⁺ signaling. Finally, we summarize Ca²⁺-mediated pharmacological interventions that could potentially lead to novel treatments for pulmonary diseases.

Here we use the SCIREQ InExpose system to simulate a biologically relevant vaping model in mice to investigate the role of calcium signaling in vape-dependent pulmonary disease as well as to investigate if there is a gender-based difference of disease. Male and female mice were vaped with JUUL Menthol (3% nicotine) using the SCIREQ InExpose system for 2 weeks. Additionally, 2-APB, a known calcium signaling inhibitor, was administered as a prophylactic for lung disease and damage caused by vaping. After 2 weeks, mice were exposed to lipopolysaccharide (LPS) to mimic a bacterial infection. Post-infection (24 h), mice were sacrificed, and bronchoalveolar lavage fluid (BALF) and lungs were taken. Vaping primed the lungs for worsened disease burden after microbial challenge (LPS) for both males and females, though females presented increased neutrophilia and inflammatory cytokines post-vape compared to males, which was assessed by flow cytometry, and cytokine and histopathological analysis. This increased inflammatory burden was controlled by calcium signaling inhibition, suggesting that calcium dysregulation may play a role in lung injury caused by vaping in a gender-dependent manner.