Calcium-Dependent Pulmonary Inflammation and Pharmacological Interventions and Mediators.

Jeffrey G Shipman,Rob U Onyenwoke,Vijay Sivaraman

doi:10.3390/biology10101053

Abstract

Simple SummaryPulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory disease syndrome (ARDS) are common throughout the world. Tobacco products can potentially lead to lung damage, which in turn contribute to worsening disease outcomes. The same can be said of E-cigarette (E-cig) use, which has recently gained attention due to its possible adverse side effects. Despite this information, little is known about the potential for causality between smoking and E-cig use, and lung damage and worsening disease outcomes. In this review, we focus on a potential inflammatory mechanism, that is, calcium (Ca2+) signaling and its importance in many normal biological processes as well as roles it may play in the adverse effects of tobacco and E-cig use. In addition, we discuss possible therapeutic small molecules that may improve pulmonary disease outcomes in the future.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.

Highlights

Because smokers’ airways are characterized by dehydrated mucus, many well-documented studies have investigated cystic fibrosis transmembrane conductance regulator-mediated regulation [11] and the critical role that calcium (Ca2+ ) signaling and, in particular, abnormal Ca2+ influx plays in cystic fibrosis [12,13,14,15] Both acute and chronic exposure to cigarette smoke lead to a chronic elevation in intracellular Ca2+ levels, and smoke from similar tobacco products is expected to exert similar effects, resulting in pulmonary disease initiation and progression [12,13,16]
This study suggests a complex role for Ca2+ mobilization in inflammation and respiratory disease development in relation to vaping
Ca2+ signaling pathways have more recently garnered attention as a potential mediator of these negative effects. These studies have demonstrated that vaping results in Ca2+ dysregulation, leading to decreases in cell viability and increases in inflammation

Summary

Introduction

Because smokers’ airways are characterized by dehydrated mucus, many well-documented studies have investigated cystic fibrosis transmembrane conductance regulator-mediated regulation [11] and the critical role that calcium (Ca2+ ) signaling and, in particular, abnormal Ca2+ influx plays in cystic fibrosis [12,13,14,15] Both acute and chronic exposure to cigarette smoke lead to a chronic elevation in intracellular Ca2+ levels, and smoke from similar tobacco products is expected to exert similar effects, resulting in pulmonary disease initiation and progression [12,13,16]. There exists a series of pumps, channels, transporters and exchangers that mediate intracellular and extracellular Ca2+ concentrations [20] This complex system allows for the manipulation of Ca2+ to trigger numerous intracellular processes including cell metabolism, proliferation, death, gene transcription, secretion, etc. The activation of these channels is a major factor in regulating the uptake of Ca2+ into the cytosol of non-neuronal cells

Transient Receptor Potential Channels

Store-Operated Calcium Entry

Conclusions