Aldehyde Trapping by ADX-102 Is Protective against Cigarette Smoke and Alcohol Mediated Lung Cell Injury.

Carmen A Ochoa,Destiny L Jordan,Claire G Nissen,Kristina L Bailey,Deanna D Mosley,Todd A Wyatt,Christopher D Bauer

doi:10.3390/biom12030393

Carmen A Ochoa, Destiny L Jordan + Show 5 more

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https://doi.org/10.3390/biom12030393

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Abstract

Most individuals diagnosed with alcohol use disorders smoke cigarettes. Large concentrations of malondialdehyde and acetaldehyde are found in lungs co-exposed to cigarette smoke and alcohol. Aldehydes directly injure lungs and form aldehyde protein adducts, impacting epithelial functions. Recently, 2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol (ADX-102) was developed as an aldehyde-trapping drug. We hypothesized that aldehyde-trapping compounds are protective against lung injury derived from cigarette smoke and alcohol co-exposure. To test this hypothesis, we pretreated mouse ciliated tracheal epithelial cells with 0–100 µM of ADX-102 followed by co-exposure to 5% cigarette smoke extract and 50 mM of ethanol. Pretreatment with ADX-102 dose-dependently protected against smoke and alcohol induced cilia-slowing, decreases in bronchial epithelial cell wound repair, decreases in epithelial monolayer resistance, and the formation of MAA adducts. ADX-102 concentrations up to 100 µM showed no cellular toxicity. As protein kinase C (PKC) activation is a known mechanism for slowing cilia and wound repair, we examined the effects of ADX-102 on smoke and alcohol induced PKC epsilon activity. ADX-102 prevented early (3 h) activation and late (24 h) autodownregulation of PKC epsilon in response to smoke and alcohol. These data suggest that reactive aldehydes generated from cigarette smoke and alcohol metabolism may be potential targets for therapeutic intervention to reduce lung injury.

Highlights

Cigarette smoking is the number one cause of preventable disability and death in the United States, and more than 16 million Americans live with a disease related to cigarette smoking including cancer, heart disease, diabetes, and chronic lung diseases such as COPD and chronic bronchitis [1]
Due to the high amounts of reactive aldehydes produced in alcohol metabolism and cigarette smoke, this study aimed to use aldehyde trapping to demonstrate the role of aldehydes in smoke and alcohol mediated bronchial epithelial dysfunction
As we found that ADX-102 prevented smoke and alcohol mediated PKCε autodownregulation, we measured the ability of aldehyde trapping to prevent smoke and alcohol induced losses in cilia motility

Summary

Introduction

Cigarette smoking is the number one cause of preventable disability and death in the United States, and more than 16 million Americans live with a disease related to cigarette smoking including cancer, heart disease, diabetes, and chronic lung diseases such as COPD and chronic bronchitis [1]. Chronic alcohol use is strongly linked to cigarette smoking. There is a well-established connection between alcohol use and cigarette smoking. More than 80% of individuals who are alcohol-dependent report that they smoke cigarettes [2]. As the lung injury effects of polysubstance abuse are understudied [3], it is important to consider the combination effects of alcohol and cigarette use to identify the mechanisms of tissue damage that occur. Alcohol use has an impact on almost every organ in the body, including the lungs

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