Date of Award

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Environmental Health, Occupational Health, and Toxicology

First Advisor

Dr. Todd A Wyatt

Abstract

From the time of discovery, people have used both alcohol and tobacco in various forms all around the world. Alcohol abuse and cigarette smoking causes thousands of preventable deaths in the US each year. Several lung diseases such as COPD, asthma, respiratory infections, pneumonia, acute respiratory distress syndrome, cancer of neck, throat, mouth and lung are associated with smoking and drinking. Even though some studies have examined the role of alcohol and cigarette smoke in lung diseases, only a few studies have focused on the role of reactive aldehydes generated in the lungs of those who abuse alcohol and smoke cigarettes. In this study, we showed that reactive aldehydes formed in lung can attack protein and DNA to form various adducts. Malondialdehyde, a reactive aldehydes formed from both alcohol metabolism and cigarette smoking forms malondialdehyde deoxyguanosine adduct (M1dG) with guanine base of DNA. Our study showed that this adduct is formed in both human bronchial epithelial cells and in lungs of mice exposed to alcohol and cigarette smoke. In bronchial epithelial cells, M1dG adduct induced DNA damage. Our study also showed that use of dietary supplement such as diallyl-disulfide (DADS), a CYP2E1 inhibitor, significantly reduced DNA damage and M1dG adduct formation showing the important role of CYP2E1 in M1dG adducts formation. These findings suggest that CYP2E1 plays a pivotal role in alcohol-induced M1dG adducts, and the use of DADS as dietary supplement can reverse the effects of alcohol on M1dG formation.

With regard to protein adduction, our other study showed that reactive aldehydes acetaldehyde and malondialdehyde, when generated in lung in large concentrations, could form hybrid adduct malondialdehyde-acetaldehyde adducts (MAA) to various biological proteins. Our study showed that this hybrid adduct, once formed, could induce inflammation in both cell and in vivo model systems. MAA reduced macrophage phagocytic, superoxide ion and nitrite ion release functions. Also, MAA induced pro-inflammatory cytokines TNF alpha and IL-6 from macrophages. But in the absence of scavenger receptor A (SRA), previously known to bind MAA in bronchial epithelial cells, the effects of MAA were diminished; suggesting an important role for SRA in MAA-mediated changes to macrophage function. These results further support our previous finding that SRA is necessary for MAA binding.

In accordance with our in vitro study, our mouse study results suggest that SRA is important for SPD-MAA induced lung injury. In the absence of SRA, there were significantly fewer total cells and neutrophils in the BAL fluid when mice were intranasally instilled with MAA for 3 weeks. In addition, there was less binding of MAA to lung epithelium and decreased neutrophil influx in the lung parenchyma of SRA KO mice. These data demonstrate that SRA plays an important role in SPD-MAA-induced inflammation in lung as evidenced by the diminished inflammation in the absence of this receptor.

Taken together, our data suggest that aldehyde adducts formation in lung is important and may provide an effective mechanism through which alcohol and cigarette smoke could initiate lung pathogenesis. Also, the role of CYP2E1 in lung aldehydes generation and SRA in MAA- mediated lung effects could be helpful in developing a novel treatment pathway for alcohol abusers who smoke cigarettes.

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