The global impact of smoking on public health remains devastating. Despite aggressive efforts to reduce cigarette consumption, smoking-related lung diseases such as COPD and lung cancer continue to dominate health care headlines. Even with successful smoking cessation, the risk of developing lung disease persists for years and perhaps decades. Passive or environmental smoke exposure increases the risk for certain lung disorders suggesting that there may be no safe threshold for smoke inhalation. How smoking results in an enduring disease risk with low or no threshold is not currently understood. The resident alveolar macrophage has been implicated in the pathophysiology of many smoking-related lung diseases. Preliminary work in our laboratory has uncovered significant changes in both microRNA expression and methylation status of CpG motifs in the promoter regions in the alveolar macrophages from active smokers compared to """"""""never"""""""" smokers. This proposal will investigate the overall hypothesis that in vivo cigarette smoke exposure alters the genomic tone of alveolar macrophages contributing to the development of smoking-related lung diseases. The focus for this project is microRNA expression profiles and gene promoter DNA methylation status as two critical regulatory points in cellular gene expression.
In Aim 1, we will examine the hypothesis that chronic cigarette smoke exposure causes a global down regulation of microRNA expression in alveolar macrophages by interfering with the microRNA maturation process. To explore the threshold needed to produce this response, we will study microRNA profiles in alveolar macrophages obtained from domestic partners of active smokers;to define the persistence of gene suppression we will study cells from ex-smokers.
In Aim 2, we will examine the hypothesis that active smoking alters DNA methylation patterns in gene promoter regions by comparing DNA CpG methylation profiles. We will study the same active smokers, ex-smokers and individuals with passive smoke exposure as in Aim 1. Finally, Aim 3 will validate the array findings (microRNA, mRNA and DNA methylation) with targeted individual assays. Differentially expressed microRNAs and altered methylated CpG islands in promoter regions will be correlated with exon-specific mRNA expression via bioinformatics analysis. In the case of microRNAs, over and under expression studies will confirm links between altered microRNAs and potential targets. Identification of a specific genomic phenotype in the alveolar macrophage from smoke-exposed subjects would provide important insight into pathogenesis of smoking-related lung disease. In addition, this could lead to an easily retrievable biomarker useful in tracking physiologically relevant smoke exposure and may be applicable to lung disease related to other inhaled toxicants.

Public Health Relevance

This project investigates the hypothesis that cigarette smoking alters alveolar macrophage gene expression via a global and durable change in microRNA levels and DNA methylation patterns. This altered genomic tone in the distal airspace directly contributes to smoking-related lung disease. If confirmed by the proposed studies, this may explain why the risk for smoking-related lung disease persists after smoking cessation as well as why passive cigarette smoke exposure is associated with a measurable risk for lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Postow, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Rhein, Bethany A; Powers, Linda S; Rogers, Kai et al. (2015) Interferon-? Inhibits Ebola Virus Infection. PLoS Pathog 11:e1005263
Jang, Jun-Ho; Bruse, Shannon; Huneidi, Salam et al. (2014) Acrolein-exposed normal human lung fibroblasts in vitro: cellular senescence, enhanced telomere erosion, and degradation of Werner's syndrome protein. Environ Health Perspect 122:955-62
Gerke, Alicia K; Pezzulo, Alejandro A; Tang, Fan et al. (2014) Effects of vitamin D supplementation on alveolar macrophage gene expression: preliminary results of a randomized, controlled trial. Multidiscip Respir Med 9:18
Gross, Thomas J; Kremens, Karol; Powers, Linda S et al. (2014) Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses. J Immunol 192:2326-38
Hassan, Ihab; Gaines, Kayla S; Hottel, Wesley J et al. (2014) Inositol-requiring enzyme 1 inhibits respiratory syncytial virus replication. J Biol Chem 289:7537-46
Dogan, Meeshanthini V; Shields, Bridget; Cutrona, Carolyn et al. (2014) The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genomics 15:151
Gross, Thomas J; Powers, Linda S; Boudreau, Ryan L et al. (2014) A microRNA processing defect in smokers' macrophages is linked to SUMOylation of the endonuclease DICER. J Biol Chem 289:12823-34
Gores, Kathryn M; Delsing, Angela S; Kraus, Sara J et al. (2014) Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy. Shock 42:115-20
Monick, Martha M; Baltrusaitis, Jonas; Powers, Linda S et al. (2013) Effects of Eyjafjallajökull volcanic ash on innate immune system responses and bacterial growth in vitro. Environ Health Perspect 121:691-8
Graff, Joel W; Powers, Linda S; Dickson, Anne M et al. (2012) Cigarette smoking decreases global microRNA expression in human alveolar macrophages. PLoS One 7:e44066

Showing the most recent 10 out of 13 publications