Emphysema/COPD poses an ever-increasing threat to world health. It is one of the few chronic diseases in which morbidity and mortality is dramatically increasing (Global Burden of Disease Study, 2002, World Health Organization). This project evaluates autophagy and lysosome function in a disease relevant cell, the alveolar macrophage. The hypothesis is that accumulation of non-degradable particulates alters homeostatic autophagy and lysosomal clearance mechanisms in smoker's macrophages. This disruption of an important cellular housekeeping function potentially alters gene expression and immune function leading directly to smoking-induced emphysema. Knowledge gained will be used to examine relevant interventions as a means of improving quality of life for individuals impacted by emphysema.
Specific Aims : The project tests whether smoking-induced defects in the autophagy/lysosomal pathway lead to decreased clearance of damaged proteins, defective degradation of harmful particulates, mitochondrial damage, altered gene expression and impaired innate immune responses.
Aim 1 will evaluate the regulation of autophagy/lysosomal pathway by cigarette smoke particulates in human alveolar macrophages. The nature of the particulate matter that builds up in smoker's alveolar macrophages will be investigated using state-of-the-art facilities available in the University of Iowa, Nanotechnology Institute. Cigarette smoke extract, control particles and smoking specific particulates will be used to examine links to the autophagy/lysosome pathway. A limited number of interventions will be tested to look for reversal of the changes to the autophagy/lysosome pathway.
Aim 2 will evaluate the role of cigarette smoke-induced autophagy/lysosomal dysfunction in lung injury and repair. Possible outcomes of a breakdown in the autophagy/lysosomal pathway, including mitochondrial dysfunction, altered gene expression and impaired immune responses will be evaluated. Any interventions found to be protective in Aim 1 will be tested for efficacy. If any of the interventions appear to reverse in vitro findings, they will be tested in a murine model of emphysema for their ability to slow or alter the disease process. Summary: Alveolar macrophages in cigarette smokers facilitate the development of emphysema. The role of autophagy/lysosome dysfunction in alveolar macrophage biology is a novel area of research. Understanding these processes may suggest interventions that would improve the overall health of individuals exposed to excessive particulates whether via smoking or via other environmental exposures.

Public Health Relevance

Death and disability from chronic obstructive pulmonary disease (COPD)/emphysema are an increasing health problem both in the US and globally. Alveolar macrophages are important mediators of lung changes in emphysema. This project investigates the role of autophagy in alveolar macrophage immune dysfunction subsequent to smoke exposure and tests a number of relevant interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Postow, Lisa
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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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
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
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
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; 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
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
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 Eyjafjallajokull volcanic ash on innate immune system responses and bacterial growth in vitro. Environ Health Perspect 121:691-8
Monick, Martha M; Beach, Steven R H; Plume, Jeff et al. (2012) Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. Am J Med Genet B Neuropsychiatr Genet 159B:141-51
Hassan, Ihab H; Zhang, Michael S; Powers, Linda S et al. (2012) Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. J Biol Chem 287:4679-89

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