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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096625-02
Application #
8066014
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Postow, Lisa
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$375,000
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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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

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