Imaging modalities in lung disease focus on the evaluation of end damage and destruction. The development of methods to image cellular processes and targets related to disease pathogenesis may allow evaluation over the time course of disease and provide prognostic information. In emphysema, exposure to tobacco smoke leads to inflammation, airspace enlargement, lung alveolar destruction, loss of alveolar blood vessels and eventual irreversible lung destruction. Studies have shown that cigarette smoke can stimulate inflammatory pathways by signaling through the receptor for advanced glycation end-products (RAGE), which binds a number of ligands that activate intracellular pathways, leading to release of inflammatory cytokines and to pathways linked to apoptosis. Through the studies described in this proposal, we seek to demonstrate lung inflammation through the quantification of cigarette smoke induced RAGE pro-inflammatory signaling and cellular apoptosis with SPECT imaging. The studies presented in this proposal will improve our understanding of the role of RAGE and apoptosis in emphysema pathogenesis.
In Aim 1, we will develop and validate an imaging methodology that targets RAGE activity in the smoke exposed mouse.
In Aim 2, we will image apoptosis in a cigarette smoke exposed rabbit model of emphysema.
In Aim 3, we will evaluate the time course of inflammation and apoptosis in the rabbit model of emphysema, correlating peak levels of RAGE and apoptosis activity with structural changes. We will also determine the effect of smoking cessation on these signals. The development of these imaging tools in relevant animal models has the potential to identify and quantify early lung damage, predict outcome and serve as a surrogate marker to assess smoking cessation and other therapies.

Public Health Relevance

The development of novel imaging methodologies utilizing biologically known pathway targets has the potential to allow functional imaging of lung disease. Inflammation and apoptosis are both implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Therefore, we propose to validate novel molecular imaging agents that target the inflammatory and apoptotic pathway in animal models of emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL116346-01
Application #
8417062
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Program Officer
Lin, Sara
Project Start
2012-09-25
Project End
2015-06-30
Budget Start
2012-09-25
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$381,010
Indirect Cost
$131,010
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Goldklang, Monica P; Tekabe, Yared; Zelonina, Tina et al. (2016) Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo. Am J Respir Cell Mol Biol 55:848-857
Goldklang, Monica P; Marks, Sarah M; D'Armiento, Jeanine M (2013) Second hand smoke and COPD: lessons from animal studies. Front Physiol 4:30