Development of ventilatory dysfunction following particulate matter (PM) exposure is a major health concern worldwide. Industrialized and developing nations have high ambient particulates and a coexisting high prevalence of metabolic syndrome (MetSyn). The contribution of these two conditions to obstructive pulmonary disease is a topic of considerable importance. The collapse of the World Trade Center (WTC) exposed over 11,000 FDNY first responders to high concentration particulate matter (WTC-PM) at a defined point in time. Between 10/2001-2/2002, serum was obtained on over 8,000 exposed FDNY first responders and is available for biomarker investigation. Since this biobank was obtained prior to disease diagnosis, the biomarkers are not caused by the disease and could reflect pathogenic pathways active during disease evolution. Our research has demonstrated that mediators of MetSyn predict abnormal forced expiratory volume in one second (FEV1) over the subsequent six years. This effect is independent of confounders such as BMI. To better dissect which component of MetSyn contribute to this effect we investigated Lysophosphatidic acid (LPA), a metabolic product of LDL. We recently reported LPA level predicts developing an abnormal FEV1. Our collaborator Dr. Schmidt has defined RAGE as a receptor for LPA. RAGE is highly expressed in the lung and is a strong predictor of FEV1 in genome wide association studies. Our preliminary murine experiments show that WTC-PM exposure produces neutrophilia, loss of FEV1, increased resistance and methacholine reactivity. RAGE deficient mice are protected from these WTC-PM effects. Pioglitazone, an FDA-approved PPAR? agonist, inhibits RAGE signaling and was studied as a potential treatment against PM-induced inflammation. Our preliminary data showed that it protects against WTC-PM-induced increased resistance, FEV loss, and neutrophilia, but not against airway hyperreactivity. Hypothesis: RAGE mediates LPA induced lung inflammation. Increased LPA interacts with PM to promote greater inflammation than either stimulus alone. Pioglitazone can attenuate PM-induced lung injury. Our hypothesis will be explored in 3 aims.
Aim 1 extends our biomarker observations to 1720 symptomatic patients who presented for evaluation before 2008.
Aim 2 will use a series of loss/gain of function experiments in murine and macrophage models to dissect the contribution of RAGE to PM/LPA interaction.
Aim 3 investigates if pioglitazone treatment attenuates early and late effects of PM-induced pulmonary inflammation via RAGE. Data generated by this grant will provide new insights into the novel role of RAGE in mediating the interaction between metabolic syndrome and pulmonary dysfunction, bringing us closer to new therapies for obstructive lung disease.

Public Health Relevance

Chronic lung disease following smoke and particulate matter exposure is a major health concern worldwide. Industrialized and developing nations have high ambient particulate levels and prevalence of coexisting metabolic syndrome. Understanding the synergistic interaction between these two major disorders will provide us new mechanistic insights and allow us to study therapies for particulate matter induced lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119326-01A1
Application #
8962412
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Punturieri, Antonello
Project Start
2015-09-07
Project End
2020-06-30
Budget Start
2015-09-07
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$416,800
Indirect Cost
$166,800
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Zeig-Owens, Rachel; Singh, Ankura; Aldrich, Thomas K et al. (2018) Blood Leukocyte Concentrations, FEV1 Decline, and Airflow Limitation. A 15-Year Longitudinal Study of World Trade Center-exposed Firefighters. Ann Am Thorac Soc 15:173-183
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Vossbrinck, Madeline; Zeig-Owens, Rachel; Hall, Charles B et al. (2017) Post-9/11/2001 lung function trajectories by sex and race in World Trade Center-exposed New York City emergency medical service workers. Occup Environ Med 74:200-203
Caraher, Erin J; Kwon, Sophia; Haider, Syed H et al. (2017) Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure. PLoS One 12:e0184331
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Aldrich, Thomas K; Vossbrinck, Madeline; Zeig-Owens, Rachel et al. (2016) Lung Function Trajectories in World Trade Center-Exposed New York City Firefighters Over 13 Years: The Roles of Smoking and Smoking Cessation. Chest 149:1419-27
Kwon, Sophia; Crowley, George; Haider, Syed Hissam et al. (2016) Nephroprotective strategies in septic shock: the VANISH trial. J Thorac Dis 8:E1508-E1510

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