Exposure to ambient particulate matter (PM) air pollution accounts up to 3.1 years of life lost in the most compared with the least polluted US cities. The mortality associated with acute exposure to ambient PM is largely due to ischemic cardiovascular events. While the mechanisms linking PM exposure with acute cardiovascular events are not fully understood, human and animal data increasingly suggest that PM-induced alterations in hemostasis resulting from lung inflammation and activation of the sympathetic nervous system play causal roles. In the first cycle of this award, we reported that acute exposure to PM causes lung macrophages to release interleukin-6 (IL-6), which accelerates arterial thrombosis in mice, a finding supported by human studies. In our preliminary data we observed that PM-induced opening of Calcium-Release Activated Calcium (CRAC) channels and mitochondrial reactive oxygen species (ROS) play a critical role in PM-induced IL-6 release. We also observed that mice exposed to inhaled PM had increased lung and systemic levels of epinephrine and norepinephrine, directly confirming data from human exposure studies suggesting that PM exposure activates the sympathetic nervous system. Surprisingly, the administration of a ?-blocker or genetic loss of the ?2-adrenergic receptor (?2AR) inhibited the PM-induced release of IL-6 and the subsequent prothrombotic state. Conversely, inhalation of a long acting ?2-agonist (formoterol) augmented the PM-induced release of IL-6 and the resulting prothrombotic state. These results suggest that activation of the sympathetic nervous system in response to PM augments the release of IL-6 from alveolar macrophages and contributes to resulting prothrombotic state. In the current proposal, we have developed 3 specific aims to test the hypothesis that stimulation of the ?2AR by locally derived catecholamines augments the PM-induced release of IL-6 from alveolar macrophages and the resulting prothrombotic state through CRAC channel and ROS- mediated augmentation of cAMP production.
In aim 1, we will determine whether the activation of alveolar macrophage ?2ARs is required for the PM-induced release of IL-6 and the resulting prothrombotic state.
In aim 2, we will determine whether PM-induced opening of CRAC channels and generation of mitochondrial ROS amplify the ?2AR/cAMP-dependent augmentation of IL-6 release.
In aim 3, we will determine whether autocrine catecholamine signaling in alveolar macrophages augments PM-induced IL-6 release and the resulting prothrombotic state. Our findings provide a novel mechanistic paradigm linking PM-induced lung inflammation and activation of the sympathetic nervous system with an increased risk of thrombosis leading to ischemic cardiovascular events. In addition, our observation that the administration of a widely used inhaled long acting ?2AR agonist augments PM-induced IL-6 release and thrombosis provides a potential mechanism to explain the increasing body of evidence showing that the use of inhaled ?2-agonists is associated with increased mortality in patients with COPD and asthma.

Public Health Relevance

Exposure to ambient particulate matter (PM) air pollution accounts up to 3.1 years of life lost in the most compared with the least polluted US cities. This application seeks to determine how activation of the sympathetic nervous system worsens lung inflammation and the tendency toward clotting that follows exposure to PM. Understanding these mechanisms will help develop strategies to prevent PM associated deaths and may have important implications for patients with COPD and asthma who use inhaled ?-adrenergic agonists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015024-09
Application #
8916719
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schug, Thaddeus
Project Start
2006-09-01
Project End
2017-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Wu, David; Woods, Parker S; Duong, Heng T et al. (2018) Role of Cellular Metabolism in Pulmonary Diseases. Am J Respir Cell Mol Biol 59:127-129
Soberanes, Saul; Misharin, Alexander V; Jairaman, Amit et al. (2018) Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metab :
Hamanaka, Robert B; Nigdelioglu, Recep; Meliton, Angelo Y et al. (2018) Inhibition of Phosphoglycerate Dehydrogenase Attenuates Bleomycin-induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol 58:585-593
Mutlu, Ece A; Comba, I??n Y; Cho, Takugo et al. (2018) Inhalational exposure to particulate matter air pollution alters the composition of the gut microbiome. Environ Pollut 240:817-830
Hamanaka, Robert B; Mutlu, Gökhan M (2018) Particulate Matter Air Pollution: Effects on the Cardiovascular System. Front Endocrinol (Lausanne) 9:680
Mutlu, Gökhan M; Budinger, G R Scott (2018) Letter by Mutlu and Budinger Regarding Article, ""Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification"". Circulation 137:1203-1204
Wu, David; Huang, Ru-Ting; Hamanaka, Robert B et al. (2017) HIF-1? is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. Elife 6:
Wu, David; Hamanaka, Robert B; Fang, Yun et al. (2017) Letter by Wu et al Regarding Article, ""Mechanical Activation of Hypoxia-Inducible Factor 1? Drives Endothelial Dysfunction at Atheroprone Sites"". Arterioscler Thromb Vasc Biol 37:e197-e198
Hamanaka, Robert B; Mutlu, Gökhan M (2017) PFKFB3, a Direct Target of p63, Is Required for Proliferation and Inhibits Differentiation in Epidermal Keratinocytes. J Invest Dermatol 137:1267-1276
Misharin, Alexander V; Morales-Nebreda, Luisa; Reyfman, Paul A et al. (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214:2387-2404

Showing the most recent 10 out of 53 publications