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 beta-blocker or genetic loss of the beta2-adrenergic receptor (beta2AR) inhibited the PM-induced release of IL-6 and the subsequent prothrombotic state. Conversely, inhalation of a long acting beta2-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 beta 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 beta 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 beta 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 beta 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 beta2-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 that use inhaled beta-adrenergic agonists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES015024-06A1
Application #
8238627
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Nadadur, Srikanth
Project Start
2006-09-01
Project End
2017-05-31
Budget Start
2012-09-14
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$347,625
Indirect Cost
$122,625
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Peteranderl, Christin; Morales-Nebreda, Luisa; Selvakumar, Balachandar et al. (2016) Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest 126:1566-80
Chiarella, Sergio E; Budinger, G R Scott; Mutlu, Gökhan M (2015) β₂-Agonist therapy may contribute to the air pollution and IL-6-associated risk of developing severe asthma with dual-positive TH2/TH17 cells. J Allergy Clin Immunol 135:290-1
Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L et al. (2015) Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 52:503-12
Bharat, Ankit; Cunningham, Scott A; Scott Budinger, G R et al. (2015) Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 7:284re3
Barreiro, Esther; Sznajder, Jacob I; Nader, Gustavo A et al. (2015) Muscle dysfunction in patients with lung diseases: a growing epidemic. Am J Respir Crit Care Med 191:616-9
Ghio, Andrew J; Soukup, Joleen M; Dailey, Lisa A et al. (2015) Wood Smoke Particle Sequesters Cell Iron to Impact a Biological Effect. Chem Res Toxicol 28:2104-11
Chiarella, Sergio E; Soberanes, Saul; Urich, Daniela et al. (2014) β₂-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. J Clin Invest 124:2935-46
Budinger, G R Scott; Mutlu, Gökhan M (2014) β2-agonists and acute respiratory distress syndrome. Am J Respir Crit Care Med 189:624-5
Budinger, G R Scott; Mutlu, Gökhan M (2014) Reply: β2-agonists and acute respiratory distress syndrome. Am J Respir Crit Care Med 189:1448
Radigan, Kathryn A; Morales-Nebreda, Luisa; Soberanes, Saul et al. (2014) Impaired clearance of influenza A virus in obese, leptin receptor deficient mice is independent of leptin signaling in the lung epithelium and macrophages. PLoS One 9:e108138

Showing the most recent 10 out of 40 publications