: Ambient participate matter (PM) air pollution contributes significantly to cardiopulmonary morbidity and mortality. There are strong epidemiologic data that link daily levels of ambient PM to hospitalizations for cardiopulmonary disease and daily rates of cardiovascular mortality. Acute exposure to increased levels of PM is also associated with increased risk of acute myocardial infarction, and ischemic stroke. However, the mechanisms by which PM elicits these pathologic events and increases cardiovascular mortality are largely unknown. Exposure of animals and humans to PM alters hemostasis;increasing the levels of fibrinogen, and von Willebrand factor and inducing peripheral arterial thrombosis. In support of a PM-induced prothrombotic state, we have recently observed that exposure of mice to well-characterized PM collected from ambient air in Dusseldorf, Germany caused shortening of the bleeding, prothrombin and partial thromboplastin times, and increased the platelet count and the levels of factor VIII. Moreover, exposure of mice to PM increased bronchoalveolar lavage fluid levels of IL-6, which promotes coagulation and enhances platelet production and thrombin formation. Accordingly, we found that generation of intravascular thrombin was increased 24 hours after exposure to PM. The effect of PM-exposure on thrombin formation was abrogated in mice with targeted deletion of IL-6. Similarly, inhibition of beta-adrenergic receptors, an important regulator of IL-6, attenuated PM-induced thrombin generation. PM-induced stimulation of inflammation and cytokine release has been suggested to be due to the generation of reactive oxygen species (ROS) by epithelial cells and macrophages. These new findings led us to hypothesize that PM causes IL-6 release, which causes a hyper-coagulable state via a ROS-dependent mechanism. To test our hypothesis, we propose to (1) determine whether PM-induced IL-6 production and the resultant hyper-coagulable state are mediated by alveolar macrophages, alveolar epithelial cells, or both, (2) determine whether the PM-induced generation of ROS is required for IL-6 production and the resultant hyper-coagulable state, and (3) determine the role of beta-adrenergic receptors in modulation of the PM-induced IL-6 production and hyper-coagulable state. The studies we are proposing address an important human health problem and could lead to the development of novel therapies to diminish PM-induced cardiovascular events and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015024-04
Application #
7678502
Study Section
Special Emphasis Panel (ZES1-JAB-C (ON))
Program Officer
Nadadur, Srikanth
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$383,302
Indirect Cost
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
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