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Title: β₂-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis.

Authors: Chiarella, Sergio E; Soberanes, Saul; Urich, Daniela; Morales-Nebreda, Luisa; Nigdelioglu, Recep; Green, David; Young, James B; Gonzalez, Angel; Rosario, Carmen; Misharin, Alexander V; Ghio, Andrew J; Wunderink, Richard G; Donnelly, Helen K; Radigan, Kathryn A; Perlman, Harris; Chandel, Navdeep S; Budinger, G R Scott; Mutlu, Gökhan M

Published In J Clin Invest, (2014 Jul)

Abstract: Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β2-adrenergic receptor (β2AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β2AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β2AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β2AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β2AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β2AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.

PubMed ID: 24865431 Exiting the NIEHS site

MeSH Terms: Adenylyl Cyclases/biosynthesis; Adrenergic beta-2 Receptor Agonists/administration & dosage*; Adrenergic beta-2 Receptor Agonists/adverse effects*; Animals; Antithrombin III/biosynthesis; Bronchoalveolar Lavage Fluid/chemistry; Catecholamines/biosynthesis; Colforsin/administration & dosage; Humans; Interleukin-6/biosynthesis*; Macrophages, Alveolar/drug effects; Macrophages, Alveolar/physiology; Male; Mice; Mice, Knockout; Particulate Matter/administration & dosage*; Particulate Matter/adverse effects*; Peptide Hydrolases/biosynthesis; Propranolol/administration & dosage; Propranolol/adverse effects; Reactive Oxygen Species/metabolism; Receptors, Adrenergic, beta-1/deficiency; Receptors, Adrenergic, beta-1/genetics; Receptors, Adrenergic, beta/deficiency; Receptors, Adrenergic, beta/genetics; Thrombosis/etiology*

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