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Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response
Michael A. Flierl1, Daniel Rittirsch1, Brian A. Nadeau1, J. Vidya Sarma1, Danielle E. Day1, Alex B. Lentsch2, Markus S. Huber-Lang3, Peter A. Ward1*
1 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 2 The Laboratory of Trauma, Sepsis &Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America, 3 Department of Trauma-, Hand- and Reconstructive Surgery, University of Ulm Medical School, Ulm, Germany

Abstract
Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show thatboth epinephrine and norepinephrine directly activate NFkB in macrophages, causing enhanced release of proinflammatory cytokines (TNFa, IL-1b, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes.Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-b-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels ofphagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related toa2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to bea compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of a2-adrenoceptors.
Citation: Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, et al. (2009) Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response. PLoS ONE 4(2): e4414.doi:10.1371/journal.pone.0004414 Editor: Patricia Bozza, Instituto Oswaldo Cruz and FIOCRUZ, Brazil Received September 25, 2008; Accepted December 16, 2008; Published February 12, 2009 Copyright: ß 2009 Flierl et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal author and source are credited. Funding: This study was supported by NIH grants GM29507, GM61656 and HL-31963 (P.A.W.), NIH grants DK56029 and AG025881 (A.B.L.) and Deutsche Forschungsgemeinschaft grants HU 823/2-2 and HU 823/2-3 (M.H.-L.). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CompetingInterests: The authors have declared that no competing interests exist. * E-mail: pward@umich.edu

Introduction
During an immune response, the central nervous system and the immune system communicate with each other [1]. The major pathway systems involved in this cross-talk are the hypothalamicpituitary-adrenal (HPA) axis and the autonomic nervous system [1–3]. Activation of the vagus-dominated...