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5260.Full.Pdf Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase This information is current as of September 26, 2021. Jerry A. Nick, Scott K. Young, Patrick G. Arndt, Jonathan G. Lieber, Benjamin T. Suratt, Katie R. Poch, Natalie J. Avdi, Ken C. Malcolm, Christian Taube, Peter M. Henson and G. Scott Worthen J Immunol 2002; 169:5260-5269; ; Downloaded from doi: 10.4049/jimmunol.169.9.5260 http://www.jimmunol.org/content/169/9/5260 http://www.jimmunol.org/ References This article cites 77 articles, 41 of which you can access for free at: http://www.jimmunol.org/content/169/9/5260.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Selective Suppression of Neutrophil Accumulation in Ongoing Pulmonary Inflammation by Systemic Inhibition of p38 Mitogen-Activated Protein Kinase1 Jerry A. Nick,2*§ Scott K. Young,* Patrick G. Arndt,*§ Jonathan G. Lieber,† Benjamin T. Suratt,§ Katie R. Poch,* Natalie J. Avdi,* Ken C. Malcolm,† Christian Taube,† Peter M. Henson,†‡ and G. Scott Worthen*§ The p38 mitogen-activated protein kinase (MAPK) signaling pathway regulates a wide range of inflammatory responses in many different cells. Inhibition of p38 MAPK before exposing a cell to stress stimuli has profound anti-inflammatory effects, but little is known about the effects of p38 MAPK inhibition on ongoing inflammatory responses. LPS-induced activation of p38 MAPK in human neutrophils was inhibited by poststimulation exposure to a p38 MAPK inhibitor (M39). Release of TNF-␣, macrophage- Downloaded from inflammatory protein (MIP)-2 (MIP-1␤), and IL-8 by LPS-stimulated neutrophils was also reduced by poststimulation p38 MAPK inhibition. In contrast, release of monocyte chemoattractant protein-1 was found to be p38 MAPK independent. Ongoing che- motaxis toward IL-8 was eliminated by p38 MAPK inhibition, although the rate of nondirectional movement was not reduced. A murine model of acute LPS-induced lung inflammation was used to study the effect of p38 MAPK inhibition in ongoing pulmonary inflammation. Initial pulmonary cell responses occur within4hofstimulation in this model, so M39 was administered4hor12h after exposure of the animals to aerosolized LPS to avoid inhibition of cytokine release. Quantities of TNF-␣, MIP-2, KC, or http://www.jimmunol.org/ monocyte chemoattractant protein-1 recovered from bronchial alveolar lavage or serum were not changed. Recruitment of neu- trophils, but not other leukocytes, to the airspaces was significantly reduced. Together, these data demonstrate the selective reduction of LPS-induced neutrophil recruitment to the airspaces, independent of suppression of other inflammatory responses. These findings support the feasibility of p38 MAPK inhibition as a selective intervention to reduce neutrophilic inflammation. The Journal of Immunology, 2002, 169: 5260–5269. apid accumulation of neutrophils to a site of inflamma- Stress-induced responses of many cell types are regulated by tion is a defining early event of innate immunity. Neu- signal transduction via the mitogen-activated protein kinase by guest on September 26, 2021 R trophil recruitment to the airspaces is induced by cyto- (MAPK)3 superfamily (7). Like all mammalian cells, the neutro- kines, chemokines, and other inflammatory mediators released by phil contains at least three distinct families of MAPKs: the p42/44 resident alveolar macrophages and other cells of the lung. Neutro- extracellular signal-regulated kinase (ERK) MAPKs, c-Jun NH2- phils are induced to leave the pulmonary vasculature, migrate terminal kinases (JNKs), and p38 MAPKs (8–10). In the setting of through the lung interstitium, and ultimately accumulate in the inflammation, cytokine release and other functional responses by airways through a complex series of events including sequential pulmonary host defense cells are regulated to varying degrees by changes in cell size and stiffness, up-regulation of adhesion mol- p38 MAPK. For example, inhibition of p38␣ MAPK blocks ecules, cytoskeletal rearrangement, and chemotaxis (1–4). A sec- TNF-␣ and IL-8 release by LPS-stimulated monocyte/macrophage ondary recruitment of monocytes and macrophages typically fol- (10–12), IL-8 release by bronchial epithelial cells, and up-regula- lows the initial neutrophil influx, and the neutrophil itself may tion of the ICAM-1 in endothelial cells when exposed to inflam- serve to amplify and perpetuate the recruitment of other leukocytes matory stimuli (13, 14). The response of neutrophils to these cy- to the airspaces in certain disease states (5, 6). In a number of tokines and other proinflammatory mediators is also regulated by inflammatory lung diseases such as cystic fibrosis and the acute p38 MAPK. In stimulated neutrophils, p38␣ MAPK regulates dis- respiratory distress syndrome, neutrophil recruitment is prolonged tinctly different functions, including adhesion, activation of NF- and likely contributes to airway injury. ␬B, synthesis of TNF-␣ and IL-8, superoxide anion release, che- motaxis, and apoptosis (15–18). As a short-lived, terminally differentiated primary cell, the neu- Departments of *Medicine and †Pediatrics, and ‡Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206; and §Division of Pulmo- trophil appears to use fewer of the available intracellular signal nary Science and Critical Care Medicine, University of Colorado School of Medicine, transduction mechanisms, relying on the p38 MAPK cascade to Denver, CO 80262 regulate functional responses to nearly every type of environmen- Received for publication December 7, 2001. Accepted for publication August tal stress. For example, in monocytes or macrophage cell lines, 21, 2002. LPS can activate p42/44 (ERK) MAPK and JNK as well as the p38 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3 Abbreviations used in this paper: MAPK, mitogen-activated protein kinase; ERK, 1 This work was supported by Grants HL68743, HL03657, HL-40784, HL-34303, extracellular signal-regulated kinase; JNK, c-Jun NH -terminal kinase; MIP, mac- HL-09640, and GM-30324 from the National Institutes of Health. 2 rophage-inflammatory protein; MCP, monocyte chemoattractant protein; ATF, acti- 2 Address correspondence and reprint requests to Dr. Jerry A. Nick, National Jewish vated transcription factor; BAL, bronchial alveolar lavage; MI, McCutcheon index; Medical and Research Center, K613d, 1400 Jackson Street, Denver, CO 80206. NDM, nondirectional movement; MPO, myeloperoxidase; MAPKAP, MAPK-acti- E-mail address: [email protected] vated protein. Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 5261 ␣ MAPK cascade, and LPS-induced TNF- release can be blocked glycoproteins (29, 30). Activated transcription factor-21–110 (ATF-21–110) through selective inhibition of any of these kinases (10, 19–24). In was prepared as previously described (15, 25). contrast, LPS stimulation of neutrophils does not result in activa- Animals tion of the p42/44 (ERK) MAPKs or the JNKs (25–27). Reflecting the relatively greater dependence of neutrophils on signal trans- Female C57BL/6 mice (Harlan Sprague Dawley, Indianapolis, IN) 6–12 duction via p38 MAPK, a 1000-fold less concentration of a p38 wk of age and weighing 16–20 g were used in all experiments. They were ␣ given commercial pellet food and water ad libitum. All experiments were MAPK inhibitor is required to block release of TNF- , macro- performed in accordance with the Animal Welfare Act and the Public phage-inflammatory protein (MIP)-2, or KC in neutrophils com- Health Service Policy on Humane Care and Use of Laboratory Animals pared with murine alveolar macrophages (12). after review of the protocol by the Animal Care and Use Committee of the Acute aerosolized exposure to LPS serves as a model for pul- National Jewish Medical and Research Center. Anesthesia was provided by a single i.p. injection of 333 mg/kg Avertin. Avertin was prepared by monary inflammation and is of significant clinical interest. LPS is mixing 10 g of tribromoethyl alcohol (Aldrich, Milwaukee, WI) with 10 ml not an effective chemoattractant for neutrophils, but it can trigger of teriary amyl alcohol (Aldrich) and diluting this stock to a 2.5% solution an inflammatory cascade via synthesis of cytokines and chemo- in sterile saline. kines by resident alveolar macrophages, local mast cells, fibro- Murine bronchial alveolar lavage (BAL) blasts, epithelia, and endothelial cells. The subsequent
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