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3 Requires the Eicosanoid Hepoxilin a Pseudomonas Aeruginosa Polymorphonuclear Cell Transmigration Induced by Pseudomonas aeruginosa Requires the Eicosanoid Hepoxilin A 3 This information is current as Bryan P. Hurley, Dario Siccardi, Randall J. Mrsny and Beth of September 24, 2021. A. McCormick J Immunol 2004; 173:5712-5720; ; doi: 10.4049/jimmunol.173.9.5712 http://www.jimmunol.org/content/173/9/5712 Downloaded from References This article cites 40 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/173/9/5712.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Polymorphonuclear Cell Transmigration Induced by 1 Pseudomonas aeruginosa Requires the Eicosanoid Hepoxilin A3 Bryan P. Hurley,*† Dario Siccardi,*†‡ Randall J. Mrsny,† and Beth A. McCormick2*† Lung inflammation resulting from bacterial infection of the respiratory mucosal surface in diseases such as cystic fibrosis and pneumonia contributes significantly to the pathology. A major consequence of the inflammatory response is the recruitment and accumulation of polymorphonuclear cells (PMNs) at the infection site. It is currently unclear what bacterial factors trigger this response and exactly how PMNs are directed across the epithelial barrier to the airway lumen. An in vitro model consisting of human PMNs and alveolar epithelial cells (A549) grown on inverted Transwell filters was used to determine whether bacteria are capable of inducing PMN migration across these epithelial barriers. A variety of lung pathogenic bacteria, including Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa are indeed capable of inducing PMN migration across A549 mono- layers. This phenomenon is not mediated by LPS, but requires live bacteria infecting the apical surface. Bacterial interaction with Downloaded from the apical surface of A549 monolayers results in activation of epithelial responses, including the phosphorylation of ERK1/2 and secretion of the PMN chemokine IL-8. However, secretion of IL-8 in response to bacterial infection is neither necessary nor sufficient to mediate PMN transepithelial migration. Instead, PMN transepithelial migration is mediated by the eicosanoid hep- oxilin A3, which is a PMN chemoattractant secreted by A549 cells in response to bacterial infection in a protein kinase C- dependent manner. These data suggest that bacterial-induced hepoxilin A3 secretion may represent a previously unrecognized inflammatory mechanism occurring within the lung epithelium during bacterial infections. The Journal of Immunology, 2004, http://www.jimmunol.org/ 173: 5712–5720. iseases involving bacterial-induced lung inflammation of proteases and reactive oxygen species. However, these mecha- have been described, including bacterial-associated nisms are nonspecific and can lead to lung tissue damage, which if D bronchitis, pneumonia, and chronic conditions of pa- excessive, contributes to the pathology of the disease (7). tients having a mutation in the cystic fibrosis transmembrane con- To reach the airway lumen, PMNs are required to travel through ductance regulator (1–3). Several bacterial species have been im- several distinct tissue compartments within the alveolar wall (8, 9). plicated as causes of pneumonia, including Streptococcus PMNs must first escape the alveolar capillary, which involves the pneumoniae, Chlamydia pneumoniae, Haemphilus influenzae, termination of their flow through the vessel followed by adherence by guest on September 24, 2021 Klebsiella pneumoniae, Legionella pneumophila, Escherichia coli, to the lumen surface of the endothelium. The majority of PMNs and Pseudomonas aeruginosa (1, 3–5). Pseudomonas aeruginosa migrate across the junctions that connect the endothelial cells. (PA)3 is the bacterial pathogen most associated with lung damage Once across the endothelial barrier, PMNs navigate the endothelial due to inflammation in individuals with cystic fibrosis (2). basement membrane through pre-existing holes allowing PMNs to One of the pathogenic hallmarks of both cystic fibrosis and gain access to the interstitial space. PMNs then must travel through pneumonia is the accumulation of large numbers of neutrophils or the extracellular matrix that encompasses the interstitial space, polymorphonuclear cells (PMNs) in the lumen of the lower airway where fibroblasts are thought to provide further directional guid- (1, 2, 6). PMNs present in the lumen can aid in eradicating of- ance. PMNs can then interact with the epithelial basement mem- fending bacteria via potent killing mechanisms, including release brane and basolateral surface of the epithelium. Finally, PMNs migrate between the epithelial cells to the apical surface of the epithelial barrier where they gain access to the airway lumen (8, 9). *Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, This process involves the integrated actions of cytokines, adhesion MA 02129; †Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02155; and ‡Cardiff University, School of Pharmacy, Cardiff, molecules with specificity for particular ligands as well as highly Wales timed and compartmentalized secretion of various PMN-specific Received for publication April 12, 2004. Accepted for publication August 17, 2004. chemokines such as IL-8 (8–10). Despite significant progress in The costs of publication of this article were defrayed in part by the payment of page this area of study, the specific molecular mechanism governing charges. This article must therefore be hereby marked advertisement in accordance PMN migration through each compartment to the lumen remains with 18 U.S.C. Section 1734 solely to indicate this fact. to be defined. 1 This work was supported by the National Institutes of Health Grant DK 56754 (to B.A.M.) and by a Pilot and Feasibility Grant from the Cystic Fibrosis Foundation (to Although there are numerous reports of various bacterial prod- B.A.M.). Salary support for B.P.H. was provided by the Ruth L. Kirschstein National ucts capable of inducing IL-8 secretion in several different primary Research Service Award Individual Fellowship awarded by the National Institute of and transformed airway epithelial cell lines (5, 6, 11, 12), it is Allergy and Infectious Diseases. unclear at present whether epithelial IL-8 production by lung ep- 2 Address correspondence and reprint requests to Dr. Beth A. McCormick, Mucosal Immunology Laboratories, Massachusetts General Hospital, CNY 114 (114-3503), ithelial cells is sufficient for mediating transepithelial PMN migra- Charlestown, MA 02129. E-mail address: [email protected] tion. Thus, the objective of this study was to specifically investi- 3 Abbreviations used in this paper: PA, Pseudomonas aeruginosa; PMN, polymor- gate the molecular mechanisms that are responsible for the final phonuclear cell; T-EDTA, trypsin-EDTA; LDH, lactose dehydrogenase; PKC, protein step of PMN recruitment during bacterial infection, namely, PMN ␣ kinase C; CCL, chelerytherine chloride; CDC, cinnamyl-3,4-dihydroxy- -cyanocin- transepithelial transmigration using a reductionistic in vitro model. namate; HXA3, hepoxilin A3; MAP, mitogen-activated protein; MAPK, MAP kinase; 12-LO, 12-lipoxygenase; 5-LO, 5-lipoxygenase. Our approach to investigate the molecular mechanisms responsible Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 5713 for a distinct phase of bacterial-mediated inflammation in the lung was added to the basolateral chamber (bottom). After 2 h, the amount of has revealed new insight into how bacteria interact with the lung HRP that translocated to the basolateral chamber was quantified by a HRP epithelium. We have uncovered a previously unrecognized inflam- activity assay. matory pathway in the lung epithelium involving the secretion of Cell viability assay the eicosanoid hepoxilin A3 (HXA3). HXA3 is an arachidonic acid metabolite synthesized mainly through the actions of 12-lipoxy- To determine whether the bacterial infection resulted in toxicity to the A549 monolayers, release of the enzyme lactose dehydrogenase (LDH) genases, which can induce the release of calcium from intracellular into the supernatant of monolayers under infected conditions was com- stores of various cell types, including PMNs, via an intracellular G pared with uninfected monolayers. As a positive control for cell death, protein-coupled receptor (13). This action has been reported to Triton X-100 was added to monolayers. As with the PMN transmigration ϳ result in a diverse array of biological functions in various cell assay, inverted monolayers were washed and equilibrated in HBSS for 30 min. Monolayers were then flipped
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