@article{812239b051a240af9cfd96752769a65e,
title = "ALX receptor ligands define a biochemical endotype for severe asthma",
abstract = "BACKGROUND. In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS. ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS. Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS. Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation.",
author = "{the National Heart Lung and Blood Institute's Severe Asthma Research Program-3 Investigators} and Isabell Ricklefs and Ioanna Barkas and Duvall, {Melody G.} and Manuela Cernadas and Grossman, {Nicole L.} and Elliot Israel and Bleecker, {Eugene R.} and Mario Castro and Erzurum, {Serpil C.} and Fahy, {John V.} and Gaston, {Benjamin M.} and Denlinger, {Loren C.} and Mauger, {David T.} and Wenzel, {Sally E.} and Comhair, {Suzy A.} and Coverstone, {Andrea M.} and Fajt, {Merritt L.} and Hastie, {Annette T.} and Johansson, {Mats W.} and Peters, {Michael C.} and Phillips, {Brenda R.} and Levy, {Bruce D.}",
note = "Funding Information: The authors thank the study participants, the SARP-3 investigators and clinical research coordinators, and the data-coordinating center. See supplemental Acknowledgments for SARP-3 consortium details. We also thank Guangli Zhu for her expert technical assistance. This study was conducted with the support of grants that were awarded by the NHLBI as follows: Elliot Israel and Bruce Levy, Harvard Medical School U10 HL109172; Eugene Bleecker, Wake Forest University U10 HL109164; Mario Castro, Washington University U10 HL109257; Serpil Erzurum, Cleveland Clinic (Co-PI, Virginia-Cleveland Consortium) U10 HL109250; John Fahy, UCSF U10 HL109146; Benjamin Gaston, Case Western Reserve University U10 HL109250; Nizar Jarjour, University of Wisconsin U10 HL109168; Sally Wenzel, University of Pittsburgh U10 HL109152; David Mauger, Penn State University U10 HL109086-04; the work was also supported in part by R01-HL122531 (BDL), a fellowship from the German Society for Pediatric Pneumology (IR), and K12-HD047349 (MGD). In addition, this program is supported through the following NIH National Center for Advancing Translational Sciences (NCATS) awards: UL1 TR001420 to Wake Forest University, UL1 TR000427 to the University of Wisconsin, UL1 TR001102 to Harvard University, and UL1 TR000454 to Emory University. See supplemental acknowledgments for the NHLBI SARP-3 investigators{\textquoteright} details. The interests of Bruce Levy were reviewed and are managed by the Brigham and Women{\textquoteright}s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. Funding Information: The authors thank the study participants, the SARP-3 investigators and clinical research coordinators, and the data-coordinating center. See supplemental Acknowledgments for SARP-3 consortium details. We also thank Guangli Zhu for her expert technical assistance. This study was conducted with the support of grants that were awarded by the NHLBI as follows: Elliot Israel and Bruce Levy, Harvard Medical School U10 HL109172; Eugene Bleecker, Wake Forest University U10 HL109164; Mario Castro, Washington University U10 HL109257; Serpil Erzurum, Cleveland Clinic (Co-PI, Virginia-Cleveland Consortium) U10 HL109250; John Fahy, UCSF U10 HL109146; Benjamin Gaston, Case Western Reserve University U10 HL109250; Nizar Jarjour, University of Wisconsin U10 HL109168; Sally Wenzel, University of Pittsburgh U10 HL109152; David Mauger, Penn State University U10 HL109086-04; the work was also supported in part by R01-HL122531 (BDL), a fellowship from the German Society for Pediatric Pneumology (IR), and K12-HD047349 (MGD). In addition, this program is supported through the following NIH National Center for Advancing Translational Sciences (NCATS) awards: UL1 TR001420 to Wake Forest University, UL1 TR000427 to the University of Wisconsin, UL1 TR001102 to Harvard University, and UL1 TR000454 to Emory University. See supplemental acknowledgments for the NHLBI SARP-3 investigators' details. The interests of Bruce Levy were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. Publisher Copyright: {\textcopyright} 2017 American Society for Clinical Investigation. All rights reserved.",
year = "2017",
month = jul,
day = "20",
doi = "10.1172/JCI.INSIGHT.93534",
language = "English (US)",
volume = "2",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "14",
}