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JCI Insight. 2017 Jul 20;2(14). pii: 93534. doi: 10.1172/jci.insight.93534. [Epub ahead of print]

ALX receptor ligands define a biochemical endotype for severe asthma.

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Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, and.
Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA.
Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, Washington University, St. Louis, Missouri, USA.
Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, Pennsylvania, USA.
Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.



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).


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]).


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.


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.


Severe Asthma Research Program-3 (SARP-3; NCT01606826)FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.

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