ALX receptor ligands define a biochemical endotype for severe asthma
Isabell Ricklefs, Ioanna Barkas, Melody G. Duvall, Manuela Cernadas, Nicole L. Grossman, Elliot Israel, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Loren C. Denlinger, David T. Mauger, Sally E. Wenzel, Suzy A. Comhair, Andrea M. Coverstone, Merritt L. Fajt, Annette T. Hastie, Mats W. Johansson, Michael C. Peters, Brenda R. Phillips, Bruce D. Levy, the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators
Isabell Ricklefs, Ioanna Barkas, Melody G. Duvall, Manuela Cernadas, Nicole L. Grossman, Elliot Israel, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Loren C. Denlinger, David T. Mauger, Sally E. Wenzel, Suzy A. Comhair, Andrea M. Coverstone, Merritt L. Fajt, Annette T. Hastie, Mats W. Johansson, Michael C. Peters, Brenda R. Phillips, Bruce D. Levy, the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators
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Clinical Research and Public Health Inflammation Pulmonology

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

Authors

Isabell Ricklefs, Ioanna Barkas, Melody G. Duvall, Manuela Cernadas, Nicole L. Grossman, Elliot Israel, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Loren C. Denlinger, David T. Mauger, Sally E. Wenzel, Suzy A. Comhair, Andrea M. Coverstone, Merritt L. Fajt, Annette T. Hastie, Mats W. Johansson, Michael C. Peters, Brenda R. Phillips, Bruce D. Levy, the National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators

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Figure 5

BALF SAA and LXA4 levels are distinct in clinically severe and nonsevere asthma.

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BALF SAA and LXA4 levels are distinct in clinically severe and nonsevere...
(A) The number and percentages of asthma subjects with BALF levels of LXA4 and SAA that were below (low) or above (high) the median value were identified and subjects were grouped into 4 phenotypes based on LXA4 and SAA levels. Noted are subjects in the LXA4hiSAAlo group (beige quadrant) and LXA4loSAAhi group (purple quadrant). The relationship between individual subject levels of LXA4 and SAA was determined for all asthma subjects. (B) The 4 groups of subjects based on BALF SAA and LXA4 low and high cohorts were determined for subjects and stratified by asthma severity; NSA (left), SA (right). (C) The relationship between the SAA/LXA4 ratio and BAL neutrophils (%) was determined in n = 120 asthma subjects. Pearson correlation r value and significance are noted and regression line is shown. (D–F) Scatter plots show comparisons of subjects in the LXA4hiSAAlo group (beige) to subjects in the LXA4loSAAhi group (purple) for measures of (D) inflammation (BALF neutrophils [%]), (E) asthma symptoms (ACQ and ACT scores), and (F) lung function (percentage predicted FEV1 and FVC). (G) Subjects in the LXA4hiSAAlo and LXA4loSAAhi groups were assigned to clinical clusters as defined in SARP-1 (5) and the percentage of subjects assigned to NSA and SA clusters is indicated. n = 51 NSA and n = 69 SA subjects.*P < 0.05, **P < 0.01 by 2-tailed Student’s t test. BALF, bronchoalveolar lavage fluid; LXA4, lipoxin A4; SAA, serum amyloid A; NSA, nonsevere asthma; SA, severe asthma; ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; SARP, Severe Asthma Research Program.