title: Circulating myeloid-derived suppressor cells are increased and activated in pulmonary hypertension.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders and orchestrate immune cell responses therein. Pulmonary hypertension (PH) is associated with inflammation, autoimmunity, and lung vascular remodeling. Immature myeloid cells are found in the lungs of humans and animals with PH, and we hypothesized that they would be increased in the blood of patients with PH compared with control subjects.
  
  
  METHODS
  Twenty-six children with PH and 10 undergoing cardiac catheterization for arrhythmia ablation were studied. Five milliliters of fresh blood were analyzed using flow cytometry. Results were confirmed using magnetic bead sorting and immunofluorescence, while quantitative polymerase chain reaction and intracellular urea concentration assays were used as measures of MDSC arginase-1 activation.
  
  
  RESULTS
  Flow cytometry demonstrated enrichment of circulating MDSCs among patients with PH (n = 26; mean, 0.271 × 10(6) cells/mL ± 0.17; 1.86% of CD45(+) population ± 1.51) compared with control subjects (n = 10; mean, 0.176 × 10(6) cells/mL ± 0.05; 0.57% of CD45(+) population ± 0.29; P < .05). Higher numbers of circulating MDSCs correlated to increasing mean pulmonary artery pressure (r = 0.510, P < .05). Among patients with PH, female patients had a twofold increase in MDSCs compared with male patients. Immunofluorescence analysis confirmed the results of flow cytometry. Quantitative reverse transcription polymerase chain reaction assay results for arginase-1 and measurement of intracellular urea concentration revealed increased activity of MDSCs from patients with PH compared with control subjects.
  
  
  CONCLUSIONS
  Circulating activated MDSCs are significantly increased in children with PH compared with control subjects. Further investigation of these cells is warranted, and we speculate that they might play significant immunomodulatory roles in the disease pathogenesis of PH.
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, Colorado. Electronic address: michael.yeager@ucdenver.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Dmitry D
authors.initials: DD
authors.lastname: Belchenko
authors.affiliation: Department of Pediatrics, Pulmonary Hypertension Program and Pediatric Heart Lung Center, Children's Hospital, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Kelley L
authors.initials: KL
authors.lastname: Colvin
authors.affiliation: Department of Pediatrics, Omori Medical Center, Toho University, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takatsuki
authors.affiliation: Department of Pediatrics, Pulmonary Hypertension Program and Pediatric Heart Lung Center, Children's Hospital, University of Colorado, Denver, Aurora, Colorado.
authors.forename: D Dunbar
authors.initials: DD
authors.lastname: Ivy
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado, Denver, Aurora, Colorado; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000293:Adolescent; D001145:Arrhythmias, Cardiac / Q000601:surgery; D006328:Cardiac Catheterization; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000276:immunology; D056747:Immunomodulation; D007223:Infant; D008297:Male; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D016133:Polymerase Chain Reaction; D055815:Young Adult