title: Obesity impairs apoptotic cell clearance in asthma.
abstract: BACKGROUND
  Asthma in obese adults is typically more severe and less responsive to glucocorticoids than asthma in nonobese adults.
  
  
  OBJECTIVE
  We sought to determine whether the clearance of apoptotic inflammatory cells (efferocytosis) by airway macrophages was associated with altered inflammation and reduced glucocorticoid sensitivity in obese asthmatic patients.
  
  
  METHODS
  We investigated the relationship of efferocytosis by airway (induced sputum) macrophages and blood monocytes to markers of monocyte programming, in vitro glucocorticoid response, and systemic oxidative stress in a cohort of adults with persistent asthma.
  
  
  RESULTS
  Efferocytosis by airway macrophages was assessed in obese (n=14) and nonobese (n=19) asthmatic patients. Efferocytosis by macrophages was 40% lower in obese than nonobese subjects, with a mean efferocytic index of 1.77 (SD, 1.07) versus 3.00 (SD, 1.25; P<.01). A similar reduction of efferocytic function was observed in blood monocytes of obese participants. In these monocytes there was also a relative decrease in expression of markers of alternative (M2) programming associated with efferocytosis, including peroxisome proliferator-activated receptor δ and CX3 chemokine receptor 1. Macrophage efferocytic index was significantly correlated with dexamethasone-induced mitogen-activated protein kinase phosphatase 1 expression (ρ=0.46, P<.02) and baseline glucocorticoid receptor α expression (ρ=0.44, P<.02) in PBMCs. Plasma 4-hydroxynonenal levels were increased in obese asthmatic patients at 0.33 ng/mL (SD, 0.15 ng/mL) versus 0.16 ng/mL (SD, 0.08 ng/mL) in nonobese patients (P=.006) and was inversely correlated with macrophage efferocytic index (ρ=-0.67, P=.02).
  
  
  CONCLUSIONS
  Asthma in obese adults is associated with impaired macrophage/monocyte efferocytosis. Impairment of this anti-inflammatory process is associated with altered monocyte/macrophage programming, reduced glucocorticoid responsiveness, and systemic oxidative stress.
authors.affiliation: Department of Pediatrics, National Jewish Health, University of Colorado School of Medicine, Denver, CO 80206, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Fernandez-Boyanapalli
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
authors.forename: Christena
authors.initials: C
authors.lastname: Kolakowski
authors.forename: Elysia
authors.initials: E
authors.lastname: Min
authors.forename: Brian
authors.initials: B
authors.lastname: Day
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000097:blood; D017209:Apoptosis; D001249:Asthma / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D018384:Oxidative Stress; D047494:PPAR delta / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000276:immunology; D013183:Sputum / Q000166:cytology
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D005938:Glucocorticoids; D047494:PPAR delta; D019707:Receptors, Chemokine; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; C027576:4-hydroxy-2-nonenal