title: IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers.
abstract: BACKGROUND
  Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma.
  
  
  OBJECTIVE
  This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to (1) assess the safety of the IL-1 receptor antagonist anakinra in conjunction with inhaled LPS and (2) to test the hypothesis that IL-1 blockade will suppress the acute neutrophil response to challenge with inhaled LPS.
  
  
  METHODS
  In a phase I clinical study 17 healthy volunteers completed a double-blind, placebo-controlled crossover study in which they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose, 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach.
  
  
  RESULTS
  Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo. Subjects tolerated the anakinra treatment well without an increased frequency of infections attributable to anakinra treatment.
  
  
  CONCLUSIONS
  Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC. Electronic address: michelle_hernandez@med.unc.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hernandez
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC.
authors.forename: Katherine
authors.initials: K
authors.lastname: Mills
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC.
authors.forename: Martha
authors.initials: M
authors.lastname: Almond
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC.
authors.forename: Krista
authors.initials: K
authors.lastname: Todoric
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aleman
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Center for Environmental Medicine, Asthma, & Lung Biology, University of North Carolina, Chapel Hill, NC.
authors.forename: David B
authors.initials: DB
authors.lastname: Peden
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000627:therapeutic use; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D011292:Premedication; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012140:Respiratory Tract Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013183:Sputum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1
keywords: Endotoxin; IL-1 receptor antagonist; IL-1β; LPS; anakinra; asthma; induced sputum; innate immunity; neutrophil