title: Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium.
abstract: BACKGROUND
  There is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation.
  
  
  OBJECTIVE
  We studied the disappearance of NPs from the epithelium by sequential lung retention and clearance and bronchoalveolar lavage (BAL) measurements in healthy adult Wistar Kyoto (WKY) rats at various times over 6 months after administration of a single 60- to 100-min intratracheal inhalation of iridium-192 ((192)Ir)-radiolabeled NPs. A complete (192)Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point.
  
  
  RESULTS
  Directly after inhalation we found free NPs in the BAL; later, NPs were predominantly associated with alveolar macropages (AMs). After 3 weeks, lavageable NP fractions decreased to 0.06 of the actual NP lung burden. This is in stark contrast to the AM-associated fraction of micron-sized particles reported in the literature. These particles remained constant at about 0.8 throughout a 6-month period. Three weeks after inhalation, 80% of the retained Ir NPs was translocated into epithelium and interstitium.
  
  
  CONCLUSIONS
  There is a strong size-selective difference in particle immobilization. Furthermore, AM-mediated NP transport to the larynx originates not only from the NP fraction retained on the epithelium but also from NPs being reentrained from the interstitium to the luminal side of epithelium. We conclude that NPs are much less phagocytized by AMs than large particles but are effectively removed from the lung surface into the interstitium. Even from these interstitial sites, they undergo AM-mediated long-term NP clearance to the larynx.
authors.affiliation: GSF - National Research Center for Environment and Health, Institute of Inhalation Biology, Neuherberg/Munich, Germany. manuela.behnke@gsf.de
authors.forename: Manuela
authors.initials: M
authors.lastname: Semmler-Behnke
authors.forename: Shinji
authors.initials: S
authors.lastname: Takenaka
authors.forename: Steffanie
authors.initials: S
authors.lastname: Fertsch
authors.forename: Alexander
authors.initials: A
authors.lastname: Wenk
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seitz
authors.forename: Paula
authors.initials: P
authors.lastname: Mayer
authors.forename: Günter
authors.initials: G
authors.lastname: Oberdörster
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Kreyling
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D045604:Extracellular Fluid / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000032:analysis*; D010316:Particle Size; D011650:Pulmonary Alveoli / Q000737:chemistry*; D051381:Rats; D011921:Rats, Inbred WKY; D020545:Respiratory Mucosa / Q000737:chemistry*