Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium

Abstract

BackgroundThere is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation.Objectives and MethodsWe 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 (192Ir)–radiolabeled NPs. A complete 192Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point.ResultsDirectly 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.ConclusionThere 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.

Application of Magnetic Particle Imaging to Pulmonary Imaging Using Nebulized Magnetic Nanoparticles

“…The time course of the average MPI value (Figure 4) was very similar to the retention curve of iridium (Ir)-192 nanoparticles with 17-to 20-nm median diameter in the total lung of rats measured using single photon emission computed tomography [14]. Semmler et al [15] reported that Ir-192 nanoparticles were cleared predominantly by mucociliary clearance from the peripheral lung via the airways and larynx into the gastrointestinal tract and were found in feces, and that the fecal excretion observed throughout the entire study of retention during 6 months confirmed the predominance of this clearance pathway.…”

“…The observation time in these studies, however, is limited by the short half-life of the radioisotopes. In limited cases, clearance of inhaled nanoparticles from the rat lung has been measured over 6 months using radioisotopes with longer half-life such as Ir-192 [14] [15] as mentioned above. Similar studies may be possible using magnetic resonance imaging (MRI) after inhalation of superparamagnetic iron oxide.…”

Radical-Containing Ultrafine Particulate Matter Initiates Epithelial-to-Mesenchymal Transitions in Airway Epithelial Cells

“…Our findings cumulatively support EMT as a potential process by which EPFR-containing PM induces smooth muscle remodeling, a significant component of the asthma phenotype. Studies that have followed the route of PM deposition after inhalation have readily identified particles in the lung interstitial space within the first few hours of exposure (54,55). Therefore, these processes may be occurring very shortly after inhalation, and repeated exposure may contribute to progressive airway remodeling.…”

Nanoparticle delivery in infant lungs

“…Although it is generally known (17) that the nose is efficient at trapping both very large (>5 μm) or very small (<10 nm) particles by inertial impaction and diffusion, respectively, particles of the sizes we used (20 and 80 nm) most likely bypass the upper and central airways and directly enter and deposit deep within the lung. It is important to emphasize that because there is no fast clearance mechanism in the acinus, particles deposited in this region of the lung remain there for extended periods (16,18). Having particles remain in the acinus for extended periods is advantageous for therapeutic drug delivery in a number of ways; for instance, it prolongs the time available for a drug agent to be released, and it increases the chance that the particle crosses the air/blood barrier.…”