Knowledge on particle deposition in children's lungs is essential for realistic estimates of health risks posed by aerosol exposure of children, and also to determine the correct dose for therapeutic drugs delivered by inhalation, but this problem has received little attention. Currently, it is assumed that children's lungs are a small-size version of the adult one, and scaled-down adult lung models are used for the assessment of deposition efficiency. It is well established, however, that during postnatal development the lungs are not only growing in size, but they also undergo dramatic structural changes. Our previous studies provided evidence that the structure of the lung periphery is a major determinant of particle behavior; particularly, we have discovered a new mechanism of particle transport -chaotic mixing-, operating in the fully alveolated ducts of adult lungs. We hypothesize that age-associated changes in lung anatomy, such as progressive alveolation, lead to major changes in particle mixing and deposition, predicting that deposition peaks in very young children with lungs that have become largely alveolated already but are still small in size. To test this hypothesis, we propose to perform a study combining theoretical and experimental approaches building on our expertise. (1) We will perform analytical and numerical analyses to elucidate the relationship between progressive alveolation and the appearance of chaotic flow phenomena and associated mixing. (2) We will test the findings of these mathematical predictions in simplified and well-controlled physical models with expandable walls and different degrees of alveolation. (3) Excised lungs of developing piglets at different stages of alveolation will be used to do inhalation exposure and flow visualization experiments. The results of these approaches taken together will give us a comprehensive view of the relationship between alveolar geometry and the appearance of chaotic mixing mechanisms in the lung that may result in a sudden change in the extent of particle deposition. At the same time the findings of this project may lay down the foundation for realistic and rationally based inhalation dosimetry in children - a matter of great clinical importance. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074022-02
Application #
6793683
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (03))
Program Officer
Berberich, Mary Anne
Project Start
2003-09-01
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$246,000
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Kreyling, Wolfgang G (2016) Discovery of unique and ENM- specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats. Toxicol Appl Pharmacol 299:41-6
Henry, Frank S; Tsuda, Akira (2016) Onset of alveolar recirculation in the developing lungs and its consequence on nanoparticle deposition in the pulmonary acinus. J Appl Physiol (1985) 120:38-54
Kreyling, Wolfgang G; Hirn, Stephanie; Möller, Winfried et al. (2014) Air-blood barrier translocation of tracheally instilled gold nanoparticles inversely depends on particle size. ACS Nano 8:222-33
Kojic, Milos; Filipovic, Nenad; Tsuda, Akira (2013) A mesoscopic bridging scale method for fluids and coupling dissipative particle dynamics with continuum finite element method. Comput Methods Appl Mech Eng 197:821-833
Tsuda, Akira; Henry, Frank S; Butler, James P (2013) Particle transport and deposition: basic physics of particle kinetics. Compr Physiol 3:1437-71
Henry, F S; Haber, S; Haberthür, D et al. (2012) The simultaneous role of an alveolus as flow mixer and flow feeder for the deposition of inhaled submicron particles. J Biomech Eng 134:121001
Semmler-Behnke, Manuela; Kreyling, Wolfgang G; Schulz, Holger et al. (2012) Nanoparticle delivery in infant lungs. Proc Natl Acad Sci U S A 109:5092-7
Tsuda, Akira; Laine-Pearson, Fiona E; Hydon, Peter E (2011) Why chaotic mixing of particles is inevitable in the deep lung. J Theor Biol 286:57-66
Butler, James P; Tsuda, Akira (2011) Transport of gases between the environment and alveoli--theoretical foundations. Compr Physiol 1:1301-16
Kojic, M; Butler, J P; Vlastelica, I et al. (2011) Geometric hysteresis of alveolated ductal architecture. J Biomech Eng 133:111005

Showing the most recent 10 out of 36 publications