The influence of hydrogen peroxide and histamine on lung permeability and translocation of iridium nanoparticles in the isolated perfused rat lung.
BACKGROUND
Translocation of ultrafine particles (UFP) into the blood that returns from the lungs to the heart has been forwarded as a mechanism for particle-induced cardiovascular effects. The objective of this study was to evaluate the role of the endothelial barrier in the translocation of inhaled UFP from the lung into circulation.


METHODS
The isolated perfused rat lung (IPRL) was used under negative pressure ventilation, and radioactive iridium particles (18 nm, CMD, 192Ir-UFP) were inhaled during 60 minutes to achieve a lung burden of 100-200 microg. Particle inhalation was done under following treatments: i) control perfusion, ii) histamine (1 microM) in perfusate, iii) luminal histamine instillation (1 mM), and iv) luminal instillation of H2O2. Particle translocation to the perfusate was assessed by the radioactivity of 192Ir isotope. Lung permeability by the use of Tc99m-labeled diethylene triamine pentaacetic acid (DTPA). In addition to light microscopic morphological evaluation of fixed lungs, alkaline phosphatase (AKP) and angiotensin converting enzyme (ACE) in perfusate were measured to assess epithelial and endothelial integrity.


RESULTS
Particle distribution in the lung was homogenous and similar to in vivo conditions. No translocation of Ir particles at negative pressure inhalation was detected in control IPL, but lungs pretreated with histamine (1 microM) in the perfusate or with luminal H2O2 (0.5 mM) showed small amounts of radioactivity (2-3 % dose) in the single pass perfusate starting at 60 min of perfusion. Although the kinetics of particle translocation were different from permeability for 99mTc-DTPA, the pretreatments (H2O2, vascular histamine) caused similar changes in the translocation of particles and soluble mediator. Increased translocation through epithelium and endothelium with a lag time of one hour occurred in the absence of epithelial and endothelial damage.


CONCLUSIONS
Permeability of the lung barrier to UFP or nanoparticles is controlled both at the epithelial and endothelial level. Conditions that affect this barrier function such as inflammation may affect translocation of NP.
Particle Research Core, Institute für Umweltmedizinische Forschung an der Heinrich-Heine Universität gGmbH, Auf'm Hennekamp 50, D-40225 Düsseldorf, Germany. james.meiring@med.uni-muenchen.de
James J
JJ
Meiring
Paul J A
PJ
Borm
Karim
K
Bagate
Manuela
M
Semmler
Jürgen
J
Seitz
Shinji
S
Takenaka
Wolfgang G
WG
Kreyling