Biokinetics of nanoparticles and susceptibility to particulate exposure in a murine model of cystic fibrosis

Abstract

BackgroundPersons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations.MethodsChloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation.ResultsCftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte-colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15-hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice.ConclusionsDespite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution.

Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure

“…These metabolites derive from AA and LA; PGF 2α is a COX metabolite (in part produced from PGE 2 ), while 15-HETE and 9-HODE are LOX metabolites. 15-HETE has antioxidant and pro-resolving properties [62] and was significantly downregulated in BAL fluid in a murine cystic fibrosis model after nanoparticle exposure [63]. Hence, the trend towards decreased levels of 15-HETE in BW may indicate a lack of protection against the harmful effects of biodiesel exhaust exposure in more proximal parts of the lung, where, based on previous petrodiesel studies, more signs of an inflammatory response have been detected in traditional inflammatory markers, compared to BAL [17, 18, 50].…”

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

“…The NM accumulation in the spleen was primarily in the red pulp and was associated with a modest loss of cellularity in this region (most evident at day 1 post exposure). The data indicated that exposure to high doses of these Ag NMs via intranasal instillation caused systemic distribution and oxidative imbalance in the blood (Genter et al 2012).…”

“…Numerous organs were collected 24 h after the end of the exposure period. The authors found no differences in the translocation of NM quantities between the two mice models, whereas significant quantities of NMs were detected in skin (∼0.1% of total dose), GT (∼0.1% of total dose), heart (∼0.01% of total dose), liver (∼0.0001% of total dose), kidneys (∼0.0001% of total dose), brain (∼0.01% of total dose), urine (∼0.1% of total dose) and the carcass (∼1% of total dose) of the animals (Geiser et al 2014).…”

“…The skin, airways and the gastrointestinal tract (GT) are in constant contact with the external environment, so it is not surprising to find that all three systems are primary exposure sites for NMs. However some materials are able to translocate to secondary organs situated at a distance from the original point of entry (Geiser et al 2014, Lipka et al 2010 (Figure 2). …”

Biokinetics of engineered nano-TiO2 in rats administered by different exposure routes: implications for human health

“…Tracking and visualizing individual nanoparticles in complex and dynamic biological systems, especially in live organisms, remains a daunting task today. Translocation of ENM from the lungs seems to happen at low rates in general (<0.001-1%) (Geiser & Kreyling, 2010;Geiser et al, 2014;Moller et al, 2008;Scheuch et al, 2008), much smaller than the earliest translocation values (Nemmar et al, 2002). It is not our intention to criticize any of the mentioned studies, but rather to remind ourselves that for a combination of reasons (lack of metrology technology, lack of experience working with ENM, enthusiasm of early discoveries, good faith assumptions, etc.,), high-quality studies on nanoparticle biokinetics in animals and especially in humans have been difficult to produce.…”