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Research Highlights

May 2009

Nanotoxicology Research Gives Clues to Impact of Inhaling Particles

Combined capabilities identify how nanoparticles interact with lung cells

Portrait of Galya Orr
Galya Orr
Journal cover  of Toxicology and Applied Pharmacology
Selected images demonstrate the engagement of a positively charged 500-nanometer amorphous silica particle (red) in a motion along microvillus as it interacts with syndecan-1 molecules (green). Enlarged View

Results: By combining single-molecule microscopy and nanoparticle engineering, scientists at Pacific Northwest National Laboratory showed how nano-sized particles interact with lung cells. Their results, which were published in a recent cover article in Toxicology and Applied Pharmacology, provide insights about the mechanisms underlying of inhaled nanomaterials.

Dr. Galya Orr and her colleagues found that some positively charged nanomaterials seek out a specific cellular protein that gives them a free pass into alveolar type II epithelial cells in the lungs. The protein, known as syndican-1, is an integral plasma membrane protein that participates in cell proliferation, migration and organization.

Alveoli are tiny air sacs within the lungs where oxygen and carbon dioxide are exchanged. The alveolar type II cell regulates surfactant (wetting agent) metabolism, ion transport and alveolar repair in the lung. These cells are a potential target for inhaled engineered nanoparticles, which can cause inflammation and lead to respiratory diseases.

The researchers showed that positively charged nanomaterials attach to syndican-1 on the plasma membrane of cells. This specific attachment is critical to internalizing nanoparticles in alveolar cells, which do not accumulate larger particles. The consequence of this interaction may be inflammation and, eventually, disease or migration of the nanoparticles into the bloodstream.

Why it matters: Sand-like synthetic amorphous silica particles at the submicron scale (<10-6 or 1 millionth of a meter) and nanoscale (<10-9 or 1 billionth of a meter) are being explored for drug delivery and medical imaging and sensing. These particles have been also used in a wide array of industrial applications, such as the food, cosmetic and paint industries, creating a significant source of potential human exposure through inhalation.

Much is already known about how microscale particles such as bacteria or combustion byproducts get into and affect cells. And, in fact, the human body has evolved cells and molecular processes to deal with these larger particles.

"Cell surface proteins have been created, over time, that protect the cells from bacteria and other contaminated products for particles in the 0.5- to 10.0-micrometer range," said PNNL senior scientist Dr. Joel Pounds. "However, as human exposure to engineered nanomaterials as small as proteins or viruses becomes more likely, it is very important to understand how cells deal with these new materials. That question is the focus of Galya's research program."

According to Orr, "Knowing more about the cellular interactions and fate of the particles, which drive the cellular response, and ultimately determine the impact on human heath, will help us to understand what makes a particle toxic or biocompatible."

Methods: The scientists used time-lapse fluorescence imaging at the Department of Energy's EMSL and materials science capabilities at PNNL to follow one particle at a time as it interacts with the living cell. This approach allowed them to identify cellular processes and molecular interactions that could not be otherwise observed.

What's next: Nanomaterials come in many sizes, shapes, and physical properties. More research is needed to understand how cells process materials with other properties, and the intracellular fate. Because it is impossible to study each and every particle, the PNNL team is working to develop prediction approaches for nanotoxicity.

Related highlight: Measurements at the Genome-Scale Made in Nanotoxicity Study.

Acknowledgments: This work was supported by an Environmental Protection Agency STAR grant and the Air Force Research Laboratory through the Oregon Nanoscience and Microtechnologies Institute-Safer Nanomaterials and Nanomanufacturing Initiative and the Environmental Biomarkers Initiative at PNNL. The work was performed in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy national scientific user facility located at PNNL.

Reference: Orr G, DJ Panther, KJ Cassens, JL Phillips, BJ Tarasevich, and JG Pounds.  2009.  "Syndecan-1 mediates the coupling of positively charged submicrometer amorphous silica particles with actin filaments across the alveolar epithelial cell membrane." Toxicology and Applied Pharmacology 236(2):210-220.

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