Environmental Factor, July 2009, National Institute of Environmental Health Sciences
LSU ONES Awardee Links Protein Misfolding to Ultrafine PM
By Eddy Ball
On June 2, NIEHS grantee (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7489369) Stephania Cormier, Ph.D., spoke as part of the Organics and Free Radicals Session of the 11th International Congress on Combustion By-Products and Their Health Effects at the Environmental Protection Agency conference center in Research Triangle Park, N.C. (see related Spotlight story). Cormier presented the latest data from her studies on differential protein expression and post-translational modification in lung tissue of rodent neonates exposed to surrogate combustion-generated ultrafine particulate matter (PM) with persistent free radicals and the link to increased risk for adult-onset inflammatory lung disease.
Cormier (http://ceidr.lsu.edu/staticpages/index.php?page=20060920160811674) is an assistant professor of pharmacology at the Louisiana State University School of Medicine in New Orleans and a 2006 NIEHS Outstanding New Environmental Scientist awardee. She is investigating the gene-environment interactions triggered by air pollution PM measuring 0.1 microns or less in diameter.
Her group is particularly interested in the role of ultrafine PM in the predisposition to adult airway inflammatory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, resulting from exposure in the developing lung. As she explained, lung development takes up to three years in humans and ten days in rats, creating a window of enhanced susceptibility to the adverse effects of PM exposure.
"Asthma and related respiratory diseases affect 100 to 150 million people worldwide and 20 million in the United States alone," Cormier explained. These diseases are responsible for an estimated health care cost of $16.1 billion annually, "more than the health care costs associated with HIV/AIDS and tuberculosis combined." She added that the dramatic increase in these diseases in recent years — "50 percent per decade" — argues against genetic drift as a primary cause and points to the involvement of environmental factors.
The experiments by Cormier's group exposed 7-day-old Norway Brown rats 20 minutes per day for one week to DCB230 — a combustion-generated engineered PM 0.1 containing free radicals. Cormier said using the DCB230 surrogate eliminated the size and sample variability and chemical complexity of PM collected in the atmosphere. With the engineered pollutant particle system, she was able to associate a specific PM component with downstream effects on protein expression and control for aggregation.
On day 15, the research team isolated and analyzed rodent lungs with a proteomics strategy and identified genes with expression differences of at least 0.3 fold. The team found variation in 16 proteins between DCB230 and vehicle — a copper oxide/silica substrate that causes a very limited inflammatory response. Among the proteins of interest affected by DCB230 exposure were Hsp 60, a heat-shock protein implicated in mitochondrial protein folding; annexin VII, a protein expressed in response to reactive oxygen species; and cofilin-1, a protein associated with COPD and dexamethsone insensitive asthma. Changes in the expression of other markers of oxidative stress and inflammation were also observed.
Cormier said the results are consistent with her hypothesis that persistent semiquinone-type radicals generate intracellular reactive oxygen species triggering oxidative stress in the neonatal lung. This oxidative stress in turn causes the lung to undergo structural changes and permanent alteration of adaptive immune response, leading to hyper-responsiveness. These changes contribute to the airflow limitation and long-term lung dysfunction found in patients with asthma and COPD.
"The observed proteome changes following exposure to DCB230 indicate a link to the protein-misfolding diseases and may therefore present common targets for therapeutic intervention," she concluded. The findings may also have implications in the determination of air quality standards for PM 0.1, which is not currently regulated.
Coauthors of the study include LSU Postdoctoral Fellow Shrilatha Balakrishna, Ph.D., research specialist Terry Ahlert, Ph.D. students Dahui You and Baher Fahmy, Danielle Major, LSU chemist Slawo Lomnicki and environmental scientist Barry Dellinger, Ph.D.