A recent University of Iowa study reveals a new immune defense mechanism in normal airways and may help explain why people with cystic fibrosis (CF) are particularly susceptible to bacterial lung infections. The findings also may point the way to new approaches for treating the disease.
The UI study shows how two enzymes generate and use reactive oxygen species (ROS) to destroy bacteria in normal airways. The team also found that this process is defective in airway tissue and cells containing the CF gene mutation. The study is published in the Nov. 2 online issue of the American Journal of Respiratory and Critical Care Medicine.
"Among the host defense systems that we know of in the airway, at least in cell culture and tissue explants, this is one of the most efficient antibacterial system we have identified," said Botond Banfi, M.D., Ph.D., UI assistant professor of anatomy and cell biology and senior study author. "The findings suggest that one reason for CF patients' weakened innate immunity might be the absence of this natural oxidative host defense mechanism."
Banfi added that correcting the problem by reconstituting the oxidative system might represent a totally new approach for preventing the onset of bacterial lung infections that often become chronic and eventually fatal in CF patients.
Working with airway cells and tissues from rats, cows and humans, the UI team uncovered the oxidative system, which produces hypothiocyanite -- a highly effective antibacterial compound. Banfi and his colleagues, including Patryk Moskwa, M.D., Ph.D., a UI postdoctoral fellow and first author of the study, showed that one airway enzyme (Duox) makes hydrogen peroxide and a second enzyme (lactoperoxidase) uses the hydrogen peroxide to convert a small molecule called thiocyanate into the bacteria-killing hypothiocyanite.
The UI researchers also showed that the critical thiocyanate cannot be transported across airway cells with the CF mutation, which means that hypothiocyanite is not produced. In other words, without thiocyanate the oxidative antibacterial system breaks down.
These results suggest that thiocyanate may not be present in the airway surface liquid of individuals with CF. Banfi and his colleagues intend to test that hypothesis by comparing thiocyanate levels in airway surface liquid from CF patients and from healthy individuals.
Thiocyanate is naturally present in body fluids like blood and saliva. Despite its name and its chemical relationship to cyanide, thiocyanate is not toxic. Hypothiocyanite is also harmless to human cells and tissues, but the UI team found that it is extremely efficient at killing bacteria including those most commonly associated with fatal lung infections in CF patients - Staphylococcus aureus and Pseudomonas aeruginosa.
"If we could reconstitute thiocyanate concentrations in the airway surface liquid, perhaps using a nebulizer, it might boost host defenses in CF patients and help prevent bacterial lung infections," Banfi said.
In addition to Banfi and Moskwa, the UI team included graduate student, Daniel Lorentzen; Katherine Excoffon, Ph.D., associate research scientist; Joseph Zabner, M.D., professor of internal medicine; Paul McCray, M.D., the Roy J. Carver Chair in Pulmonary Research and professor of pediatrics; and William Nauseef, M.D., professor of internal medicine. Corinne Dupuy at INSERM in Paris, France also was part of the research team.
The study was funded in part by the Cystic Fibrosis Foundation.
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