Penn study finds that antioxidant found in vegetables has implications for treating cystic fibrosis

November 16, 2009

PHILADELPHIA - Scientists at the University of Pennsylvania School of Medicine discovered that a dietary antioxidant found in such vegetables as broccoli and cauliflower protects cells from damage caused by chemicals generated during the body's inflammatory response to infection and injury. The finding has implications for such inflammation-based disorders as cystic fibrosis (CF), diabetes, heart disease, and neurodegeneration.

Through cell-culture studies and a synthesis of known antioxidant biochemistry, Zhe Lu, MD, PhD , Professor of Physiology, Yanping Xu , MD, PhD , Senior Research Investigator, and Szilvia Szép , PhD, postdoctoral researcher, showed that the antioxidant thiocyanate normally existing in the body protects lung cells from injuries caused by accumulations of hydrogen peroxide and hypochlorite, the active ingredient in household bleach. These potentially harmful chemicals are made by the body as a reaction to infection and injury. In addition, thiocyanate also protects cells from hypochlorite produced in reactions involving MPO, an enzyme released from germ-fighting white blood cells during inflammation. They published their finding this week in the Proceedings of the National Academy of Sciences. Lu is also an Investigator of the Howard Hughes Medical Institute.

"Dr. Lu's work throws new light on how the genetic defect underlying CF leads to the lung illnesses that are the leading cause of death," said Bert Shapiro, Ph.D., who oversees membrane structure grants at the National Institutes of Health's National Institute of General Medical Sciences (NIGMS). "His team's findings suggest that the lungs of people with the disease are more susceptible to the damaging effects of cellular oxidants. While the idea is tantalizing and creative, further testing is needed to confirm it."

The research team demonstrated that in three additional cell types used to extend their ideas to other inflammation-related conditions - cardiovascular disease, neurodegeneration, and diabetes - thiocyanate at blood concentrations of at least 100 micromolar (micromoles per liter) greatly reduces the toxicity of MPO in cells, including those lining blood vessels. Humans naturally derive thiocyanate from some vegetables and blood levels of thiocyanate in the general population vary from 10 to 140 micromolar.

This comparison raises the possibility, the authors point out, that without an adequate dietary supply of thiocyanate, hypochlorite produced by the body during inflammation would cause additional collateral damage to cells, thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis.

Connection to CF

For over a decade Lu and colleagues have been exploring the inner workings of ion channels and how this knowledge relates to the pathology of such diseases as CF. The CF disease originates from mutations in the CF transmembrane conductance regulator (CFTR) protein, an ion channel protein in the cell membrane commonly thought to transport mainly chloride ions. It has, however, remained a mystery why a defect in a chloride-transporting channel leads to cystic fibrosis, a disease with exaggerated inflammation in both the lungs and the digestive system.

Lung injuries inflicted by excessive inflammation and recurring infection cause about ninety percent of CF patients' symptoms and mortality. Although known as a chloride channel, CFTR also conducts thiocyanate ions, important because, in several ways, they can limit potentially harmful accumulations of hydrogen peroxide and hypochlorite, chemicals produced by the body to fight germs.

In CF patients, there is also a high incidence of diabetes, partly caused by damage to the pancreas. Type 2 diabetes is also associated with higher levels of MPO in the blood. The researchers found that the MPO-caused injuries to pancreas cells and endothelial cells used in their experiments can be greatly reduced by as little as 100 micromolar thiocyanate. Their finding raises the possibility that MPO, in the absence of adequate thiocyanate, contributes to diabetes.

In the cell-based experiments, thiocyanate at concentrations below 100 micromolar did not eliminate hypochlorite accumulation and did not fully protect against MPO toxicity. Conceivably, inadequate thiocyanate levels would aggravate MPO-produced injuries in patients suffering from inflammatory diseases, surmise the authors.

Links to Other Diseases

In other studies, MPO activity has been linked to lung cancers among smokers and also implicated in neurodegenerative diseases. Intriguingly, people with congenital MPO deficiency are less likely to develop cardiovascular diseases. The research team found that MPO-caused injuries to nerve cells, as well as to blood vessel-lining endothelial cells, can be greatly reduced by 100 micromolar thiocyanate.

Genetic defects in the CFTR predispose CF patients' lungs to excessive inflammation entangled with recurring lung infection. Defective CFTR channels would be expected to result in lower thiocyanate concentrations in the affected regions within the respiratory, as well as the digestive systems, leaving tissues inadequately protected from accumulated hydrogen peroxide and overproduced hypochlorite.

Conceptually, delivering thiocyanate directly to the digestive and respiratory systems might be a therapy for CF disease, propose the researchers. As for the general population, individuals with low blood levels of thiocyanate may be at risk for chronic injuries by MPO, predisposing them to inflammatory or inflammation-mediated diseases. Many investigators have proposed developing drugs that specifically inhibit MPO-catalyzed hypochlorite production to combat these diseases, but natural thiocyanate not only decreases MPO-catalyzed formation of hypochlorite but also rapidly, once it is made, neutralizes it.

"In light of the obvious implications of this protective action of thiocyanate against the cell-damaging effect of MPO activity with regard to both CF disease and general population health, my colleagues and I will vigorously investigate the potential health benefit of thiocyanate," says Lu. He emphasizes though, "until the research community acquires a better understanding of both positive and negative impacts of thiocyanate on human health, it would be unwise for anyone to self-administer thiocyanate because like many other chemicals, thiocyanate has adverse side effects at improper doses and/or under inappropriate conditions."
-end-
The research was funded by NIGMS and the Howard Hughes Medical Institute.

This release can be found at: http://www.uphs.upenn.edu/news/News_Releases/2009/11/antioxidant-cystic-fibrosis/

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.

Penn's School of Medicine is currently ranked #3 in U.S. News & World Report's survey of research-oriented medical schools, and is consistently among the nation's top recipients of funding from the National Institutes of Health, with $267.2 million awarded in the 2008 fiscal year.

Penn Medicine's patient care facilities include:Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2008, Penn Medicine provided $282 million to benefit our community.

University of Pennsylvania School of Medicine

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.