Vitamin D deficiency linked with airway changes in children with severe asthma

Wednesday, 25 September 2013

Islamabad, Sep 26 (Newswire): Children with severe therapy-resistant asthma (STRA) may have poorer lung function and worse symptoms compared to children with moderate asthma, due to lower levels of vitamin D in their blood, according to researchers in London.

Lower levels of vitamin D may cause structural changes in the airway muscles of children with STRA, making breathing more difficult. The study provides important new evidence for possible treatments for the condition.

The findings were published in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

"This study clearly demonstrates that low levels of vitamin D are associated with poorer lung function, increased use of medication, worse symptoms and an increase in the mass of airway smooth muscle in children with STRA," said Atul Gupta, MRCPCH, M.D., a researcher from Royal Brompton Hospital and the National Heart and Lung Institute (NHLI) at Imperial College and King's College London. "It is therefore plausible that the link between airway smooth muscle mass and lung function in severe asthma may be partly explained by low levels of vitamin D."

While most children with asthma can be successfully treated with low doses of corticosteroids, about 5 to 10 percent of asthmatic children do not respond to standard treatment. These children have severe therapy-resistant asthma, or STRA, experience more asthma episodes and asthma-related illnesses, and require more healthcare services, than their treatment-receptive peers.

Although previous studies of children with asthma have linked increases in airway smooth muscle mass with poorer lung function and in vitro studies have established a connection between levels of vitamin D and the proliferation of airway smooth muscle, this is the first study to evaluate the relationship between vitamin D and the pathophysiology of children with STRA.

"Little is known about vitamin D status and its effect on asthma pathophysiology in these patients," Dr. Gupta noted. "For our study, we hypothesized that children with STRA would have lower levels of vitamin D than moderate asthmatics, and that lower levels of vitamin D would be associated with worse lung function and changes in the airway muscle tissue."

The researchers enrolled 86 children in the study, including 36 children with STRA, 26 with moderate asthma and 24 non-asthmatic controls, and measured the relationships between vitamin D levels and lung function, medication usage and symptom exacerbations. The researchers also examined tissue samples from the airways of the STRA group to evaluate structural changes in the airway's smooth muscle.

At the conclusion of the study the researchers found children with STRA had significantly lower levels of vitamin D, as well as greater numbers of exacerbations, increased use of asthma medications and poorer lung function compared to children with moderate asthma and non-asthmatic children. Airway muscle tissue mass was also increased in the STRA group.

"The results of this study suggest that lower levels of vitamin D in children with STRA contribute to an increase in airway smooth muscle mass, which could make breathing more difficult and cause a worsening of asthma symptoms," Dr. Gupta said.

The findings suggest new treatment strategies for children suffering from difficult-to-treat asthma, he added.

"Our results suggest that detecting vitamin D deficiency in children with STRA, and then treating that deficiency, may help prevent or reduce the structural changes that occur in the airway smooth muscle, which in turn may help reduce asthma-related symptoms and improve overall lung function," Dr. Gupta said.

Before any widespread treatment recommendations can be made, however, larger studies will need to be conducted to confirm the results, he added.

"The determination of the exact mechanism between low vitamin D and airway changes that occur in STRA will require intervention studies," Dr. Gupta said. "Hopefully, the results of this and future studies will help determine a new course of therapy that will be e

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Virus kills breast cancer cells in laboratory

Islamabad, Sep 26 (Newswire): A nondisease-causing virus kills human breast cancer cells in the laboratory, creating opportunities for potential new cancer therapies, according to Penn State College of Medicine researchers who tested the virus on three different breast cancer types that represent the multiple stages of breast cancer development.

Adeno-associated virus type 2 (AAV2) is a virus that regularly infects humans but causes no disease. Past studies by the same researchers show that it promotes tumor cell death in cervical cancer cells infected with human papillomavirus. Researchers used an unaltered, naturally occurring version of AAV2 on human breast cancer cells.

"Breast cancer is the most prevalent cancer in the world and is the leading cause of cancer-related death in women," said Samina Alam, Ph.D., research associate in microbiology and immunology. "It is also complex to treat."

Craig Meyers, Ph.D., professor of microbiology and immunology, said breast cancer is problematic to treat because of its multiple stages.

"Because it has multiple stages, you can't treat all the women the same. Currently, treatment of breast cancer is dependent on multiple factors such as hormone-dependency, invasiveness and metastases, drug resistance and potential toxicities. Our study shows that AAV2, as a single entity, targets all different grades of breast cancer."

Cells have multiple ways of dying. If damage occurs in a healthy cell, the cell turns on production and activation of specific proteins that allow the cell to commit suicide. However, in cancer cells these death pathways are often turned off, while the proteins that allow the cell to divide and multiply are stuck in the "on" position.

One way to fight cancer is to find ways to turn on these death pathways, which is what researchers believe is happening with the AAV2 virus. In tissue culture dishes in the laboratory, 100 percent of the cancer cells are destroyed by the virus within seven days, with the majority of the cell death proteins activated on the fifth day. In another study, a fourth breast cancer derived cell line, which is the most aggressive, required three weeks to undergo cell death

"We can see the virus is killing the cancer cells, but how is it doing it?" Alam said. "If we can determine which viral genes are being used, we may be able to introduce those genes into a therapeutic. If we can determine which pathways the virus is triggering, we can then screen new drugs that target those pathways. Or we may simply be able to use the virus itself."

Research needs to be completed to learn how AAV2 is killing cancer cells and which of its proteins are activating the death pathways.

According to Meyers, the cellular myc gene seems to be involved. While usually associated with cell proliferation, myc is a protein also known to promote cell death. The scientists have observed increased expression of myc close to the time of death of the breast cancer cells in the study. They report their results in a recent issue of Molecular Cancer.

AAV2 does not affect healthy cells. However, if AAV2 were used in humans, the potential exists that the body's immune system would fight to remove it from the body. Therefore, by learning how AAV2 targets the death pathways, researchers potentially can find ways to treat the cancer without using the actual virus.

In ongoing studies, the Penn State researchers have also shown AAV2 can kill cells derived from prostate cancer, methoselioma, squamous cell carcinoma, and melanoma. A fourth line of breast cancer cells -- representing the most aggressive form of the disease -- was also studied in a mouse breast tumor model, followed by treatment with AAV2. Preliminary results show the destruction of the tumors in the mice, and researchers will report the findings of those mouse studies soon.

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Newly identified antibodies may improve pneumonia vaccine design

Islamabad, Sep 26 (Newswire): Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how a novel type of antibody works against pneumococcal bacteria.

The findings, which could improve vaccines against pneumonia, appear in the September/October issue of mBio, the online journal of the American Society for Microbiology.

Until recently, scientists thought that antibodies work against pneumococcal bacteria by killing them with the help of immune cells. However, several years ago, Einstein researchers discovered antibodies that were very effective against experimental pneumococcal disease in mice even though they were not able to induce bacterial killing by immune cells.

In the current study, the researchers examined how these antibodies interact with pneumococcal bacteria and found that they cause the bacteria to clump together, enhancing a phenomenon called quorum sensing.

"Quorum sensing is a way that bacteria communicate with one another," explained senior author Liise-anne Pirofski, M.D., professor of medicine and of microbiology & immunology, chief of infectious diseases at Einstein and Montefiore Medical Center, the University Hospital for Einstein, and the Selma and Dr. Jacques Mitrani Professor in Biomedical Research at Einstein.

"Here, the ability of antibodies to enhance quorum sensing causes the bacteria to express genes that could kill some of their siblings, something called fratricide, and weaken the defense mechanisms that enable bacteria to survive and grow in a hostile environment."

The National Foundation for Infectious Diseases estimates that 175,000 people are hospitalized with pneumococcal pneumonia in the United States each year. In addition, pneumococcal bacteria cause 34,500 bloodstream infections and 2,200 cases of meningitis annually.

There are two pneumococcal vaccines: one for adults and one for infants and children. The pediatric pneumococcal conjugate vaccine has dramatically reduced the incidence of pneumococcal disease in children and adults by protecting vaccinated children and by reducing person-to-person transmission of the bacterium, (a phenomenon known as herd protection). However, the vaccine doesn't cover all strains of disease-causing pneumococcus, and the vaccine currently used for adults does not prevent pneumonia.

Fortifying current pneumococcal vaccines to stimulate antibodies that make pneumococcal bacteria less able to protect themselves -- or kill them directly -- could enhance their effectiveness.

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