Asthma medication may have psychiatric side effects

In a Pharmacology Research & Perspectives study, the asthma medication montelukast (trade name Singulair) was linked with neuropsychiatric reactions such as depression and aggression, with nightmares being especially frequent in children.

For the study, investigators examined all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase®, until 2016.

“Because of the high incidence of neuropsychiatric symptoms–especially nightmares–after using montelukast in both children and adults, the clinician should discuss the possibility of these adverse events with the patient and parents,” said Meindina Haarman, lead author of the study.

Wistar scientists develop novel immunotherapy technology for prostate cancer

A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific protein. This is the first application of the new technology, called DNA-encoded monoclonal antibody (DMAb), for cancer immunotherapy. The study was published online in Cancer Immunology, Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Traditional treatments are invasive and can impair the quality of life of patients, underscoring the need for alternative therapeutic strategies, including immunotherapy. One of the immunotherapeutic approaches that has been explored thus far relies on the use of monoclonal antibodies that specifically target a protein present on the surface of prostate cancer cells called prostate specific membrane antigen (PSMA) to elicit an anti-tumor immune response and control the cancer. Although promising, this strategy is limited by the production cost required to make these therapeutic antibodies. Additionally, multiple infusions are often required to achieve efficacy.

Wistar researchers devised a novel DNA-based approach in which an engineered DNA plasmid is constructed and used to deliver the instructions to make the desired anti-PSMA antibody so that the therapy can be generated in the patient’s body in a sustained manner. This research has important implications for the use of DNA-encoded monoclonal antibody technology as a platform for delivering the next generation of immunotherapies for cancer and many human diseases.

“This is an important demonstration of the possibilities opened up for immunotherapy by DMAb technology to direct in vivo production of antibodies of major relevance to human cancer,” said David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. “There is a great need for such new approaches for prostate disease as well as many other cancers. As recent data suggest, PSMA is an important cancer antigen expressed on many human prostate, bladder, renal as well as ovarian cancers, so additional study of the possible benefits of this therapy are important.”

The new technology was tested in mice for the ability to generate antibodies in their blood stream that would target human PSMA as well as target PSMA-positive tumors. Results showed that antibodies were able to bind to the cancer cells and recruited specific immune cells called natural killer cells, resulting in shrinkage of the tumor, significantly improving survival.

“Our data provide proof of concept that DMAb engineered DNA plasmids can be successfully used to target important cancers,” said Kar Muthumani, M.Sc., Ph.D., assistant professor in the Translational Tumor Immunology Program at Wistar, member of the Vaccine & Immunotherapy Center and lead author of the study. “The unique features of our synthetic DNA-based system make it a promising novel approach for cancer therapy, alone or in combination with other treatments.”

Trials show unique stem cells a potential asthma treatment

A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

The Monash Biomedicine Discovery Institute (BDI) scientists provided the experimental expertise to test Cynata Therapeutics’ induced pluripotent stem cell-derived mesenchymal stem cells (MSCs) in a model of experimental asthma. Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from adult cells; they have the ability to be differentiated into a variety of tissue types and, in this case, MSCs that can regenerate damaged lung tissue.

Lead researchers Associate Professor Chrishan Samuel and Dr Simon Royce tested the efficacy of the MSCs on three key components of asthma in a preclinical model of chronic allergic airways disease: inflammation; airway remodeling (structural changes that occur in lungs as a result of prolonged inflammation); and airway hyperresponsiveness (the clinical symptom of asthma).

The study, published in the FASEB Journal, found that the MSCs could effectively reduce inflammation, reversed signs of airway remodelling and completely normalised airway/lung fibrosis and airway hyperresponsiveness, particularly when delivered intranasally.

It concluded that they may provide a novel stand-alone therapy or an adjunct therapy for groups of asthma sufferers who do not respond to current (corticosteroid) therapy.

“Most importantly, what we found was you can treat fibrosis (hardening or scarring of the lung) very effectively,” said Associate Professor Samuel, who heads the Monash BDI’s Fibrosis Laboratory.

“When we’ve tested other types of stem cells they haven’t been able to fully reverse scarring and lung dysfunction associated with asthma – we’ve had to combine them with anti-scarring drugs to achieve that. These cells were remarkable on their own as they were able to effectively reverse the scarring that contributes to lung dysfunction and difficulty in breathing,” he said.

One in nine – or around 2.5 million- Australians have asthma.

Further research will be conducted to test the MSCs in combination with, or compared to a clinically-used corticosteroid. Clinical trials using the cells as a novel target for asthma are then envisaged.

Cynata Therapeutics Limited is an Australian clinical-stage stem cell and regenerative medicine company developing therapies based on its proprietary Cymerus™ stem cell technology platform.

Bronchial Thermoplasty Helps Asthma Patients Reduce Severe Attacks, Hospitalizations and ER Visits

In a new study presented at the 2017 American Thoracic Society International Conference, adult asthma patients treated with bronchial thermoplasty (BT) had fewer severe exacerbations and were able to reduce their ER visits and hospitalizations in the two years following treatment.  Approved by the FDA in 2010, BT is a new device-based therapy that uses a series of three radio-frequency treatments to open the airways of adults with severe, persistent asthma whose symptoms are not adequately controlled by inhaled corticosteroids or long-acting beta-agonists.

To date, more than 6,800 patients in 33 countries have been treated with BT.

The “Post-FDA Approval Clinical Trial Evaluating BT in Severe Persistent Asthma” (PAS2 study), which involves hundreds of patients at dozens of research centers, looks at the long-term effects and safety of BT.

“The results of the PAS2 study suggest that after a single series of BT procedures, patients experience long-term improvement in their asthma control,” said lead author Geoffrey Chupp, MD, from Yale School of Medicine.  “These results indicate that BT works across the spectrum of severe asthma patients. We believe BT should be more widely considered as a treatment option in patients with poorly controlled severe asthma.”

Two-hundred eighty four patients were enrolled in the study at 27 centers in the U.S. and Canada.  Two-hundred seventy-nine study subjects had at least one BT procedure, and 271 had all three procedures.  In the 12 months prior to the first BT procedure, 78 percent of subjects had at least one severe exacerbation, 16 percent required hospitalization and 29 percent had ER visits.  In the first year follow up, 50.6 percent had severe exacerbations; 45.4 percent had exacerbations in the second year follow up.  Asthma-related hospitalizations and ER visits also saw significant, continuing reductions:  14.4 percent and 12.7 percent of subjects had hospitalizations, respectively, in

Researchers take an important step toward an HIV vaccine

Vaccines are an essential tool for preventing and treating serious infectious diseases such as polio, chicken pox and measles. But so far it has not been possible to develop vaccines capable of contributing to the treatment and prevention of chronic infectious diseases such as HIV and hepatitis C.

This new research paves the way for vaccines that, as opposed to conventional methods, boosting the parts of the immune system attacking the viral genes, which are the least active during the infection. This prolongs the resistance of the immune system to the virus.

Traditional vaccines typically cause a strong stimulation of the parts of the immune system, that are most responsive to the specific virus. But the reaction to the vaccine and the infection is often so intense that the immune system ‘loses momentum’ and consequently is not able to completely eliminate the virus. Researchers have therefore designed a vaccine which boosts the cells of the immune system responsible for the less exposed parts of the virus. As a result, the cells are able to distribute the ‘work load’ and retain the defense against the virus attack for a longer period of time. This gives the immune system time to build a more efficient defense, which may then defeat the remaining of the virus.

“We’re presenting an entirely new vaccine solution. Our vaccine supports the work of the immune system in developing an effective combating mechanism against the virus, rather than immediately combating the toughest parts of the virus. In combination with other vaccines, this approach can prove to have a highly efficient effect,” says Research Team Leader and Associate Professor Peter Holst of the Department of Immunology and Microbiology.

In 2008, the research team decided to develop a new vaccine strategy, which generates so-called strong immune responses against weak immunostimulatory parts of viruses. Research initially focused on experiments on mice and later on monkeys.

Now, the results of the research team show, that this technology can control the SIV virus infection (simian immunodefiency virus) in monkeys. SIV is a chronic infectious disease and a highly realistic representation of HIV. The results are an important step toward developing a vaccine against HIV and other chronic infections.

“The next phase of our work is to build virus control in all infected animals and later in humans. We’re convinced that it’s possible to identify further improvements in our experiments and thus achieve a well-functioning vaccine, initially against HIV, but also against other chronic infections,” says Peter Holst.

City Living Can Make Asthma Worse for Poor Children, Study Finds

Results of a new study by Johns Hopkins researchers using national data add to evidence that living in inner cities can worsen asthma in poor children. They also document persistent racial/ethnic disparities in asthma.

A report of the study’s findings, published in The Journal of Allergy and Clinical Immunology on March 8, shows that urban living and black race are strong independent risk factors for increased asthma morbidity — defined as higher rates of asthma-related emergency room visits and hospitalizations — but urban living does not increase the risk for having asthma.

“Our findings serve as evidence that there are differences between risk factors linked to developing asthma and those linked to making asthma worse if you already have it,” says Corinne Keet, M.D., Ph.D., associate professor of pediatrics at the Johns Hopkins University School of Medicine and the paper’s lead author.

To the researchers’ knowledge, few previous studies have been conducted on a national level to determine the effects of inner-city living on both asthma prevalence and severity. While Keet’s previous work published in 2015 using a national survey showed that living in an urban area was not a risk factor for having asthma, that study didn’t allow for analysis of asthma morbidity.

The research team sought to determine those effects by analyzing information gathered by the U.S. Centers for Medicare and Medicaid Services on the health care utilization of 16,860,716 children ages 5 to 19 who were enrolled in Medicaid in 2009 and 2010.

The team first narrowed the pool of data to children who had at least one asthma-related outpatient or Emergency Department visit over the two-year period. Based on the county they lived in, these 1,534,820 children were categorized by urbanization status and based on their ZIP code, categorized as living in a poor or not poor neighborhood.

Urbanization status identification took into account locations including urban, suburban, medium metro, and a category that combined smaller metro and rural regions. Inner-city residence was defined as living in an urban county and ZIP code where at least 20 percent of households were below the federal poverty line, defined as an income of less than $22,050 for a family of four in 2009.

The team excluded states that were missing more than 10 percent of data on race/ethnicity, states in which all major race/ethnicity groups were not represented and states that did not have urban areas.

The results for 18 states that met the study’s final guidelines showed that children who lived in nonurban areas were 18 to 21 percent less likely to be at risk for hospitalizations, even after accounting for race/ethnicity. The researchers also found that compared to non-Hispanic white children, black children and children of “other” races had 89 and 61 percent, respectively, higher risks of asthma-related hospitalizations.

Unlike other racial/ethnic groups, Hispanic children who live in a nonurban area did not experience reduced risks of emergency room visits or hospitalizations. And contrary to Keet’s previous studies, which reported that poverty was protective against asthma prevalence rates for Hispanic children, the team found no similar association for asthma morbidity.

Keet says that among the Medicaid population she studied, 30 percent of asthma-related hospitalizations were likely attributable to socioeconomic, geographic and/or racial/ethnic disparities; 19 percent of hospitalizations were estimated to be attributable to black race/ethnicity; 4 percent were attributable to living in a poor area; and 7 percent were attributable to living in an urban area.

Children who lived in inner-city areas had an overall 40 percent higher risk of asthma-related emergency room visits and 62 percent higher risk of asthma-related hospitalizations. After adjusting for race/ethnicity, risk was lowered to 14 percent and 30 percent higher for emergency room visits and hospitalizations, respectively.

While this study did not look at any specific environmental exposures associated with urbanization, the findings are in keeping with previous work that shows that certain risk factors concentrated in urban areas, such as exposure to mice and cockroach allergens and air pollution, are associated with asthma morbidity.

Keet says the new study affirms her team’s earlier finding that asthma rates or prevalence were not affected by residing in inner-city areas, strengthening evidence that risk factors for the cause of asthma are independent of those that worsen it. For example, exposure to pest allergens is associated with increased asthma morbidity but protects high-risk children from developing allergies.

“These results show that despite several decades of research on racial/ethnic and geographic disparities in asthma morbidity, there are still very large differences in rates of emergency room visits and hospitalizations by race and neighborhood characteristics. These findings emphasize that we need to redouble our efforts to find comprehensive solutions to address asthma disparities,” concludes Keet.

The study’s two main limitations were that not all states could be included because of differences in Medicaid data collection, and that it is possible that some of the differences in emergency room visits and hospitalizations could be related to how patients seek care for asthma, rather than only reflecting underlying disease severity.

Children with Asthma May Be at Higher Obesity Risk

Children with asthma may be more likely to become obese later in childhood or in adolescence, according to new research published online ahead of print in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

In “Effects of Childhood Asthma on the Development of Obesity among School-Aged Children,” researchers report that young children with asthma were 51 percent more likely to become obese over the next decade as children who did not have asthma. The researchers also found that the use of asthma rescue medications reduced the risk of becoming obese by 43 percent.

“Asthma and obesity often occur together in children, but it is unclear whether children with asthma are at higher risk for onset of obesity or whether obese children develop asthma, or both, said Zhanghua Chen, PhD, lead study author and a postdoctoral research associate of preventive medicine at the Keck School of Medicine at the University of Southern California. “Our findings add to the literature that early-life asthma history may lead to increased risk of childhood obesity.”

In their prospective study, Dr. Chen and her colleagues analyzed the records of 2,171 kindergarteners and first graders who were not obese at the time they enrolled in the Southern California Children’s Health Study (CHS). At enrollment, 13.5 percent of the children had asthma. The children were followed for up to 10 years (average: 6.9 years). During that time, 15.8 percent of all the children enrolled in the study developed obesity. Researchers confirmed study results in a different group of children, recruited in the 4th grade to participate in the CHS.

The researchers accounted for a number of factors that might have biased results, including whether the children had health insurance or were overweight at enrollment, ethnicity, family income, smoking exposure at home and physical activity.
These confounding factors also did not explain the finding that the use of rescue asthma medications appeared to reduce the risk of developing obesity.

Frank D. Gilliland, MD, PhD, senior study author and Hastings Professor of Preventive Medicine at the university, said the fact that rescue, but not controller, asthma medications reduced obesity was a surprise and warranted further study. He added, however, that overall study findings reinforce the importance of early diagnosis and treatment of asthma, which may short circuit “the vicious cycle of asthma increasing the development of obesity and obesity causing increased asthma symptoms.”

Study limitations include relying on parents to report asthma diagnosis, limited information about exercise and no information about diet. Still, study findings, the authors said, suggest commonsense strategies for children with asthma that can improve their overall health while reducing the risk of obesity. Among those strategies, they said, are eating a healthy diet, increasing physical activity and achieving asthma control through medication and better understanding of symptom triggers.

Asthma Research Unexpectedly Yields New Treatment Approach For Inherited Enzyme Disease

Experiments designed to reveal how a protein protects the lungs from asthma-related damage suggest a new way to treat a rare disease marked by the inability of cells to break down fats, according to a report in EBioMedicine published online Oct. 25.

The study results address Gaucher’s disease, which is caused by a genetic glitch in cell structures called lysosomes that process fats and remove cellular waste. Found mostly in Jews of Eastern and Central European origin, the condition may come with joint pain, blood disorders, enlarged spleens and livers, memory loss, and lung damage.

At a cellular level, Gaucher’s disease is associated with abnormally low production of the protein progranulin, as well as with the misplaced buildup of the enzyme beta-glucocerebrosidase, or GBA, outside lysosomes, instead of inside where it is needed.

Led by researchers from NYU Langone Medical Center, the new study found that a manufactured version of progranulin reversed most effects of Gaucher’s disease in mouse and human cell studies, including GBA accumulation.

“Our results suggest a new way to treat Gaucher’s disease that corrects abnormal enzyme delivery by progranulin to lysosomes, as opposed to current treatment strategies that temporarily replenish lysosomal GBA stores, which are then steadily consumed,” says senior study investigator Chuanju Liu, PhD, a professor in the Departments of Orthopaedic Surgery and Cell Biology at NYU Langone. The research team and NYU Langone hold a patent on related, potential therapies.

Among the study’s other key findings was that progranulin must bind to other molecules to transport the enzyme to lysosomes, specifically the protective “heat shock” protein 70. If unshielded, cellular GBA molecules fold up and stick together outside lysosomes.

Researchers also found that adding synthetic progranulin, or Pcgin, to blood cells obtained from patients with Gaucher’s, led to a 40 percent reduction in GBA clumping within a week. Pcgin was used because it is chemically more stable than progranulin and poses no risk of uncontrolled tumor-like cell growth in test animals, say the authors.

“Our new experiments are the first to explain why reduced progranulin is a key characteristic of Gaucher’s, and why the mice engineered to lack the protein serve as such a good model to test new therapies,” says lead study investigator Jian Jinlong, MD, PhD, an associate research scientist at NYU Langone.

Along with their role in brain disorders, progranulin shortages had been tied by previous research to cell swelling in asthmatic lungs. In the current set of experiments in progranulin-deficient mice, adding Pcgin reduced lung-tissue swelling by as much as 60 percent, an effect seen with current GBA-replacement treatments.

According to Liu, further research is needed to determine the precise mechanism by which progranulin reduces cell swelling, a process that would likely yield even more drug targets for Gaucher’s disease.

Experts estimate that as many as one in 50,000 Americans has some form of Gaucher’s, while one in 500 Jews of Ashkenazi descent has the disease.

New anti-cancer strategy mobilizes both innate and adaptive immune response

Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount a response to cancer cells. Now, scientists from the RIKEN Center for Integrative Medical Sciences have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form. In the study published in Cancer Research, they found that the vaccine made it possible for killer CD8+T-cells–important players in the immune response against cancer–to enter the tumor microenvironment and target cancerous cells.

According to Shin-ichiro Fujii, leader of the Laboratory for Immunotherapy, who led the study, “Cancer cells have different sensitivities to the innate or adaptive response, so it important to target both in order to eradicate it. We have developed a special type of modified cell, called aAVC, which we found can do this.”

The aAVC cells are not taken from the subject’s own body but are foreign cells. The cells are modified by adding a natural killer t-cell ligand, which permits them to stimulate natural killer T-cells, along with an antigen associated with a cancer. The group found that when these cells are activated, they in turn promote the maturation of dendritic cells, which act as coordinators of the innate and acquired response. Dendritic cells are key because they allow the activation of immune memory, where the body remembers and responds to a threat even years later.

To find whether it worked in actual bodies, they conducted experiments in mice with a virulent form of melanoma that also expresses a model antigen called OVA. Tests in mice showed, moreover, that aggressive tumors could be shrunken by vaccinating the animals with aAVC cells that were programmed to display OVA antigen. Following the treatment, the tumors in the treated animals were smaller and necrotic in the interior–a sign that the tumor was being attacked by the killer CD8+T-cells.

Fujii continues, “We were interesting in finding a mechanism, and were able to understand that the aAVC treatment led to the development of blood vessels in the tumors that expressed a pair of important adhesion molecules, ICAM-1 and VCAM-1, that are not normally expressed in tumors. This allowed the killer CD8+T cells to penetrate into the tumor.”

They also found that in animals that had undergone the treatment, cancer cells injected even a year later were eliminated. “This indicates,” says Fujii, “that we have successfully created an immune memory that remembers the tumor and attacks it even later.”

Looking to the future, Fujii says, “Our therapy with aAVC is promising because typical immunotherapies have to be tailor-made with the patient’s own cells. In our case we use foreign cells, so they can be made with a stable quality. Because we found that our treatment can lead to the maturation of dendritic cells, immunotherapy can move to local treatment to more systemic treatment based on immune memory.”

Penn and Rutgers Researchers Discover New Pathway That May Trigger Asthma

Asthma is an enormous public health problem that continues to grow larger, in part because scientists don’t fully understand how it is caused. Existing therapies don’t cure the disease and often don’t even significantly alleviate the symptoms. Now, scientists from the Perelman School of Medicine at the University of Pennsylvania and Rutgers University have identified a biological pathway that potentially explains why current asthma therapies don’t work well in many cases—and might be targeted to help those patients.

Asthma is a chronic condition that affects more than 25 million people in the United States alone, including more than 7 million children. It accounts for nearly 2 million ER visits annually and about 1.5 million patient-days of hospital inpatient care.

“Only 60 percent of asthma patients have an inflammatory or allergic component to their asthma and 40 percent of asthma patients wheeze in part due to intrinsic abnormalities of epithelial and smooth muscle cells,” said co-senior author Edward E. Morrisey, PhD, a professor of Cell and Developmental Biology and director of the Penn Center for Pulmonary Biology at Penn.

“Curiously, these patients are refractory to current therapies,” said co-senior author Reynold A. Panettieri, Jr., MD, Vice Chancellor of Translational Medicine and Science at Rutgers. “There’s a real need to understand the non-inflammatory aspects of asthma, and with this study we’re getting closer to that understanding.”

The study, which appears in the current issue of the Journal of Clinical Investigation, is a collaboration between the Morrisey laboratory and the laboratory of Panettieri, an asthma specialist who moved from Penn Medicine to Rutgers Biomedical and Health Sciences last summer.

Clues from Goblet Cells
The discovery of the possible new asthma pathway emerged from basic research by Morrisey and colleagues on the developmental biology of the epithelial layer of cells that line the lung and its airways. In experiments published in 2012, they found that the transcription factors Foxp1 and Foxp4—which can switch certain gene programs on or off—normally repress the production of mucus-secreting goblet cells in the lung epithelia of mice. Genetic inactivation of these two transcription factors caused goblet cells to differentiate abnormally.

Increased goblet cell differentiation in the airways is a hallmark of asthma. From this, the Morrisey lab investigated whether loss of the Foxp1/4 genes, specifically in the airway epithelium of the lung, also causes an asthma-like condition in mice.

In an initial set of experiments, the team, including first author Shanru Li, a staff scientist in the Morrisey lab, studied the physiological function of airways lacking the Foxp1/4 genes in adult mice. “We found that the airways of these mice did indeed behave like asthmatic human airways,” Morrisey said.
A classic sign of asthma is airway hyper-responsiveness (AHR)—an abnormally strong tendency for the smooth muscle cells underlying the airway epithelium to contract and cause a partial closure of the airway. The team found that the mice lacking airway Foxp1/4 showed significantly greater signs of AHR, compared to control mice, especially when experimentally challenged with airway irritants. “At the high doses of the challenge the Foxp1/4-knockout mice basically started to die because their airways closed off,” Morrisey said.
Intriguingly, the airway lining in the Foxp1/4-knockout mice did not show signs of the type of inflammation that is typically associated with asthma and targeted with standard asthma drugs.

Neuropeptide Y – The Key to Non-inflammatory Asthma?
To find out the principal cause of the hyper-responsiveness in the airways of these mice, the researchers looked at the gene expression patterns of the affected airway epithelial cells, comparing them to the patterns seen in control mice that have normal levels of Foxp1/4 expression.

“Because only Foxp1/4 genes were missing from the airway epithelium of these mutant mice, we hypothesized that epithelial cells in the mutants were secreting a factor that was causing the underlying smooth muscle cells to contract. Therefore, we looked specifically for expression changes in genes encoding molecules that could be secreted from the epithelial cells and be received by the airway smooth muscle cells,” Morrisey said.

One such molecule, neuropeptide Y (NPY), stood out well above the rest—it was not expressed in control airway epithelial cells but was expressed at high levels in the airway epithelia of the knockout mice.

NPY is a signaling molecule and neurotransmitter found abundantly in the nervous system and some other parts of the body. Its many biological actions include stimulating the constriction of blood vessels. Previous research has linked variants of its gene to increased asthma risk, but NPY hasn’t been known to have a direct role in asthma.

Morrisey’s team showed that NPY has a significant role in asthma by deleting the NPY gene while at the same time deleting the Foxp1/4 genes. This resulted in the airway hyper-responsiveness that is observed in Foxp1/4-mutant mice to return to almost normal levels. Importantly, since changes in NPY expression have been linked to asthma in humans, the investigators tested whether NPY could directly cause airway hyper-responsiveness in human lung tissue. These experiments showed that when normal human lung airways are exposed to NPY, they exhibit a marked increase in hyper-responsiveness to methacholine challenge. In all of these experiments, the inflammatory response remained unchanged, indicating that NPY did not cause alterations in the immune response that could cause asthmatic symptoms.

“These data strongly suggest that NPY can cause airway hyper-responsiveness in human lungs and could be a causative mechanism in human asthma,” Morrisey said.
“Further, the molecular mechanisms mediating airway hyper-responsiveness occur at the level of smooth muscle where NPY amplifies smooth muscle contraction at all mediators by activating Rho Kinase, a pivotal signaling molecule in the bronchoconstriction pathway,” Panettieri said. It also suggests that inhibiting NPY activity in people with asthma, perhaps with an inhaled medication, might help the millions of patients who get little or no benefit from current asthma therapies.

Pharmaceutical companies have already developed compounds that block NPY signaling for other applications such as obesity and hypertension. “Testing whether these NPY inhibitors would help human asthma patients would be worthwhile given the results of our studies” Morrisey said.
In addition to setting up tests of NPY-blocking drugs, he and his team hope to replicate their mouse-model findings in a larger animal model of asthma, which better simulates the human disease.