Novel Pathway May Trigger Non-inflammatory Asthma

Researchers have discovered a new pathway that may trigger asthma and also explain why current asthma therapies do not work in many cases, according to a new study.

Current therapies for asthma target the inflammatory response or promote relaxation of airway smooth muscle shortening. While these treatments are effective in the short term, the underlying cause of asthma remains elusive, and many patients are insensitive to conventional therapy.

[[{"type":"media","view_mode":"media_crop","fid":"48194","attributes":{"alt":"","class":"media-image media-image-right","height":"311","id":"media_crop_1534965570702","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5745","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 8px; float: right;","title":"©decade3D-anatomy-online/Shutterstock.com","typeof":"foaf:Image","width":"316"}}]]“Only 60% of asthma patients have an inflammatory or allergic component to their asthma and 40% 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 the University of Pennsylvania.

These patients are refractory to current therapies, added co-senior author Reynold A. Panettieri, Jr., MD, Vice Chancellor of Translational Medicine and Science at Rutgers University. “There’s a real need to understand the non-inflammatory aspects of asthma,” he said.

The researchers published their results on April 18, 2016 in Journal of Clinical Investigation.

They found that neuropeptide Y may be the key to non-inflammatory asthma. Neuropeptide Y 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 it has not been known to have a direct role in asthma.

Morrisey and Panettieri’s research suggests that neuropeptide Y has a significant role in asthma. They deleted the gene for neuropeptide Y while at the same time deleting genes for two transcription factors, Foxp1 and Foxp4. Previously, they had found that these transcription factors normally repress the production of mucus-secreting goblet cells in the lung epithelia of mice. Deleting the neuropeptide Y and Foxp1/4 genes resulted in the airway hyper-responsiveness that is observed in Foxp1/4-mutant mice returning to almost normal levels.

They also tested whether neuropeptide Y could directly cause airway hyper-responsiveness in human lung tissue. These experiments showed that when normal human lung airways are exposed to neuropeptide Y, they exhibit a marked increase in hyper-responsiveness to methacholine challenge. In all of these experiments, the inflammatory response remained unchanged, indicating that neuropeptide Y did not cause alterations in the immune response that could cause asthmatic symptoms.

“These data strongly suggest that neuropeptide Y can cause airway hyper-responsiveness in human lungs and could be a causative mechanism in human asthma,” Morrisey said.

The molecular mechanisms mediating airway hyper-responsiveness occur at the level of smooth muscle where neuropeptide Y amplifies smooth muscle contraction, noted Panettieri.

The researchers suggest that inhibiting neuropeptide Y activity in asthma patients, perhaps with an inhaled medication, might be effective in those who show no benefit with current medications.

Compounds that block neuropeptide Y signaling have already been developed for other applications, such as obesity and hypertension. The researchers believe it would be worthwhile to test these neuropeptide Y inhibitors in asthma patients as well.

Source

Li S, Koziol-White C, Jude J, et al. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness. J Clin Invest.  Published online April 18, 2016   doi:10.1172/JCI81389