Lungs' Mast Cells Could Provide New Treatment Target For Asthma, Other Respiratory Disease

Reporting in the online edition of Proceedings of the National Academy of Sciences, a team at Weill Cornell Medical College explains that during an immune response, mast cells release the enzyme — called renin — which in turn produces angiotensin, a potent constrictor of the smooth muscle that lines airways.

Mast cells are normally present in small numbers in all organs, and are best known for their role in allergy, shock, wound healing and defense against pathogens.

"Back in 2005, our team was the first to discover that mast cells in the heart released renin locally, which elicited heart arrhythmias by triggering angiotensin production within the heart," explained co-senior author Dr. Roberto Levi, professor of pharmacology at Weill Cornell Medical College.

"Now, we've expanded those findings to the lungs, where similar mechanisms appear to work locally to help trigger constriction in the airway," he says.

Renin is no stranger to medical research — for decades, doctors have known that the enzyme is produced by the kidney in relatively large quantities for systemic use throughout the body. But the Weill Cornell team was the first to discover that mast cells also produced their own "local" supply of the enzyme, at a variety of body sites.

"In the heart and now the lungs, this localized production of renin appears to have a profound effect on nearby tissues," says co-senior author Dr. Randi Silver, associate professor of physiology and biophysics at Weill Cornell.

"More study is needed, of course, but our finding suggests that drugs that target renin might prove effective agents in dampening asthma or other respiratory diseases," she says. "These types of 'renin inhibitors' are, in fact, currently being developed by the pharmaceutical industry right now."

The genesis of the new study came through the efforts of the study's lead author, Arul Veerappan, now a postdoctoral researcher in Dr. Silver's laboratory. He looked closely at rings of bronchial tissue from rodents, discovering that mast cells in these rings released renin along with other substances.

"You ended up getting the same biochemical cascade that we had seen elsewhere — newly produced renin bringing about a local rise in angiotensin in tissues," Veerappan says.

Research led by co-author Alicia Reid, also a postdoctoral associate in Dr. Silver's lab, led to another first. Using a technology Reid developed, the researchers confirmed for the first time that mast cells from human lung tissue release a form of renin that is nearly identical to renin found in human mast cells grown in culture or human kidney renin.

"That's a big achievement, because it supports the notion that the mechanism we have discovered is not just a laboratory phenomenon — it's actually occurring in the living human lung," Dr. Levi notes.

New research suggests that local renin production may also be crucial in diseases marked by tissue fibrosis (stiffening). In fact, Dr. Silver's lab is now looking at the role locally produced renin might play in a rare, deadly illness called idiopathic pulmonary fibrosis (IPF), where lung tissue becomes increasingly inflexible over time.

"We're interested in any disease in which we can also detect local renin/angiotensin production because it appears to be linked to fibrosis, vasoconstriction, and now bronchoconstriction," Dr. Silver explains.

The goal of all this research: new treatment targets for a range of illnesses.

"Of course, we already have antihypertensive medicines — such as ACE inhibitors and angiotensin receptor blockers -- that focus on curbing angiotensin in a more systemic way," says Dr. Levi. "But if we could find agents that dampen this renin-angiotensin cascade locally — in the heart or the lung, for example — that could prove to be a formidable new weapon against disease."

This work was funded by grants from the U.S. National Institutes of Health.

Co-researchers include Racha Estephan, Nathan O'Connor, Maria Thadani-Mulero, and Mariselis Salazar-Rodriguez — all of the Weill Cornell Medical College.