New target found for asthma

Jan 29 2008

An enzyme released by mast cells in the lungs appears to play a key role in the tightening of airways that is a hallmark of asthma -- pointing to a potential new target for treatment against the illness.

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.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient.

http://www.med.cornell.edu.