BATON ROUGE - Two LSU researchers in the School of Veterinary Medicine received a $164,000 grant from the United States Department of Agriculture (National Research Initiative Competitive Grants Program) to investigate endothelin-1, a naturally occurring substance in humans and animals, and its role in equine recurrent airway obstruction (RAO).

RAO is a common equine respiratory condition characterized by bronchoconstriction, pulmonary inflammation, increased mucus secretion, and pulmonary emphysema in later stages of the disease. It is identified in horses with conditions such as chronic obstructive pulmonary disease (COPD) and summer pasture-associated obstructive pulmonary disease (SPAOPD), both also known as "heaves."

COPD commonly affects the lower respiratory system of horses in the northern United States during the winter months. SPAOPD is a similar disease affecting the lower respiratory system, but is more commonly seen in Louisiana and other southern states when horses are out to pasture.

Heaves is similar to asthma in humans because it is believed to be an allergic-mediated, inflammatory disease of the lower airways. Horses affected with it generally develop severe coughing, mucus plugging of the airways, and have difficulty breathing, especially at the end of expiration.

The disease is usually progressive with each subsequent year, can be difficult to treat, and can be very devastating to the horse, possibly requiring euthanasia in severe cases. According to LSU veterinarians, heaves is generally a substantial problem for horses in Louisiana, and it was estimated several years ago that three to five percent of horses in the Southeast were affected with the condition.

Although the clinical characteristics and manifestations of heaves are well recognized, the pathogenesis is complex, multifactorial, and currently not well understood. Dr. Changaram Venugopal, lead investigator of the research and professor of veterinary physiology, pharmacology and toxicology, and Dr. Rustin Moore, professor of equine surgery and director of the LSU Equine Health Studies Program, will attempt to understand what may be triggering the development and/or propagation of heaves by investigating endothelin-1 and endothelin receptors as a possible link.

Collaborating investigators include Drs. Julian Oliver, a veterinary pathologist at Aventis Pharmaceuticals, and John Vanden Heuvel of the Center for Molecular Toxicology at Pennsylvania State University.

According to Venugopal, endothelin-1 is a peptide produced predominantly by endothelial cells, which are cells that line the blood vessels, as well as other cells and tissues in the body. Endothelin-1, which has several biologic and pathologic functions, is a potent constrictor of blood vessels. Within the lungs, stimulation of endothelin receptors, ET_A and ET_B, leads to constriction of the airway (bronchi) smooth

muscle and increased secretion of mucus by the epithelial cells lining the airways. Endothelin is also associated with other disease processes such as heart failure, hypertension, cardiomyopathy and pulmonary hypertension.

Increased production of endothelin has been observed in horses with heaves, implying that there is a link between increased endothelin levels and onset of the condition. Although there is evidence from other laboratories and from Venugopals preliminary studies that other substances besides endothelin-1 possibly also have a role in the onset and propagation of heaves, research suggests that endothelin-1 may be playing a role in this complex pathologic process.

Knowing that stimulation of endothelin receptors contributes to the obstruction of the airways via bronchoconstriction and increased mucus production, the hypothesis of their study is that an alteration in the distribution and activity of these receptors may be a major cause of airway hyperresponsiveness and mucus hypersecretions.

"A future goal of this research would be to search for appropriate antagonists that block the endothelin receptors, hopefully producing therapeutic effects in these horses" said Venugopal.

Since horses with RAO share several similar features with asthma in humans, horses with SPAOPD provide a reasonable, naturally-occurring model for studying human asthma. Venugopal believes this research may also potentially contribute to human medicine and understanding of asthma. "We hope that we will be able to gain additional knowledge of the cause of this disease, benefitting both comparative biomedical science, as well as potential clinical applicability in human and veterinary medicine."

Venugopal has researched equine respiratory diseases since 1981 through numerous projects in human and animal species. He received his veterinary degree from Kerala University and a masters degree in neuropharmacology at Calicut University, both in India. He also received a masters degree in cardiovascular pharmacology and a doctorate in pulmonary pharmacology at the Massachusetts College of Pharmacy and Applied Health Sciences. He completed post-doctoral work at Harvard on asthma and other airway diseases before coming to LSUs veterinary school in 1981. Most recently he completed work on dinucleotide polymorphism of the endothelin-1 gene in humans with asthma during a sabbatical at Harvard University.