The findings suggest that impaired airway relaxation -- as opposed to active constriction -- may be a more important cause of asthma than previously recognized. The results may also yield a novel approach to therapy, the researchers said.
"In thinking about asthma, scientists have generally focused on processes that actively constrict airways or lead to inflammation, making it difficult to get air in or out," said HHMI investigator Jonathan Stamler, M.D. "We haven't paid much attention to how airways are normally kept open. Our findings suggest the disease may stem from a deficit in the natural bronchodilator that normally relaxes airways."
The Duke team reported in the May 26, 2005, early online version of the journal Science that it had discovered a natural compound, nitrosoglutathione (GSNO), that helps keep airways open. Mice with elevated levels of GSNO were much less susceptible than normal animals to getting asthma, the team found. Moreover, animals deficient for GSNO developed asthma.
People with asthma are also deficient in GSNO, notes first author Loretta Que, M.D., also of Duke. Therefore, drugs that increase GSNO levels could offer a new approach to treating the airway obstruction in asthma.
"The mice closely resemble the human condition, which makes this particularly exciting as a potential new approach toward asthma therapy," Que said.
GSNO is a molecule in the nitric oxide family. Earlier studies suggested that nitric oxide (NO) might regulate the dilation of airways, with the exhaled breath of patients with asthma showing elevated levels of NO, Stamler said. However, studies in which researchers have manipulated NO levels in mice did not change the animals' response to allergens, he noted.
More recently, evidence from the Duke group has indicated that a family of NO-carrying molecules called S-nitrosothiols (SNOs) might mediate NO's role throughout the body, and offer new therapeutic approaches to diseases of the heart, lung and blood.
Last year the researchers showed that SNOs played a critical role in septic shock, a common cause of death in intensive care units. Earlier this year they showed that SNOs are deficient in the blood of patients with sickle cell disease. Now, the link between GSNO deficiency and asthma further suggests that SNOs might play a protective role in many diseases.
In the current study, Stamler's team examined the airway responses of normal mice and those lacking an enzyme called GSNO reductase, which breaks down SNOs. The Duke researchers earlier showed that the enzyme governs GSNO levels in many tissues, including the lung.
Normal mice prone to asthma exhibit increased GSNO reductase levels, resulting in lower concentrations of lung GSNO following allergen exposure, the researchers found. In contrast, mice with elevated GSNO were protected from the airway hyper-reactivity that makes breathing difficult in asthma.
"Our findings indicate that GSNO reductase is critical for regulation of airway tone under normal conditions and in response to allergic challenge, and that an imbalance of GSNO, and perhaps of other S-nitrosothiols, may contribute fundamentally to asthma," Stamler said.
"Our results further suggest that the GSNO deficit seen in patients with asthma may result from increased GSNO reductase activity," he continued. "The enzyme may therefore offer a novel target for therapies designed to alleviate airway obstruction."
The work was supported by the National Institutes of Health and the Sandler Program for Asthma Research. Stamler is a paid consultant for Nitrox LLC, a biotechnology company developing NO-based drugs for disorders of the heart, lung and blood. Additional authors include Limin Liu, David Schwartz, Yun Yan, of Duke, and Stephen Gavett, of the U.S. Environmental Protection Agency.
Journal
Science