May 5, 1999 Medical researchers have found that adding a simple molecular chain to a standard medication for lung disease creates a new therapy that shows promise for difficult-to-treat cases resulting from acute lung injury. Scientists from the University of California San Francisco led the team, which also included researchers from the University of Rochester and the Karolinska Institute in Sweden.
The standard medication is artificial surfactant, a detergent-like liquid that is administered directly into the lungs. Studies in animal models showed the extra molecular chain--made of a compound bio-compatible with mammalian tissue--appears to act as a protective barrier, allowing normal function of a key substance that lines the air spaces in the lungs. This substance is natural surfactant, a lung secretion that is vital to normal pulmonary function because it keeps the lungs from collapsing after each breath.
Reporting today (May 4) at the annual meeting of the Pediatric Academic Societies in San Francisco, principal investigator H. William Taeusch, MD, of UCSF, said rats with diseased lungs treated with the enhanced medication had improved oxygen levels in the blood, an indication that lung function is not compromised.
"The study findings are dramatic, and we are excited at the potential of someday successfully treating infants and adults who have lung problems that don't respond well to current treatment. We have been frustrated with the poor outcome in these groups, and our results suggest that we could be on the road to a much-improved therapy," said Taeusch, who is a UCSF professor of pediatrics and chief of the Department of Pediatrics at the UCSF-affiliated San Francisco General Hospital Medical Center.
Some 5,000-10,000 infants and 100,000 adults in the U.S. suffer from acute lung injury every year. Their disease differs from premature babies who at birth suffer from respiratory distress syndrome--also known as hyaline membrane disease--and who respond very well to artificial surfactant therapy. In these premature babies, the immature lungs do not produce natural surfactant.
Artificial surfactant serves as a substitute for the missing substance until the babies' lungs mature and they begin to produce surfactant normally. The treatment is credited with saving the lives of thousands of newborns worldwide over the past two decades.
But in other patients, respiratory distress may be caused by damage to lung tissue. "In fact, the damaged tissue results in 'inactivation' of surfactant, so the very substance that is needed to help breathing is being disrupted," Tauesch said.
In newborns, lung tissue damage sometimes occurs during the birth process when meconium--fetal stool--in the amniotic fluid is inadvertently inhaled. In adults, tissue damage is associated with near-drowning, major trauma, pulmonary infection, complications related to cardiac surgery, and accidental aspiration of stomach contents.
In these forms of acute lung injury, blood or meconium interferes with normal surfactant function, making breathing and oxygenation of the blood more difficult. For example, if capillary walls inside the lungs are injured, they begin to leak blood and inflammatory debris which then fill up valuable air spaces and also inactivate the surfactant, Taeusch explained.
"Artificial surfactant is one of the treatments we have for these kinds of disorders, but the results have been very uneven. The goal in our research was to develop an 'inactivation proof' artificial surfactant," said Taeusch.
In studies with rats, the researchers compared the effectiveness of Survanta, an artificial surfactant product, and Survanta enhanced with a molecular chain, or polymer. The polymer mimics some of the effects of the natural proteins of surfactant. Not all of these proteins are incorporated in artificial surfactant because of the scientific difficulty of creating the synthetic versions.
"In our studies we overcame the absence of protein by adding the polymer," Taeusch said.
The new research on artificial surfactant is an extension of breakthrough work by UCSF scientist John Clements, MD, who was first to isolate and characterize natural lung surfactant in the 1950s. Twenty years later, he developed the first artificial surfactant. Clements is the Julius H. Comroe, Jr., professor of pulmonary biology at UCSF and served as co-investigator on the current study.
Taeusch said he plans to continue to study the mechanism of polymers in treating a variety of lung diseases. The UCSF team has applied for a patent on the polymer enhancement technique.
In addition to Taeusch and Clements, the research co-investigators are Karen W. Lu, MD, and Jon Goerke, MD, of UCSF; Pankaj Sarin, MD, of the University of Rochester; and Bengt Robertson, MD, of the Karolinksa Institute. The research was supported by grants from the UCSF Department of Pediatrics and the UCSF Committee on Research.
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