Aug. 23, 1999 Breath is essential to life.
Chemical engineers at the University of California, Santa Barbara are working to characterize and refine a special substance that is especially important to babies born prematurely: it allows them to breathe.
Worth more than all the gold in the world to these premature babies and their families, it's a miraculous lifesaver.
Without it many thousands more babies would die each year -- before ever leaving the neonatal intensive care unit. Some adults with lung disease are helped by it as well.
Called lung surfactant, this very special substance -- a mixture of lipids and proteins -- coats the inside of all mammalian lungs and allows them to draw breath, by reducing the work of breathing.
In the U.S., 40,000 premature babies per year are born without enough lung surfactant, and thousands of deaths result. The typical preemie has only 1/20 of the lung surfactant needed to breathe. Fortunately, additional lung surfactant can be administered.
For the past decade, doctors have been able to insert one of two types of lung surfactant directly into the babies' lungs. Both were approved by the Food and Drug Administration in 1989, but each has its drawbacks.
"Our research program is directed at determining basic physical measures of an ideal replacement surfactant, and relating these measures to the components found in natural lung surfactants," said Joseph A. Zasadzinski, professor of chemical engineering and materials, who has been working on lung surfactant for many years with his research group. (See website http://www.chemengr.ucsb.edu/people/faculty/zasadzinski.html)
Graduate student Junqi Ding (See website http://www.engineering.ucsb.edu/~junqi) will present the group's latest research findings, funded by the National Institutes of Health, at the national meeting of the American Chemical Society in New Orleans, on Sunday, August 22.
"An ideal replacement formulation would be a mixture of synthetic lipids, in a ratio based on a good understanding of their individual functions in lung surfactant, combined with simple peptide sequences which capture the full activity of the native lung surfactant mixture," said Zasadzinski.
"Such a mixture could be easily and cheaply produced without any batch to batch variance," he said. "The composition could be tailored to optimize the properties of the mixture for the treatment of specific cases."
Surfactant replacement therapy has been shown to reduce mortality rates by 30 to 50 percent for infants with neonatal respiratory distress syndrome. And, 80 percent of the decline in the infant mortality rate in the United States between 1989 and 1990 (the year in which surfactant therapy was introduced) could be attributed to surfactant therapy, according to the researchers.
While lung surfactant replacement therapy has been of great help, it needs improvement in order to treat infants more effectively, in a more refined way, and to begin to address adult respiratory distress syndrome, they explained.
Adult respiratory distress syndrome is a broad class of lung disease that can be related to: trauma, smoking, long term chronic obstructed lung disease, pneumonia, the hanta virus, near drowning, and other unknown causes.
When neonatal respiratory distress occurs, insufficient surfactant results in a progressive failure of the lungs, manifested clinically by
- collapsed alveoli -- the little sacs that form the lungs -- called atelectasis;
- stiff lungs or decreased lung compliance;
- decreased functional residual capacity -- a measure of the amount of air left in the lungs after exhalation;
- systemic hypoxia or oxygen starvation; and,
- lung edema -- bleeding in the lungs -- explained Zasadzinski.
The alveoli, in which the oxygen and carbon dioxide are exchanged with the blood, are very small, less than 1/10 of a millimeter in diameter, and are lined by a thin layer of liquid. When air and liquid are in contact, a strong force known as surface tension tends to compress the alveoli. The primary function of lung surfactant is to form a monolayer at the alveolar air/water interface capable of lowering the surface tension to near zero values, said Ding. The physical and chemical properties of the monolayer determine how low the surface tension can be.
That way premature babies don't have to use so much of their energy to breathe. The lower the surface tension between the liquid and the gas, the easier it is to breathe, said Zasadzinski.
The minimum surface tension upon expiration is limited by monolayer collapse, said Ding. The mechanical properties of the monolayer, especially the shear viscosity, are directly related to the mechanism of monolayer collapse.
Ding explained the use of a magnetic needle viscometer along with fluorescence microscopy, Brewster Angle Microscopy and Atomic Force Microscopy to study model surfactant systems, as well as natural surfactants, to determine the relationship between lung surfactant components and monolayer viscosity.
He reported the systematic measurements of monolayer viscosity as a function of lipid chain length, protein concentration, and temperature.
"You want the monolayer to spread easily," said Ding, "to flow and coat the alveolar surface during breathing in and out."
The research leads to questions like, "Why did nature select only a particular lipid with a 16-length carbon chain to be the main component of natural surfactant?" asked Ding. "Mother nature chose it because it's the right viscosity for expanding and contracting."
Of the two FDA-approved surfactant replacement therapies currently in use, one is a purely synthetic formulation, called Exosurf. It contains about 80 percent dipalmitoylphosphatidylcholine, or DPPC, combined with hexadecanol and tyloxapol, explained Zasadzinski. DPPC is also the main component of natural human lung surfactant (about 60 to 70 percent by weight in normal adults). But the hexadecanol and tyloxapol have no relation to natural lung surfactant.
The second formulation, called Survanta, is an organic extract of bovine lung surfactant (about 60 percent DPPC) and contains the hydrophobic lung surfactant specific proteins SP-B and SP-C, supplemented with synthetic palmitic acid (PA) and tripalmitin, said Zasadzinski. Administration of these replacement surfactants to infants has proven to be very effective.
However, progress in optimizing new replacement surfactants has been hindered by the lack of a fundamental understanding of the lung surfactant system, and the specific roles of each of the individual components, explained Zasadzinski.
Proposed replacement formulations can be divided into four classes:
- natural lung surfactant extracts,
- modified lung surfactant extracts (natural extracts supplemented with synthetic lipids, typically palmitic acid and DPPC),
- synthetic formulations modeled on natural lung surfactant, and,
- synthetic formulations with no relation to natural lung surfactant.
"Natural lung surfactant extracts have been shown to be effective both in vitro and in vivo, but human sources are limited, and animal sources are difficult and expensive to purify," said Zasadzinski. "They pose the risk of containing viral or proteinaceous contaminants. The recent link between bovine spongiform encephalopathy (mad cow disease) and human Creutzfeldt-Jakob disease is a reminder of the possible problems in introducing animal products into humans."
He continued, "As with any natural product, both natural and modified lung surfactant extracts can have a wide variability in composition from batch to batch."
"These concerns have led to the study of synthetic lung surfactant formulations for which composition can be better defined," said Zasadzinski. "Mixtures containing synthetic lung surfactant lipids with highly purified natural proteins such as SP-B and SP-C have been shown to be of comparable or better activity than many natural extracts. However, a fundamental rationale for choosing the ratio of lipids to proteins for such mixtures is still lacking."
"Furthermore, lung surfactant proteins are difficult and expensive to obtain in a highly purified form and there does not yet exist a suitable host-vector system for the large-scale production of SP-B through genetic engineering techniques (which is a common problem for surface-active proteins), although production of recombinant human SP-C has begun," said Zasadzinski.
"There are also continuing efforts to replace the proteins by simpler peptides or polymers, with variable success," he said.
He continued, "Although the mortality rate for infants with neonatal respiratory distress syndrome has been declining since the advent of successful surfactant replacement strategies, the incidence of low birth weight infants has been steadily rising. The availability of standardized replacement formulations with a fully-quantified mechanism of action could lead to a more widespread use of surfactant replacement therapy to help save the lives of both infants and adults."
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