‘Pulmonary Insults’ of Sanfilippo Type A May Be Due to Lung Lubricant
Properties of a lubricant of the small air sacs (alveoli) that is essential for normal lung function appear to be altered in Sanfilippo syndrome type A, a study in mice reported.
Changes in the mechanism and activity of this lung lubricant, known as pulmonary surfactant, “may explain the increased susceptibility of MPS IIIA [Sanfilippo type A] patients to respiratory infections and other pulmonary insults,” its researchers wrote, beyond this disease’s “devastating consequences in the brain.”
The study, “Increased alveolar heparan sulphate and reduced pulmonary surfactant amount and function in the mucopolysaccharidosis IIIA mouse,” was published in the journal Cells.
Because people with Sanfilippo, a lysosomal storage disorder, lack a working version of a protein required to break down heparan sulfate, a complex sugar molecule, this molecule accumulates inside cells and organs to toxic levels. While the brain is most affected and research focused on the disease’s neurological aspects, other organ involvement is evident.
Sanfilippo type A, the disease’s most common form, “is frequently associated with severe respiratory infection in mid to late teenage years,” the study noted.
The inner walls of the lungs are covered with a lubricant called surfactant. The lubricant helps with breathing by regulating surface tension, a force exerted by water naturally present in the lungs, and by protecting against inflammation. Alterations in its composition have been observed in other lysosomal storage disorders.
An international team of researchers, led by Sandra Orgeig at the University of South Australia, used a mouse model of Sanfilippo type A to understand if heparan sulfate buildup in the lungs could alter the pulmonary surfactant, and contribute to respiratory complications.
They found that heparan sulfate levels in these animals’ lung tissue were more than 50 times higher than levels seen in healthy mice serving as a control group. Its levels in bronchoalveolar lavage fluid (fluid from deep in the small airways) were more than 25 times higher.
Other molecules also accumulate in a patient’s body, including sugar-fat molecules called gangliosides. Levels of one such ganglioside, called GM3, were also higher in the lung tissue of Sanfilippo relative to control mice.
Likewise, levels of other key molecules in lung tissue and fluid were altered. For example, the level of specific proteins that make up the surfactant, some of which help reduce lung inflammation and fight off infection, was lower in the Sanfilippo mice. Levels of a type of fat molecule called phospholipids were reduced to almost half the levels observed in control mice.
Changes were also noted in the physical properties of the surfactant itself. These included a higher surface tension of lung surfactant in Sanfilippo mice, which can make breathing more difficult and less effective.
“Collectively these changes have contributed to a decrease in surface activity, which is likely to impact lung mechanics,” the researchers concluded, noting that this “mouse model of Sanfilippo syndrome has, for the first time … shown alterations in pulmonary surfactant contributing to respiratory dysfunction.”
The University of South Australia team plan to continue research into how Sanfilippo can affect patients’ lungs, using the incubator grant awarded by the Sanfilippo Children’s Foundation in 2019 that also supported this study.
“Overall, the results show the complex effects of Sanfilippo on the lungs. The study highlights how Sanfilippo can affect body systems other than the brain, and impact the quality of life for patients. It also may provide clues on how lung symptoms could be treated in Sanfilippo in the future,” the foundation noted on a webpage detailing this work.