Could a sugar molecule be as effective as steroids to help treat lung disease?
Using a mouse model, scientists from the RIKEN-Max Planck Joint Research Center for Systems Chemical Biology and a number of other institutes, found that keratan sulfate, a large negatively charged saccharide found in the small airway of the lung, is decreased in mice that have been exposed to cigarette smoke.
Naoyuki Taniguchi, the leader of the group, said this caused them to question if the decrease was associated with the damage that smoking causes to the lung.
The discovery could lead to the development of drugs based on glycans - biological sugar molecules - for the treatment of diseases such as COPD, which is the fourth leading cause of death worldwide.
“We are not absolutely sure of the mechanism through which smoking leads to a reduction in keratan sulfate, but felt that clearly the reduction is important in thinking about glycan-based strategies for combating emphysema and COPD,” he said.
To test their hypothesis that it might play a protective role in COPD, they prepared a repeating disaccharide element of keratan sulfate, named L4, and administered it into two mouse models of emphysema - one triggered by the enzyme elastase, and the other an exacerbation of smoking-induced emphysema caused by LPS, a toxin found in bacterial cell walls.
Writing in the American Journal of Physiology, Lung Cellular and Molecular Physiology, they stated that in the first model, treatment with L4 significantly reduced white blood cell influx, levels of inflammatory cytokine and tissue-degrading enzymes, suggesting it suppressed inflammation in the lung.
Furthermore, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone – the steroid commonly prescribed to treat COPD.
Taniguchi said: “We found that L4 was as effective as dexamethasone in reducing neutrophil. This is very exciting, because dexamethasone, the treatment currently used for COPD, is a steroid medication that can have serious side effects and can in some cases make the outcome worse.
“It will be exciting if we can show that L4—a sugar molecule which we found had no adverse effects in the mice even at high doses—can be used as a treatment for this condition, which exerts a tremendous health burden.”
Researchers now plan to try to determine exactly how L4 blocks neutrophil migration, by finding a target receptor protein, and how L4 can suppress inflammation in vivo.
“This could give us important insights into the mechanism of COPD progression and how it can be halted,” said Taniguchi.
Source: The American Journal of Physiology, Lung Cellular and Molecular Physiology.
“A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models”
Authors: Naoyuki Taniguchi, et al.