Chronic obstructive pulmonary disease (COPD) is an umbrella term for diseaes of the lungs and airways, and includes emphysema, a disease that affects over 30 million people in the United States alone, and is the fourth leading cause of death in the world. Researchers working in collaboration at RIKEN-Max Planck Joint Research Center for Systems Chemical Biology and several other institutes have found that a specific type of sugar molecule reduced the inflammatory response and progression of emphysema. According to the leader of the team that performed the work, Naoyuki Taniguchi, this discovery may open up the possibility of creating of drugs based on these biological sugar molecules in order to treat diseases like COPD. The findings were published in the American Journal of Physiology, Lung Cellular and Molecular Physiology. In the following video, learn more about emphysema.
Keratan sulfate is in a class of sugar or saccharide molecules called glycans. It resides in the small airways of the lung. The researchers determined that levels of the sugar are reduced in mice exposed to cigarette smoke. The researchers speculated that the alteration could be linked to damage in the lung caused by smoking. Taniguchi explained, "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."
To investigate whether keratan sulfate could play a protective role in COPD, the scientists engineered a molecule from repeated disaccharide units of keratan sulfate, termeed L4. The L4 was applied to two mouse models of emphysema, one in which the enzyme elastase is the cause, while the other modeled emphysema caused by smoking.
In that smoking model, L4 treatment was able to prevent destruction of the small air sacs in lungs that function to exchange gases, the alveoli. Additionally, L4 treatment reduced the penetration of neutrophils, a kind of white blood cell that indicates inflammation. There was also a reduction in inflammatory cytokine and tissue-degrading enzyme levels. While L4 was demonstrated to inhibit the enzymes, L4 did not appear to reduce the production of cytokines or reactive oxygen species directly. As such, the investigators concluded that the effect was occurring indirectly, through mechanisms likely involving neutrophils.
"We found that L4 was as effective as dexamethasone in reducing neutrophil infiltration. 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,” Taniguchi expained. “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."
Taniguchi noted that more work lies ahead. "We plan now to try to determine exactly how L4 blocks neutrophil migration, by finding a target receptor protein, and how L4 can suppress inflammation in vivo, as this could give us important insights into the mechanism of COPD progression and how it can be halted."