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May 31, 2013

A genetic link to worsening lung disease

Symptoms of lung disease could be worsened by susceptibility to infection-triggered inflammation

Figure 1: Smoking is the main cause of COPD worldwide. The symptoms of the disease are more easily exacerbated by infection in patients with the active Siglec-14 gene.

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Chronic obstructive pulmonary disease (COPD) is a form of lung disease characterized by narrowing of the airways and degeneration of lung tissue, and is a leading cause of death worldwide. The condition results from the inhalation of noxious chemicals, typically through smoking, and can worsen dramatically when the airways become infected. An international team of researchers led by Takashi Angata and colleagues of the Systems Glycobiology Research Group at the RIKEN–Max Planck Joint Research Center has now shown that this exacerbation of COPD occurs more frequently in patients with genes that actively generate the lectin or carbohydrate-binding protein Siglec-141.

COPD can be stabilized and managed using a combination of drugs and rehabilitation. Worsening of COPD due to airway infection is the main cause of COPD-related hospitalization and death. A recent study by another group of researchers discovered a subgroup of patients that are particularly susceptible to exacerbation, suggesting that the process might have a genetic basis. Angata and his colleagues, noting that the nontypeable Haemophilus influenzae (NTHi) bacterium is a major cause of COPD exacerbation and a carrier of sialic acids, reasoned that the genes that encode siglecs—sialic acid-binding lectins that are found on immune system cells—may be involved.

The researchers developed tests for the genes encoding Siglec-14, which activates the immune system, Siglec-5, which inhibits it, and a fusion gene of the two—the product of which is identical to Siglec-5. They used these tests to investigate the genotypes of COPD patients and found that those with genes for Siglec-14 suffered exacerbation significantly more frequently. In the laboratory, they also demonstrated that Siglec-14 interacts with NTHi bacteria to stimulate an inflammatory response that could potentially worsen the COPD condition in patients. The researchers suggest that inflammation elicited by pathogens other than NTHi could also be enhanced by Siglec-14.

“The assay system we used in the laboratory study may, with appropriate modifications, be useful for screening drug candidates to treat or prevent COPD exacerbation,” says Angata. “At present, only limited drug options are available to treat COPD exacerbation. A drug that has a different mode of action from the ones currently on the market may be very beneficial.”

Angata also notes that biomarker discovery is another potential application of the team’s findings. “A biomarker that could help doctors objectively diagnose COPD exacerbation would be useful,” he says.

References

  1. Angata, T., Ishii, T., Motegi, T., Oka, R., Taylor, R. E., Soto, P. C., Chang, Y-C., Secundino, I., Gao, C-X., Ohtsubo, K. et al. (2013). Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation. Cellular and Molecular Life Sciences advance online publication, 22 March 2013 (doi: 10.1007/s00018-013-1311-7). doi: 10.1007/s00018-013-1311-7 (Link)