Predictors of Chronic Obstructive Pulmonary Disease Exacerbations

Takeo Ishii; Kozui Kida

Disclosures

Curr Opin Pulm Med. 2014;20(2):138-145. 

In This Article

Conclusion

The frequent-exacerbation phenotype was reported recently,[7] and its association with inflammatory markers was mainly studied. However, in order to determine the prediction markers and targets for therapeutic intervention so as to treat COPD exacerbations and limit disease progression, we should investigate causal genetic markers such as SIGLEC14 in future research.

During evolution Siglec-14 was necessary to provide protection against bacterial infections, but it may induce unwanted and chronic inflammation in COPD during an era with a longer life expectancy, which has possibly led to the emergence of a frequent-exacerbation phenotype. We speculate that this phenotype not only causes COPD progression but also might be involved in the pathogenesis of COPD itself. We have discussed the hypothesized role of Siglec-14 in the pathogenesis of COPD as a whole (Fig. 3).[31] Antibacterial but proinflammatory molecules, such as Siglec-14, would cause repetitive exacerbations and excessive inflammatory responses, or 'repetition of vicious cycles', which could lead to local and systemic chronic inflammation. Therefore, this chronic, but repetitive and intermittent, inflammation could be a cause of the frequent-exacerbation phenotype of COPD (especially GOLD C and D), its progression, and its comorbidities (athrosclerosis,[58] osteoporosis,[59] and possibly cancers).

Figure 3.

The hypothesized role of an antibacterial but also proinflammatory molecule, Siglec-14, in the pathogenesis of COPD as a systemic disease. The antibacterial but proinflammatory lectins such as Siglec-14 may induce unwanted and chronic inflammation in COPD in a repetitive manner, which corresponds to a 'frequentexacerbation phenotype'. This phenotype causes 'local and systemic' chronic inflammation with excessive expression of proteases (e.g., MMP-9 and MMP-12), which leads to the emergence of COPD, its progression, and its comorbidities including atherosclerosis, osteoporosis, and cancers. COPD, chronic obstructive pulmonary disease; NTHi, non-typeable Haemophilus influenzae. Modified with permission from [31].

As a loss of Siglec-14, because of SIGLEC14-null allele homozygosity, is associated with a reduced risk of exacerbation and airflow obstruction in COPD,[29] this study is a good model to help determine a genetic predictor for the susceptibility to exacerbations through investigation of CNVs regarding the 'infection–inflammation–exacerbation' axis. A search for the causal genes of a frequent-exacerbation phenotype may lead to the discovery of exacerbation predictors and also to the pathogenesis of COPD.

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