Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study

Abstract

Background: The receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor that can initiate and perpetuate inflammation. Its soluble isoform (sRAGE) acts as a decoy receptor for RAGE ligands, and is thought to afford protection against inflammation. With the present study, we aimed at determining whether circulating sRAGE is correlated with emphysema and chronic cor pulmonale in chronic obstructive pulmonary disease (COPD).

Methods: In 200 COPD patients and 201 age- and sex-matched controls, we measured lung function by spirometry, and sRAGE by ELISA method. We also measured the plasma levels of two RAGE ligands, N-epsilon-carboxymethyl lysine and S100A12, by ELISA method. In the COPD patients, we assessed the prevalence and severity of emphysema by computed tomography (CT), and the prevalence of chronic cor pulmonale by echocardiography. Multiple quantile regression was used to assess the effects of emphysema, chronic cor pulmonale, smoking history, and comorbid conditions on the three quartiles of sRAGE.

Results: sRAGE was significantly lower (p = 0.007) in COPD patients (median 652 pg/mL, interquartile range 484 to 1076 pg/mL) than in controls (median 869 pg/mL, interquartile range 601 to 1240 pg/mL), and was correlated with the severity of emphysema (p < 0.001), the lower the level of sRAGE the greater the degree of emphysema on CT. The relationship remained statistically significant after adjusting for smoking history and comorbid conditions. In addition, sRAGE was significantly lower in COPD patients with chronic cor pulmonale than in those without (p = 0.002). Such difference remained statistically significant after adjusting for smoking history, comorbidities, and emphysema severity. There was no significant difference in the plasma levels of the two RAGE ligands between cases and controls.

Conclusions: sRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without airflow obstruction. Emphysema and chronic cor pulmonale are independent predictors of reduced sRAGE in COPD.

Figure 1

Box-and-whisker plot of the plasma concentration of soluble receptor for advance glycation end products (sRAGE) in the study sample (n = 401). No airflow obstruction, no emphysema (n = 201). Airflow obstruction, no or mild emphysema (n = 119). Airflow obstruction, moderate emphysema (n = 56). Airflow obstruction, severe emphysema (n = 25). Line in box: median. Box height: interquartile range. Whiskers: 10^th and 90^th percentile. P < 0.001 by Mood's median test.

Figure 2

Differences in median sRAGE between COPD patients (n = 200) and control subjects (no airflow obstruction and no emphysema, n = 201) taken as the referent category. COPD patients are categorized as a function of the presence and severity of emphysema on computed tomography (CT). Grey bars: unadjusted difference. Black bars: difference adjusted for airflow obstruction, pack-years of smoking, coronary artery disease, diabetes, and dyslipidemia. * p < 0.05, ** p < 0.01, *** p < 0.001 against the referent category.