Alterations of systemic hyaluronic acid in patients with COPD: a cross-sectional analysis

Abstract

Hyaluronic acid (HA) is a key component of the extracellular matrix. HA and its metabolism are suggested to be altered in the lungs of patients with COPD. We studied (1) systemic HA and HA metabolism in patients with COPD and smoking (SC) and non-smoking controls (NSC) and (2) the associations of HA with acute exacerbations (AE), disease severity, inflammation and cardiovascular risk in COPD. HA was measured by ELISA in plasma of 192 patients with stable COPD (GOLD II-IV), 84 SC (≥10 pack years) and 107 NSC (<10 pack years) enrolled in the ICE-Age study. mRNA expression of the enzymatic regulators HA-synthase 3 (HAS-3) and hyaluronidase 2 (HYAL-2) was assessed in PBMCs of a subset of subjects. Plasma HA was reduced in patients with COPD compared to NSC (p=0.033), but was comparable after adjusting for age and sex. Expression of HAS-3 did not differ between groups, but was substantially less detectable in more patients with COPD (56%) than SC (33.3%) and NSC (10%). Expression of HYAL-2 was enhanced in patients with COPD compared to SC (p=0.019) and NSC (p<0.001), also when adjusted for age and sex (p<0.001). HA was not associated with AEs and airway related hospitalizations in the past year, or any of the inflammatory markers (WBCs, fibrinogen, IL-6, IL-8, TNF-α and CRP) in patients with COPD. Arterial pulse wave velocity explained, to some extent (<10%), the variance in plasma HA (p=0.006). Expression of HYAL-2, but not plasma HA nor HAS-3, is enhanced in patients with COPD compared to (non)smoking controls. HA was not associated with clinical outcomes, yet, cardiovascular risk might play a role in its systemic regulation. Studies are indicated to establish the causality of our findings.