Dysregulation of lipid mediators in patients with frequent exacerbations of COPD

Abstract

Introduction: Specialised pro-resolving mediators (SPMs) are endogenously produced lipid mediators (LMs) that regulate the propagation of inflammation and promote tissue repair. We hypothesised that SPM production is dysregulated in COPD and is associated with disease severity, defined by patients with stable COPD (no exacerbations) versus patients with frequent exacerbations.

Methods: LMs were measured in plasma samples from patients with COPD (stable patients and patients with frequent exacerbations) and from healthy controls, matched for age, sex and body mass index, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LM profiles of controls were compared with those of stable COPD patients, and the LM profiles of stable COPD patients were compared with those of COPD patients with frequent exacerbations. We explored whether or not there was an association between LM profile and ever having a severe COPD exacerbation over 4.1 years of follow-up. Data are presented as mean±sem in pg·mL^-1 for LMs, or mean±sd.

Results: 49 stable COPD patients had increased levels of pro-inflammatory mediators and some SPMs, compared with 28 controls (prostaglandin (PG)D₂: 13.97±2.44 versus 0.53±0.13; p<0.001; lipoxins: 226.83±23.84 versus 59.84±20.25; p<0.01, respectively). 52 patients with frequent exacerbations had lower levels of PGD₂ (3.07±0.97 versus 13.97±2.44; p<0.01) and SPMs (D-resolvins: 8.73±1.25 versus 34.53±8.95; p<0.01; lipoxins: 53.93±9.23 versus 226.83±23.84; p<0.01) than stable COPD patients, despite having a higher neutrophil count (5.28±2.16×10⁹ L^-1 versus 4.28±1.60×10⁹ L^-1; p=0.004). Among patients with frequent exacerbations, D-resolvin levels were independently inversely associated with occurrence of severe exacerbation (OR 0.88, 95% confidence interval (CI) 0.79-0.97; p=0.03) during follow-up.

Conclusion: These findings demonstrate distinct LM profiles of stable COPD patients and patients with frequent exacerbations. In those with exacerbations, D-resolvins were downregulated, compared with stable COPD patients, and associated with future risk of severe exacerbations during follow-up. Further work is needed to understand these findings.

FIGURE 1

Distinct plasma lipid mediator (LM) profiles in stable COPD patients when compared with controls. LMs were identified and quantified in plasma from patients with COPD who were stable and matched controls using liquid chromatography–tandem mass spectrometry-based methodologies. Differences in LM concentrations between the two groups were evaluated using partial least squares discriminant analysis. a) Score plot denoting the clustering obtained between LM levels in stable COPD patients and LM levels in healthy controls. The shaded regions denote the 95% confidence regions. b) Variable importance in projection (VIP) scores, where VIP scores >1 denote mediators that contribute to the separation between the two groups. epi: epimer; LX: lipoxin; PG: prostaglandin; Rv: resolvin.

FIGURE 2

Differential regulation of lipid mediator (LM) biosynthetic pathways in stable COPD patients, compared with controls. Analysis highlighting the relative regulation of mediators identified in figure 1 with VIP scores >1 and their biosynthetic pathways in stable COPD patients when compared with controls. Stable COPD patients have general upregulation (higher abundance) of the following LMs, compared with controls: PGE₂, 15-epi-LXA₄, LXB₄, LTD4, RvE1, RvD1, RvD3, RvD5 and 17R-RvD3. There are lower levels of the following LMs in stable patients than in controls: PGF_2α, RvD2, 4S,14S-diHDHA and MCTR2. DHA: docosahexaenoic acid; n3-DPA: n3-docosapentaenoic acid; EPA: eicosapentaenoic acid; AA: arachidonic acid; LOX: lipoxygenase; COX: cyclooxygenase; CYP450: cytochromes P450; PG: prostaglandin; epi: epimer; LX: lipoxin; LT: leukotriene; Rv: resolvin; diHDHA: dihydroxydocosahexaenoic acid; MCTR: maresin conjugates in tissue regeneration.

FIGURE 3

Distinct plasma lipid mediator (LM) profiles in COPD patients with frequent exacerbations, compared with stable COPD patients. LMs were identified and quantified in plasma from COPD patients with frequent exacerbations and stable COPD patients using liquid chromatography–tandem mass spectrometry-based methodologies. Differences in LM concentrations between the two groups were evaluated using partial least squares discriminant analysis. a) Score plot denoting the clustering obtained between LM levels in patients with frequent exacerbations and LM levels in stable COPD patients. The shaded regions denote the 95% confidence regions. b) Variable importance in projection (VIP) scores, where VIP scores >1 denote mediators that contribute to the separation between the two groups. epi: epimer; LX: lipoxin; PG: prostaglandin; Rv: resolvin.

FIGURE 4

Differential regulation of lipid mediator (LM) biosynthetic pathways in COPD patients with frequent exacerbations, compared with stable COPD patients. Analysis highlighting the relative regulation of mediators identified in figure 3 with VIP scores >1 and their biosynthetic pathways in stable COPD patients, compared with patients with exacerbations. Downregulation of ALOX5–ALOX15 pathways was observed in patients with frequent exacerbations, compared with stable COPD patients. There was general downregulation of the following LMs (lower abundance) in COPD patients with exacerbations (versus stable COPD patients): PGE₂, 15-epi-LXA₄, LXB₄, 5S, 15S-diHETE, 5S-12S-diHETE, RvE2, PDX, RvD1, RvD2, RvD3, RvD5 and 17R-RvD3, n3-RvD3. DHA: docosahexaenoic acid; n3-DPA: n3-docosapentaenoic acid; EPA: eicosapentaenoic acid; AA: arachidonic acid; LOX: lipoxygenase; COX: cyclooxygenase; CYP450: cytochromes P450; ALOX: arachidonate lipoxygenase; PG: prostaglandin; epi: epimer; LX: lipoxin; diHETE, dihydroxy-eicosatetraenoic acid; PDX: protecin DX (also referred to as 10S, 17S-dihydroxydocosahexaenoic acid (diHDHA)); Rv: resolvin.