Cyclooxygenase‐ and lipoxygenase‐derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: An imbalance between proinflammatory and antiinflammatory lipid mediators

Abstract

Eicosanoids play a key role in the regulation of inflammation and fibrosis. Recently we showed that levels of 5-lipoxygenase (5-LOX)-derived proinflammatory/profibrotic leukotrienes are elevated in bronchoalveolar lavage (BAL) fluid from patients with scleroderma lung disease (SLD). The present study was undertaken to investigate whether increased levels of leukotrienes are balanced by the antiinflammatory/antifibrotic cyclooxygenase (COX)- and 15-LOX-derived eicosanoids in the lungs of patients with SLD. Levels of 5-LOX-derived leukotriene B(4) (LTB(4)), COX-derived prostaglandin E(2) (PGE(2)), and 15-LOX-derived 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxin A(4) (LXA(4)) in BAL fluid from systemic sclerosis (SSc) patients with SLD (n = 32) and without SLD (n = 16) and from healthy individuals (n = 12) were measured by enzyme-linked immunosorbent assay. Levels of LTB(4) (mean +/- SEM 248 +/- 29 pg/ml) and PGE(2) (51 +/- 10 pg/ml) in SSc patients with SLD were significantly higher compared with patients without SLD (LTB(4) 119 +/- 35 pg/ml, PGE(2) 17 +/- 3 pg/ml; P < 0.05 for both) and with healthy controls (85 +/- 12 pg/ml and 19 +/- 2 pg/ml, respectively; P < 0.05 for both). Accordingly, the mean +/- SEM PGE(2):LTB(4) ratio was similar in SSc patients with SLD (0.30 +/- 0.05), SSc patients without SLD (0.29 +/- 0.07), and controls (0.31 +/- 0.07). In contrast, levels of 15-HETE and LXA(4) in patients with SLD did not differ significantly from levels in patients without SLD or in controls. The ratio of LXA(4):LTB(4) in SLD patients (0.16 +/- 0.03) was significantly lower (P < 0.05) than that in patients without SLD (0.40 +/- 0.10) or controls (0.34 +/- 0.08). Increased production of LTB(4) in the lungs of patients with SLD is not balanced by an up-regulation of 15-LOX-derived antiinflammatory/antifibrotic eicosanoids such as 15-HETE or LXA(4). Targeting the 5-LOX/15-LOX balance may be of practical value in the treatment of SLD.