Abstract
Background: COPD is a leading cause of mortality and morbidity; however, the role of inflammatory mediators in its pathobiology remains unclear.
Aim: To investigate the influence of gender in COPD on lipid mediators levels in the bronchoalveolar compartment and serum.
Methods: Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers with normal lung function, and COPD patients (GOLD I-II/A-B) (n=114). Ninety-four lipid mediators derived from the cytochrome P450, lipoxygenase, and cyclooxygenase pathways were analyzed by liquid chromatography-mass spectrometry.
Results: Multivariate modeling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6x10-6). No differences were observed for the corresponding male population (p=1.0). Findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These lipids correlated with lung function in the female COPD group (r=0.87; p=0.0009), as well as mRNA levels of enzymes involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance in female COPD patients (r=0.72; p=0.028).
Conclusions: Findings suggest a mechanism by which goblet cell-associated cytochrome P450's in combination with sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype. Data support the inhibition of sEH as a therapeutic target for treatment of COPD.
- Copyright ©ERS 2015