Chlorinated lipid species in activated human neutrophils: lipid metabolites of 2-chlorohexadecanal

Neutrophils are important in the host response against invading pathogens. One chemical defense mechanism employed by neutrophils involves the production of myeloperoxidase (MPO)-derived HOCl. 2-Chlorohexadecanal (2-ClHDA) is a naturally occurring lipid product of HOCl targeting the vinyl ether bond of plasmalogens. Previous studies have shown that exogenously-added 2-ClHDA is oxidized to 2-chlorohexadecanoic acid (2-ClHA) and reduced to 2-chlorohexadecanol (2-ClHOH) by endothelial cells. These studies show that both 2-ClHA and 2-ClHOH are produced in activated neutrophils in an MPO- and time-dependent manner and are released by neutrophils into media. 2-ClHDA levels peak following 30 min of phorbol 12-myristate-13-acetate stimulation. In contrast, 2-ClHA and 2-ClHOH levels steadily increased over 60 min, suggesting a precursor-product relationship between 2-ClHDA and both 2-ClHA and 2-ClHOH. Additional experiments using wild-type CHO.K1 and CHO.K1 cells deficient in fatty aldehyde dehydrogenase (FALDH), FAA.K1A, demonstrated that 2-ClHDA oxidation to 2-ClHA is dependent on FALDH activity. Furthermore, mice exposed to intranasal Sendai virus displayed lung neutrophil recruitment, as well as elevated 2-ClHA levels in plasma and bronchoalveolar lavage compared with control-treated mice. Taken together, these data demonstrate, for the first time, that metabolites of 2-ClHDA are produced both in vivo as well as in isolated human neutrophils.