Production of Novel Glutathione Adducts of Halogenated Fatty Aldehydes in Inflammatory Animal Models

Abstract

α‐Halofatty aldehydes (α‐haloFALD) are liberated from plasmalogen pools found in most plasma membranes following attack by either hypochlorous acid (HOCl) or hypobromous acid (HOBr), which are enzymatically produced from hydrogen peroxide by myeloperoxidase and eosinophil peroxidase activity, respectively. Myeloperoxidase is released from the granulocytes of neutrophils, monocytes, and some tissue macrophages while eosinophil peroxidase is released from eosinophils. The exact role of α‐haloFALD in inflammatory pathologies is not entirely known, but the production of both α‐chlorofatty aldehydes (ClFALD) and α‐bromofatty aldehydes (BrFALD) by activated neutrophils and eosinophils has been previously established. The presence of a halogen at the alpha position of the aldehyde likely makes the alpha carbon susceptible to nucleophilic attack by cellular nucleophiles such as glutathione (GSH). In this study, the reactivity of the sixteen carbon ClFALD (α‐chlorohexadecanal) and BrFALD (α‐bromohexadecanal) with GSH is compared ‐‐in vitro and in primary human neutrophils and eosinophils. Both the chlorinated and brominated aldehydes are shown to be reactive with GSH and yield the same reaction product, however the brominated α‐haloFALD appears to be more reactive with GSH as the α‐bromine likely promotes a faster substitution reaction at the α‐carbon than the α‐chlorinated fatty aldehyde. The novel peptidoaldehyde products of both the chlorinated and brominated fatty aldehyde reaction with GSH (FALD‐GSH) have also been shown to be elevated in the plasma of both a rat cecal ligation puncture (CLP) sepsis model and the K/BxN inflammatory arthritis mouse model. Together, this study compares the reaction of ClFALD and BrFALD with GSH in vitro and in primary human neutrophils and eosinophils, and demonstrates the production of the resulting peptidoaldehydes, FALD‐GSH, in animal models of sepsis and inflammation‐induced arthritis. This novel class of peptidoaldehydes may prove to be a valuable biomarker of inflammatory pathologies, and future studies will investigate their role as mediators of disease.Support or Funding InformationNational Institutes of Health Grant GM115553 and MAD is an American Heart Association Pre‐Doctoral Fellow (14PRE20380048)