Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein

Abstract

Running Title: Bromofatty aldehyde modifications of glutathione and proteinAbbreviations: 2-bromohexadecanal (2-BrHDA), 2-bromohexadec-15-ynal (2-BrHDyA), 2-bromooctadecanal (2-BrODA), 2-chlorohexadecanal (2-ClHDA), 2-chlorohexadec-15-ynal (2-ClHDyA), 2-chlorooctadecanal (2-ClODA), α-chlorofatty aldehydes (α-ClFALD), α-bromofatty aldehydes (α- 2 ABSTRACT: α-Chlorofatty aldehydes (α-ClFALD) and α-bromofatty aldehydes (α-BrFALD) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared to 2-ClHDA as precursor. NaBr supplemented PMA-activated neutrophils formed more α-BrFALD and FALD-GSH compared to non-NaBr supplemented neutrophils. Primary human eosinophils, which preferentially produce HOBr and α-BrFALD accumulated FALD-GSH following PMA stimulation. Mice exposed to Br 2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs as well as elevated systemic plasma levels of FALD-GSH in comparisons to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate GSH and protein adduct formation is much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared to α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.

Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

“…Br 2 reacts with pulmonary plasmalogens to form highly reactive brominated fatty aldehydes that are quickly oxidized to brominated fatty acids (Fig. 5C) (17). In the present study, concentrations of both free and esterified brominated fatty acids were significantly increased within 15 min of exposure (Fig.…”

“…Extraction and quantification of brominated species. Brominated reactants were identified as previously described in the Ford laboratory (17). Rats were euthanized at various time intervals after Br 2 exposure.…”

“…To determine the effects of Br 2 inhalation on the cardiopulmonary system, we exposed rats to Br 2 gas (600 ppm for 30 min and 600 ppm for 45 min) and transferred them to room air. These concentrations of Br 2 and timing were chosen according to previous published reports in murine and rat models of Br 2 inhalation, in which there is a consistent incidence of mortality and morbidity (1,10,17). Br 2 inhalation at 600 ppm for 45 min resulted in 50% mortality within 48 h after exposure (Fig.…”

“…In humans, isolated cases of accidental inhalation of high concentrations of Br 2 have reported respiratory and myocardial injury, cardiac arrest, and circulatory collapse (40,43). However, systematic studies on effects of Br 2 inhalation are recently emerging (1,5,17,28,31,32,48,58,67,71). The National Research Council has put forth a LD 50 for mice at an exposure of 204 parts per million (ppm) Br 2 for 30 min, and human studies have shown eye and throat irritation at 1-ppm exposure for up to 8 h (44a).…”

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

“…Individual values and means ± SEM. *P < 0.05 vs. untreated RBCs, † P < 0.05 versus non-halogenated lipids by one-way ANOVA followed by aldehydes can also react with the antioxidant, glutathione, which exists in mM concentrations in the lung epithelial lining and plasma, to form glutathionylated fatty aldehyde (FALD-GSH) (26,29,30). We found high levels of 16-and 18-carbon FALD-GSH in the BALF ( Supplementary Figure 2A Figure 3E-F), of Br 2 exposed mice.…”