Eosinophils generate brominating oxidants in allergen-induced asthma

Wu, Weijia; Samoszuk, Michael; Comhair, Suzy; Thomassen, Mary Jane; Farver, Carol; Dweik, Raed A.; Kavuru, Mani S.; Erzurum, Serpil C.; Hazen, Stanley L.

doi:10.1172/jci9702

Cited by 272 publications

(294 citation statements)

References 63 publications

(52 reference statements)

Supporting

Mentioning

280

Contrasting

Order By: Relevance

“…Eosinophil peroxidase-derived reactive brominating species are produced during eosinophil activation (4,5), and the present results show that inhibition of their production by the inclusion of the peroxidase inhibitor azide drastically attenuates the production of 2-BrHDA by PMA-stimulated eosinophils. It should be appreciated that in both intact eosinophil 2 ϫ 10 5 neutrophils were loaded into the upper compartments of a Boyden chamber, and neutrophil chemotaxis was elicited by 100 nM fMLP, 90 nM and 90 M 2-BrHDA, or chemotaxis buffer (as indicated), measured as described under "Experimental Procedures."…”

Section: Figsupporting

confidence: 55%

“…Through the generation of reactive brominating species and their attack of viral and microbial proteins and membrane structures, eosinophil peroxidase plays a crucial role in the antiviral and antimicrobial defense mechanisms of eosinophils (3). Additionally, eosinophil peroxidase likely plays an important role through the production of reactive brominating species in asthma (4,5). In fact the involvement of eosinophil peroxidase in asthma has been suggested by the presence of bromotyrosine in the airways and sputum of asthmatics (4 -6).…”

mentioning

confidence: 99%

“…Because eosinophil peroxidase has a marked selectivity for the production of hypobromous acid at physiological halide concentrations (5,25,26), the present study was designed to determine whether the vinyl ether bond of the sn-1 aliphatic chain of plasmalogens is susceptible to bromination by reactive brominating species produced by eosinophil peroxidase and to compare this putative halogenation with that mediated by reactive chlorinating species in eosinophils. The results herein demonstrate for the first time that eosinophil peroxidase utilizes micromolar concentrations of bromide at acidic pH resulting in the production of reactive brominating species that attack the vinyl ether bond of plasmalogens leading to the production of lysophospholipids and ␣-bromo fatty aldehydes.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Eosinophil Peroxidase-derived Reactive Brominating Species Target the Vinyl Ether Bond of Plasmalogens Generating a Novel Chemoattractant, α-Bromo Fatty Aldehyde

Albert¹,

Thukkani²,

Heuertz³

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Plasmalogens are a subclass of glycerophospholipids that are enriched in the plasma membrane of many mammalian cells. The vinyl ether bond of plasmalogens renders them susceptible to oxidation. Accordingly, it was hypothesized that reactive brominating species, a unique oxidant formed at the sites of eosinophil activation, such as in asthma, might selectively target plasmalogens for oxidation. Here we show that reactive brominating species produced by the eosinophil peroxidase system of activated eosinophils attack the vinyl ether bond of plasmalogens. Reactive brominating species produced by eosinophil peroxidase target the vinyl ether bond of plasmalogens resulting in the production of a neutral lipid and lysophosphatidylcholine. Chromatographic and mass spectrometric analyses of this neutral lipid demonstrated that it was 2-bromohexadecanal (2-BrHDA). Reactive brominating species produced by eosinophil peroxidase attacked the plasmalogen vinyl ether bond at acidic pH. Bromide was the preferred substrate for eosinophil peroxidase, and chloride was not appreciably used even at a 1000-fold molar excess. Furthermore, 2-BrHDA production elicited by eosinophil peroxidase-derived reactive brominating species in the presence of 100 M NaBr doubled with the addition of 100 mM NaCl. The potential physiological significance of this pathway was suggested by the demonstration that 2-BrHDA was produced by phorbol myristate acetate-stimulated eosinophils and by the demonstration that 2-BrHDA is a phagocyte chemoattractant. Taken together, the present studies demonstrate the targeting of the vinyl ether bond of plasmalogens by the reactive brominating species produced by eosinophil peroxidase and by activated eosinophils, resulting in the production of brominated fatty aldehydes.

show abstract

Section: Figsupporting

confidence: 55%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Eosinophil Peroxidase-derived Reactive Brominating Species Target the Vinyl Ether Bond of Plasmalogens Generating a Novel Chemoattractant, α-Bromo Fatty Aldehyde

Albert¹,

Thukkani²,

Heuertz³

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although bromine is the fifth most abundant inorganic anion in human plasma and tissues, its physiological roles in terrestrial animals have not yet been established. Nonspecific bromination on tyrosine residues of proteins found in bronchoalveolar lavage fluid was reported in patients with allergen-induced asthma (19). This bromination is catalyzed by eosinophil peroxidase, which is released from allergen-activated eosinophils.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8

Tanaka

Yoshida

Miyamoto

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

181

217

View full text Add to dashboard Cite

GPR7 and GPR8 are orphan G protein-coupled receptors that are highly similar to each other. These receptors are expressed predominantly in brain, suggesting roles in central nervous system function. We have purified an endogenous peptide ligand for GPR7 from bovine hypothalamus extracts. This peptide, termed neuropeptide B (NPB), has a C-6-brominated tryptophan residue at the N terminus. It binds and activates human GPR7 or GPR8 with median effective concentrations (EC50) of 0.23 nM and 15.8 nM, respectively. In situ hybridization shows distinct localizations of the prepro-NPB mRNA in mouse brain, i.e., in paraventricular hypothalamic nucleus, hippocampus, and several nuclei in midbrain and brainstem. Intracerebroventricular (i.c.v.) injection of NPB in mice induces hyperphagia during the first 2 h, followed by hypophagia. Intracerebroventricular injection of NPB produces analgesia to s.c. formalin injection in rats. Through EST database searches, we identified a putative paralogous peptide. This peptide, termed neuropeptide W (NPW), also has an N-terminal tryptophan residue. Synthetic human NPW binds and activates human GPR7 or GPR8 with EC 50 values of 0.56 nM and 0.51 nM, respectively. The expression of NPW mRNA in mouse brain is confined to specific nuclei in midbrain and brainstem. These findings suggest diverse physiological functions of NPB and NPW in the central nervous system, acting as endogenous ligands on GPR7 and͞or GPR8.T here are a large number of orphan G protein-coupled receptors (GPCR) whose cognate ligands have yet to be identified (1, 2). The search for endogenous ligands of orphan GPCRs is important because GPCRs are in general excellent drug targets (3). GPR7 and GPR8 are two orphan GPCRs (4). They were originally cloned from human genomic DNA by degenerative PCR using primers based on the sequences of the ␦-opioid receptor and somatostatin receptor. Indeed, GPR7 and GPR8 each share Ϸ40% overall amino acid identities with opioid and somatostatin receptors. Human GPR7 and GPR8 are 70% identical to each other at the nucleotide level and 64% identical at the amino acid level. Interestingly, no orthologue exists for the GPR8 gene in rodents, indicating that GPR8 may have originated as a replicate of GPR7 after divergence of the rodent from other species in mammalian evolution (5).The observation that GPR7 and GPR8 mRNAs are expressed in distinct areas in the central nervous system (CNS) (4, 5), together with the similarity of GPR7 and GPR8 with opioid and somatostatin receptors, strongly argue for the existence of endogenous peptide ligand(s) in CNS. In this study, we have purified a neuropeptide ligand for GPR7 from the bovine hypothalamus. This peptide, termed neuropeptide B (NPB), consists of 29 aa with a unique brominated N-terminal tryptophan. Through EST database searches, we also identified another isopeptide of the same family, termed neuropeptide W (NPW). While this manuscript was being prepared, three papers were published reporting two endogenous ligands for GPR7 and GPR8 (6-8). Sequ...

show abstract

“…Although nonspecific events related to increased levels of reactive oxygen and nitrogen species in the asthmatic airway have been postulated to lead to epithelial cell loss, the precise mechanisms of effect are unknown. [12][13][14][15] In general, the human lung has an effective, well-integrated antioxidant system to combat reactive oxygen species and reactive nitrogen species injury, 12 however, the respiratory tract antioxidant capacity is impaired in asthma. 16 -18 Activity of superoxide dismutase (SOD) is lower in asthmatic lungs as compared to healthy controls, and decreases further during an asthmatic attack.…”

mentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

Self Cite

172

149

View full text Add to dashboard Cite

Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

show abstract

Eosinophils generate brominating oxidants in allergen-induced asthma

Cited by 272 publications

References 63 publications

Eosinophil Peroxidase-derived Reactive Brominating Species Target the Vinyl Ether Bond of Plasmalogens Generating a Novel Chemoattractant, α-Bromo Fatty Aldehyde

Eosinophil Peroxidase-derived Reactive Brominating Species Target the Vinyl Ether Bond of Plasmalogens Generating a Novel Chemoattractant, α-Bromo Fatty Aldehyde

Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Contact Info

Product

Resources

About