title: Hypohalous acid-modified human serum albumin induces neutrophil NADPH oxidase activation, degranulation, and shape change.
abstract: Halogenated lipids, proteins, and lipoproteins formed in reactions with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) and hypobromous acid (HOBr) can contribute to the regulation of functional activity of cells and serve as mediators of inflammation. Human serum albumin (HSA) is the major plasma protein target of hypohalous acids. This study was performed to assess the potency of HSA modified by HOCl (HSA-Cl) and HOBr (HSA-Br) to elicit selected neutrophil responses. HSA-Cl/Br were found to induce neutrophil degranulation, generation of reactive oxygen intermediates, shape change, and actin cytoskeleton reorganization. Thus HSA-Cl/Br can initially act as a switch and then as a feeder of the "inflammatory loop" under oxidative stress. In HSA-Cl/Br-treated neutrophils, monoclonal antibodies against CD18, the β subunit of β2 integrins, reduced the production of superoxide anion radicals and hydrogen peroxide as well as MPO exocytosis, suggesting that CD18 contributed to neutrophil activation. HSA-Cl/Br-induced neutrophil responses were also inhibited by genistein, a broad-specificity tyrosine kinase inhibitor, and wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, supporting the notion that activation of both tyrosine kinase and PI3K may play a role in neutrophil activation by HSA modified in MPO-dependent reactions. These results confirm the hypothesis that halogenated molecules formed in vivo via MPO-dependent reactions can be considered as a new class of biologically active substances potentially able to contribute to activation of myeloid cells in sites of inflammation and serve as inflammatory response modulators.
authors.affiliation: Department of Biophysics, Belarusian State University, Minsk 220050, Belarus. Electronic address: irinagorudko@rambler.ru.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Gorudko
authors.affiliation: Department of Biophysics, Belarusian State University, Minsk 220050, Belarus.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Grigorieva
authors.affiliation: Department of Biophysics, Belarusian State University, Minsk 220050, Belarus.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Shamova
authors.affiliation: Institute of Experimental Medicine, Saint-Petersburg 197376, Russia; Research Institute of Physico-Chemical Medicine, Moscow 119435, Russia.
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Kostevich
authors.affiliation: Institute of Experimental Medicine, Saint-Petersburg 197376, Russia; Research Institute of Physico-Chemical Medicine, Moscow 119435, Russia; State University of Saint Petersburg, Saint Petersburg 199000, Russia.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Sokolov
authors.affiliation: Research Institute of Physico-Chemical Medicine, Moscow 119435, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Mikhalchik
authors.affiliation: Department of Biophysics, Belarusian State University, Minsk 220050, Belarus.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Cherenkevich
authors.affiliation: Institute for Medical Physics and Biophysics, Medical Faculty, University of Leipzig, 04107 Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Arnhold
authors.affiliation: Research Institute of Physico-Chemical Medicine, Moscow 119435, Russia.
authors.forename: Oleg M
authors.initials: OM
authors.lastname: Panasenko
mesh_terms: D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000008:administration & dosage; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism*; D018375:Neutrophil Activation / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D016877:Oxidants; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D016877:Oxidants; D012709:Serum Albumin; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases
keywords: Degranulation; Free radicals; Human neutrophil; Human serum albumin; Hypobromous acid; Hypochlorous acid; Myeloperoxidase; Oxidative stress