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. 2015 Apr;81:38-46.
doi: 10.1016/j.freeradbiomed.2014.12.027. Epub 2015 Jan 9.

The Effects of Hypochlorous Acid and Neutrophil Proteases on the Structure and Function of Extracellular Superoxide Dismutase

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The Effects of Hypochlorous Acid and Neutrophil Proteases on the Structure and Function of Extracellular Superoxide Dismutase

Karla Morales et al. Free Radic Biol Med. .

Abstract

Extracellular superoxide dismutase (EC-SOD) is expressed by both macrophages and neutrophils and is known to influence the inflammatory response. Upon activation, neutrophils generate hypochlorous acid (HOCl) and secrete proteases to combat invading microorganisms. This produces a hostile environment in which enzymatic activity in general is challenged. In this study, we show that EC-SOD exposed to physiologically relevant concentrations of HOCl remains enzymatically active and retains the heparin-binding capacity, although HOCl exposure established oxidative modification of the N-terminal region (Met32) and the formation of an intermolecular cross-link in a fraction of the molecules. The cross-linking was also induced by activated neutrophils. Moreover, we show that the neutrophil-derived proteases human neutrophil elastase and cathepsin G cleaved the N-terminal region of EC-SOD irrespective of HOCl oxidation. Although the cleavage by elastase did not affect the quaternary structure, the cleavage by cathepsin G dissociated the molecule to produce EC-SOD monomers. The present data suggest that EC-SOD is stable and active at the site of inflammation and that neutrophils have the capacity to modulate the biodistribution of the protein by generating EC-SOD monomers that can diffuse into tissue.

Keywords: Antioxidant; Cathepsin G; Extracellular matrix protein; Free radicals; Hypochlorous acid; Inflammation; Neutrophil; Superoxide dismutase.

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