Date Published: January 30, 2017
Publisher: Public Library of Science
Author(s): Pamela S. Hair, Laura A. Sass, Neel K. Krishna, Kenji M. Cunnion, Nades Palaniyar.
Myeloperoxidase is the major peroxidase enzyme in neutrophil granules and implicated in contributing to inflammatory lung damage in cystic fibrosis. Free myeloperoxidase is present in cystic fibrosis lung fluid and generates hypochlorous acid. Here we report a new inhibitor of myeloperoxidase activity, Peptide Inhibitor of Complement C1 (PIC1). Using TMB as the oxidizing substrate, PIC1 inhibited myeloperoxidase activity in cystic fibrosis sputum soluble fractions by an average of a 3.4-fold decrease (P = 0.02). PIC1 also dose-dependently inhibited myeloperoxidase activity in a neutrophil lysate or purified myeloperoxidase by up to 28-fold (P < 0.001). PIC1 inhibited myeloperoxidase activity similarly, on a molar basis, as the specific myeloperoxidase inhibitor 4-Aminobenzoic acid hydrazide (ABAH) for various oxidizing substrates. PIC1 was able to protect the heme ring of myeloperoxidase from destruction by NaOCl, assayed by spectral analysis. PIC1 incubated with oxidized TMB reversed the oxidation state of TMB, as measured by absorbance at 450 nm, with a 20-fold reduction in oxidized TMB (P = 0.02). This result was consistent with an antioxidant mechanism for PIC1. In summary, PIC1 inhibits the peroxidase activity of myeloperoxidase in CF sputum likely via an antioxidant mechanism.
Myeloperoxidase (MPO) is a strong peroxidase present in neutrophil granules and its primary function is the generation of hypochlorous acid, the most powerful oxidant produced by neutrophils in appreciable amounts . MPO catalyzes the production of hypochlorous acid in the presence of hydrogen peroxide and chloride anion . MPO is present in the lung fluid of cystic fibrosis (CF) patients likely as the result of neutrophil degranulation or cell death [3, 4]. Multiple investigators have suggested that MPO in the lung fluid of CF patients may contribute to parenchymal destruction in addition to neutrophil elastase and other factors [5–7].
The peroxidase activity of MPO is typically contained intracellular most notably in neutrophil granules designed to fuse with phagocytized microorganisms to produce phagolysosomes. In this protected environment MPO can generate hypochlorous acid contributing to oxidative killing. However when MPO is released into the extracellular environment by neutrophil death or degranulation, it can mediate oxidative damage of host molecules including proteins, DNA and lipids leading to host tissue damage . MPO-mediated inflammation has been implicated in multiple diseases including coronary artery disease [20, 21] and glomerular and tubulointerstitial kidney diseases . Thus, the potential clinical utility of an MPO inhibitor amenable for human use appears to be high.