The Lactoperoxidase System Functions in Bacterial Clearance of Airways

Abstract

Airway mucus is a complex mixture of secretory products that provides a multifaceted defense against pulmonary infection. Mucus contains antimicrobial peptides (e.g., defensins) and enzymes (e.g., lysozyme) although the contribution of these to airway sterility has not been tested in vivo. We have previously shown that an enzymatically active, heme-containing peroxidase comprises 1% of the soluble protein in sheep airway secretions, and it has been hypothesized that this airway peroxidase may function as a biocidal system. In this study, we show that sheep airway peroxidase is identical to milk lactoperoxidase (LPO) and that sheep airway secretions contain thiocyanate (SCN(-)) at concentrations necessary and sufficient for a functional peroxidase system that can protect against infection. We also show that airway LPO, like milk LPO, produces the biocidal compound hypothiocyanite (OSCN(-)) in vitro. Finally, we show that in vivo inhibition of airway LPO in sheep leads to a significant decrease in bacterial clearance from the airways. The data suggest that the LPO system is a major contributor to airway defenses. This discovery may have significant implications for chronic airway colonization seen in respiratory diseases such as cystic fibrosis.

Increased Concentration of Iodide in Airway Secretions Is Associated with Reduced Respiratory Syncytial Virus Disease Severity

“…Lambs, like infants, have submucosal glands, which produce LPO and express sufficient levels of Duoxs and halide transport systems (23,24) to support formation of the pseudohypohalide OSCN 2 or, in the presence of sufficient I 2 , HOI. Rodents lack significant submucosal gland formation in the intrapulmonary airways and therefore lack sufficient LPO production for a fully functional oxidative defense system within the airways (31).…”

“…11 and 12 (24,25). HOI has potent microbicidal activity against bacteria (23) and viruses (26), including activity against RSV, whereas OSCN 2 exhibits little antiviral activity (24). We previously reported that I 2 is concentrated in the nasal ASL of human subjects after oral I 2 supplementation using an FDA-approved formulation (24).…”

“…The ovine respiratory tract functionally expresses the Duox/LPO/halide system (23), is susceptible to human strains of RSV, and develops microscopic lesions similar to those in infants (reviewed in References 27-30). Some other animal species used to model RSV infection (e.g., mice and rats) lack airway submucosal glands (31), which are the LPO-secreting structures in the airways of larger mammals.…”

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

“…The binding of siderophores will complement iron sequestering by lactoferrin to starve bacteria of iron and is potentially much more efficient because it only targets iron that has already been bound for bacterial use. Mucus also contains pore-forming defensins, and lactoperoxidase (Gerson, Sabater et al 2000). Finally, sputum contains natural killer cells, cytotoxic T cells, macrophages and neutrophils, whose importance in airway innate defense has been repeatedly reviewed (Cole and Waring 2002;Ganz 2004;Beisswenger and Bals 2005).…”

High Dissociation Rate Constant of Ferrous-Dioxy Complex Linked to the Catalase-like Activity in Lactoperoxidase

“…Catalase and cytoplasmic glutathione peroxidase are the major H 2 O 2 scavengers and protect cells from the toxic effects of H 2 O 2 by catalyzing its decomposition into molecular oxygen and water (4,7,8). Recently, lactoperoxidase (LPO) 1 has been identified as the major macromolecular consumer of H 2 O 2 in animal airway secretions (9,10). At this site, catalase displays very low levels of expression that are insufficient to protect the epithelium against pathogens (11,13).…”