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Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense ¹

MIKLÓS GEISZT^*, JASSIR WITTA, JUDIT BAFFI^#, KRISTEN LEKSTROM and THOMAS L. LETO²

Laboratory of Host Defenses, NIAID, National Institutes of Health,
^* Department of Physiology, Semmelweis University, Faculty of Medicine,
Department of Pharmacology, Uniformed Services University of the Health Sciences, and
^# Ocular Gene Therapy Section, NEI, National Institutes of Health, Bethesda, Maryland, USA

²Correspondence: Bldg. 10, Rm. 11N106, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: tleto{at}nih.gov

SPECIFIC AIMS

Lactoperoxidase (LPO) has long been appreciated as a potent antimicrobial enzyme in saliva, milk, and tears, although host sources of hydrogen peroxide supporting this activity have never been described; recently, several homologues of the microbicidal NADPH oxidase of phagocytes were identified in diverse tissues. Our objective was to identify potential sources of reactive oxygen species (ROS) on mucosal surfaces that may support the antimicrobial activity of LPO.

1. Duox2, a homologue of the gp91phox component of the phagocyte NADPH oxidase, is detected in major ducts of the salivary gland
We studied Duox expression in salivary glands by Northern blot and in situ hybridization. Figure 1 a shows that Duox2 mRNA is expressed in the human salivary gland; Duox1 was not detected (not shown). Northern blot also detected high Duox2 mRNA levels in rat submandibular salivary gland, using a cDNA probe from the rat Duox2 mRNA 3'-untranslated region (Fig. 1a ). In situ hybridization on rat submandibular gland sections revealed Duox2 expression within epithelial cells of intralobal, interlobal, and main excretory ducts (Fig. 1b-e ). We observe capillary networks surrounding the excretory ducts that are consistent with high oxygen demands for ROS production (Fig. 1b ). This expression pattern suggests that H₂O₂ production occurs in the final steps of saliva formation, enabling delivery of unstable ROS into the oral cavity and preventing oxidant-induced glandular tissue damage.

View larger version (126K): [in this window] [in a new window]   Figure 1. Detection of the Duox2-LPO system in salivary glands. a) Northern blot of Duox2 mRNA in human (left) and rat (right) salivary glands. b–e) Detection of Duox2 mRNA in rat submandibular gland by in situ hybridization; exposed silver grain hybridization signal appears black (60 X magnification). b) Rat Duox2 antisense probe detects Duox2 in intralobar excretory ducts. Black arrows point to capillaries surrounding duct. c) Control hybridization (Duox2 sense probe) is negative. d) Detection of Duox2 in terminal excretory duct of submandibular gland. e) Control hybridization corresponding to d) using Duox2 sense probe. f–h) Detection of LPO-Duox system mRNA transcripts in human parotid gland. Frames represent superimposed bright-field (Giemsa stained) and polarized epi-illumination images; hybridization signal appears red (60 X magnification). f) Duox2 antisense probe detected this mRNA in larger excretory ducts of human parotid gland. g) LPO expression is seen within serous acini. h) Sodium iodide symporter (NIS) mRNA is detected within intercalated ducts. i–k) Corresponding control hybridization (sense probes) from Duox2 (i), LPO (j), and NIS (k).

2. Duox2, LPO, and the sodium iodide symporter exhibit segregated sites of expression in salivary glands
We also detected Duox2-LPO components in the human parotid gland by in situ hybridization; the Duox2 transcript is most abundant within major ducts (Fig. 1f ), similar to rat tissues. The sodium iodide symporter (NIS), which also transports thiocyanate, was previously detected in this gland, although I^– and SCN^– transport mechanisms in saliva have not been described. Our in situ hybridizations suggest this transport occurs in smaller, intercalated ducts, where the highest NIS mRNA levels were observed (Fig. 1g ). In contrast, LPO mRNA was detected deep within the gland’s serous acini (Fig. 1h ). Thus, the sites for synthesis or secretion of various LPO-Duox components are segregated in this tissue and LPO becomes active only in late stages of saliva formation, as it encounters H₂O₂ before delivery into the oral cavity.

3. Duox2 and LPO mRNAs are detected in the rectum
We examined Duox2 mRNA levels in several human gastrointestinal tissues and observed low levels of Duox2 in the cecum and the ascending colon. We detected much higher Duox2 expression in the human and rat rectum. In situ hybridization with rat rectum showed Duox2 is expressed in rectal epithelial cells, predominantly within the gland’s lower half (not shown). To confirm that Duox2-expressing tissues produce H₂O₂, as in the thyroid gland, we examined H₂O₂ levels in rectal glands isolated from rectal mucosa. H₂O₂ release from these preparations is completely blocked by 10 µM diphenyleniodonium (DPI), a potent NADPH oxidase inhibitor. High Duox2 expression in the rectum is consistent with a host defense function. In the presence of H₂O₂, LPO functions as an antimicrobial protein in milk, saliva, and tears, although its presence in the intestinal tract has not been recognized. Using a cDNA probe corresponding to the 3'-untranslated region of rat LPO mRNA, we also detected LPO expression in the rat rectum (not shown).

4. LPO is expressed in submucosal glands of airways
Recent work has documented high LPO expression in sheep airways (it comprises as much as 1% of secreted protein) and shown that inhibition of LPO reduces airway bacterial clearance. We performed in situ hybridization on human trachea and bronchium and showed high LPO expression within submucosal glands (Fig. 2 a, c), where it localizes to serous acini.

View larger version (105K): [in this window] [in a new window]   Figure 2. Detection of LPO and Duox1 in human trachea and bronchium. In situ hybridization with LPO and Duox1 transcripts in trachea (a, e) and bronchium (c, g). Shown are bright-field, Giemsa-stained images superimposed with epi-illumination images, in which exposed silver grain hybridization signals appear red (75X magnification). LPO antisense probe (a, c) reveals expression in serous acini of submucosal glands (arrowheads), whereas epithelial layers (arrows) are negative. Abundant Duox1 expression is detected along epithelium of the trachea (e) and bronchium (g). i–k) Involvement of Duox1 in H2O2 release by normal human airway epithelial cells, NHBE. i) Northern blot analysis of Duox1 expression in human trachea (Tr) and cultured NHBE cells. j) Chemiluminescence assays of ionomycin-stimulated H2O2 release by NHBE cells (150,000 cells/ well). Squares, ionomycin-stimulated chemiluminescence; triangles, stimulated activity after prior DPI treatment; diamonds, chemiluminescence without stimulus. k) Effects of Duox1 antisense (AS) and control oligonucleotides (1 µM; 48 h) on H2O2 release by NHBE cells. Results are combined averages from 4 independent experiments (8 assays).

5. Duox1 expression is detected in epithelial cells of major airways
We examined Duox expression in human trachea and the bronchium and we observed high Duox1 expression within pseudostratified epithelium of trachea and bronchi (Fig. 2e, g ), suggesting that Duox1 is a likely H₂O₂ source for LPO in these tissues.

6. Duox1 produces H₂O₂ in cultured human bronchial epithelial cells
Cultured human bronchial epithelial (NHBE) cells were tested for H₂O₂ release in response to ionomycin, since thyroid gland H₂O₂ production is stimulated by calcium. We detected Duox 1 mRNA by Northern blot in human trachea and NHBE cells (Fig. 2i ). Low-passage cultures produced significant H₂O₂ but no detectable superoxide; this response is DPI sensitive (Fig. 2j ). To explore if H₂O₂ production can be attributed to Duox1, the cells were treated with 1 µM antisense oligonucleotide (nt 417-437). Figure 2k shows that significant reductions in H₂O₂ release were observed after a 48 h treatment when compared with cells treated with a partially-scrambled version of this 21-mer.

CONCLUSIONS AND SIGNIFICANCE

The LPO system has long been considered an effective host defense mechanism. Its antimicrobial properties include activity against a range of Gram-positive and -negative organisms. Salivary levels of LPO and thiocyanate in the presence of H₂O₂ have potent killing activities, although the H₂O₂ sources supporting LPO have remained unknown. Our experiments suggest two NADPH oxidase homologues, Duox1 and Duox2, may provide H₂O₂ for LPO on several mucosal surfaces. We found that Duox enzymes are expressed not only in the thyroid gland, but also in salivary glands, rectum, trachea, and bronchium. The expression patterns are consistent with a host defense function. We also demonstrate Duox2 and LPO expression in the rectum and that rectal gland H₂O₂ production is DPI-sensitive. Finally, we detect high Duox1 levels along mucosal surfaces of trachea and bronchium. Its importance as a source of H₂O₂ in airway epithelia was suggested in experiments showing H₂O₂ release is stimulated by ionomycin, inhibited by DPI, and suppressed by Duox1 antisense oligonucleotides. These properties are not only consistent with structural features of the Duox enzymes, but agree with observations on the role of calcium in ROS release by thyrocytes.

LPO and Duox oxidase coexpression in salivary glands, rectum, trachea, and bronchium suggests these enzymes act in concert. We showed that components of the Duox-LPO system are synthesized or secreted at distinct sites, in a manner well suited for mucosal host defense (Fig. 3 ): LPO is produced deep within serous acini of submucosal or salivary glands; iodide and thiocyanate substrates are delivered within intercalated, interlobular ducts whereas H₂O₂, the most labile substrate, is generated by Duox enzymes expressed along terminal excretory ducts and epithelial surfaces, where it may readily convert to more potent antimicrobial oxidants. The Duox-LPO system provides one more microbicidal arm to the arsenal of mucosal defenses, with properties uniquely adapted to this environment. Unlike phagocytes, mucosal epithelial cells generate reactive oxidants that are released into the extracellular medium. Abundant LPO in these secretions generates less potent antimicrobial agents, primarily hypothiocyanate, less toxic to host tissues. Furthermore, the conversion of H₂O₂ to toxic hydroxyl free radicals by free iron (Fenton reaction) would be effectively prevented by lactoferrin, another abundant component of airway secretions.

View larger version (24K): [in this window] [in a new window]   Figure 3. Model of expression and secretion of antimicrobial Duox-LPO components in salivary glands. LPO is secreted deep within serous acini of the gland (a), whereas the sodium iodide symporter (NIS) transports iodide and thiocyanate substrates into intercalated ducts (b). Activation occurs in final stages of saliva formation in major excretory ducts (c), where Duox2 produces H2O2 and the reactive metabolites of iodide and thiocyanate are formed.

In cystic fibrosis (CF), innate defenses of the airway are compromised, leading to life-threatening pulmonary complications; the cause of this is poorly understood. The multi-component nature of the Duox-LPO system suggests several mechanisms by which the CF airway surface could alter this oxygen-dependent host defense system. The reduced volume of salivary, tracheal, and bronchial secretions in CF could affect the delivery of one or more components of the Duox-LPO system. As the CF transmembrane conductance regulator (CFTR) is also permeable to thiocyanate, it is possible that thiocyanate and hypothiocyanate levels are reduced on the CF airway surface. Finally, increased O₂ consumption observed in CF airway epithelial cells and generation of hypoxic environments along airway surfaces could reduce ROS production by CF epithelial cells. It is of interest that infections by pathogens observed in CF are also characteristic of chronic granulomatous disease, where phagocytic ROS-production is deficient. Pseudomonas aeruginosa, the most frequent pathogen of CF patients, grows within hypoxic, mucopurulent masses in CF airways, suggesting alterations in local ROS generation may be particularly relevant to chronic infections characteristic of CF.

Overproduction of ROS has a role in the pathogenesis of pulmonary fibrosis, asthma, and other respiratory distress syndromes, although the underlying mechanisms are poorly understood. Most work has focused on roles of activated inflammatory leukocytes or environmental agents as sources of toxic ROS. The discovery of Duox1 as a novel ROS source in the bronchial epithelium provides a new candidate mediator of these disease processes.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1104fje; doi: fj.02-1104fje

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