Characterisation of the human plunc gene, a gene product with an upper airways and nasopharyngeal restricted expression pattern

Bingle, Colin D.; Bingle, Lynne

doi:10.1016/s0167-4781(00)00196-2

Cited by 100 publications

(118 citation statements)

References 15 publications

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“…The PLUNC family are secreted proteins that are subdivided into short (SPLUNCs) and long (LPLUNCs) members, which contain either 1 or 2 domains respectively (12,13). The original PLUNC gene, which is now called SPLUNC1, comprises up to 10% of total protein in the airway surface liquid, and can readily be detected in both nasal lavage and tracheal secretions (14)(15)(16).…”

mentioning

confidence: 99%

SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

Garcı́a-Caballero

Rasmussen

Gaillard

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

140

182

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Many epithelia, including the superficial epithelia of the airways, are thought to secrete “volume sensors,” which regulate the volume of the mucosal lining fluid. The epithelial Na + channel (ENaC) is often the rate limiting factor in fluid absorption, and must be cleaved by extracellular and/or intracellular proteases before it can conduct Na + and absorb excess mucosal liquid, a process that can be blocked by proteases inhibitors. In the airways, airway surface liquid dilution or removal activates ENaC. Therefore, we hypothesized that endogenous proteases are membrane-anchored, whereas endogenous proteolysis inhibitors are soluble and can function as airway surface liquid volume sensors to inhibit ENaC activity. Using a proteomic approach, we identified short palate, lung, and nasal epithelial clone (SPLUNC)1 as a candidate volume sensor. Recombinant SPLUNC1 inhibited ENaC activity in both human bronchial epithelial cultures and Xenopus oocytes. Knockdown of SPLUNC1 by shRNA resulted in a failure of bronchial epithelial cultures to regulate ENaC activity and airway surface liquid volume, which was restored by adding recombinant SPLUNC1 to the airway surface liquid. Despite being able to inhibit ENaC, recombinant SPLUNC1 had little effect on extracellular serine protease activity. However, SPLUNC1 specifically bound to ENaC, preventing its cleavage and activation by serine proteases. SPLUNC1 is highly expressed in the airways, as well as in colon and kidney. Thus, we propose that SPLUNC1 is secreted onto mucosal surfaces as a soluble volume sensor whose concentration and dilution can regulate ENaC activity and mucosal volumes, including that of airway surface liquid.

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mentioning

confidence: 99%

SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

Garcı́a-Caballero

Rasmussen

Gaillard

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

140

182

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“…These results are consistent with those of a previous report. 13 PLUNC was expressed in P208T, whereas other gastric cancer tissue samples did not express PLUNC.…”

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confidence: 85%

“…12 The human PLUNC gene shows a similar expression pattern, including localization to the tracheal epithelium. 13 PLUNC was also identified as a marker of non-small-cell lung carcinoma. 14 Immunohistochemical analysis of PLUNC in lung cancer revealed that PLUNC is commonly expressed in adenocarcinoma, mucoepidermoid carcinoma, and bronchoalveolar carcinoma and is absent from small cell carcinoma and squamous cell carcinoma.…”

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confidence: 99%

Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach

et al. 2008

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Gastric cancer is one of the most common malignancies worldwide. In this study, we screened for genes upregulated in gastric cancer by comparing gene expression profiles from serial analysis of gene expression and microarray and identified the palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) gene. Immunostaining for PLUNC in 140 gastric cancer cases revealed strong and extensive staining of PLUNC in hepatoid adenocarcinoma of the stomach, whereas 7% of conventional gastric cancer cases showed focal immunostaining of PLUNC. Gastric hepatoid adenocarcinoma is an extrahepatic tumor characterized by morphologic similarities to hepatocellular carcinoma. To investigate the utility of PLUNC immunostaining in the diagnosis of gastric hepatoid adenocarcinoma, six cases of gastric hepatoid adenocarcinoma (six primary tumors and two associated liver metastases) were studied further. PLUNC staining was observed in all six primary hepatoid adenocarcinomas. PLUNC staining was observed in both the hepatoid adenocarcinoma and tubular/papillary adenocarcinoma components of primary tumors, although PLUNC staining was preferentially localized in tubular/papillary adenocarcinoma components. Staining of PLUNC was also detected in both liver metastases. PLUNC staining was not observed in 52 cases of primary hepatocellular carcinoma or in normal adult or fetal liver. These results indicate that PLUNC is a novel marker that distinguishes gastric hepatoid adenocarcinoma from primary hepatocellular carcinoma.

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“…It has recently been demonstrated that airway epithelial cells in mice and human beings express high levels of short palate, lung, and nasal epithelium clone 1 (SPLUNC1). 3,4 SPLUNC1 is a member of the PLUNC family, which encompasses 10 genes located on human chromosome 20q11. 5 Because SPLUNC1 has been predicted to share structural similarities with bactericidal permeability-increasing protein, it was hypothesized that it may be involved in host defense against bacterial infection.…”

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confidence: 99%

SPLUNC1 Promotes Lung Innate Defense Against Mycoplasma pneumoniae Infection in Mice

Gally

Smith

et al. 2011

The American Journal of Pathology

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Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is highly expressed in normal airways, but is dramatically decreased in allergic and cigarette smoke exposure settings. We have previously demonstrated SPLUNC1 in vitro antibacterial property against Mycoplasma pneumoniae (Mp). However, its in vivo biological functions remain unclear. The objectives of this study were to determine the in vivo functions of SPLUNC1 following bacterial (eg, Mp) infection, and to examine the underlying mechanisms. We generated SPLUNC1-deficient mice and utilized transgenic mice overexpressing human SPLUNC1 exclusively within the airway epithelium. These mice were infected with Mp and, twenty-four hours post infection, their host defense responses were compared to littermate controls. Mp levels and inflammatory cells increased in the lungs of SPLUNC1 ؊/؊ mice as compared to wild type controls. SPLUNC1 deficiency was shown to contribute to impaired neutrophil activation. In contrast, mice overexpressing hSPLUNC1 exclusively in airway epithelial cells demonstrated lower Mp levels. Furthermore, neutrophil elastase activity was significantly increased in mice overexpressing hSPLUNC1. Lastly, we demonstrated that SPLUNC1 enhanced Mp-induced human neutrophil elastase (HNE) activity, and HNE directly inhibited the growth of Mp. Our findings demonstrate a critical in vivo role of SPLUNC1 in host defense against bacterial infection, and likely provide a novel therapeutic approach to restore impaired lung innate immune responses to bacteria in patients with chronic lung diseases.

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Characterisation of the human plunc gene, a gene product with an upper airways and nasopharyngeal restricted expression pattern

Cited by 100 publications

References 15 publications

SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage

Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach

SPLUNC1 Promotes Lung Innate Defense Against Mycoplasma pneumoniae Infection in Mice

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