Differential epithelial expression of the putative innate immune molecule SPLUNC1 in Cystic Fibrosis

Bingle, Lynne; Barnes, Frances A.; Cross, Simon S.; Rassl, Doris M.; Wallace, William; Campos, Michael; Bingle, Colin D.

doi:10.1186/1465-9921-8-79

Cited by 53 publications

(79 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…SPLUNC1 expression is increased in CF lungs, especially in the surface epithelium of the proximal and distal airways (38) and this up-regulation may be due to the increased inf lammation in seen CF lungs (1). However, CF lungs are typified by Na ϩ hyperabsorption and mucus dehydration (39), so it is unlikely that SPLUNC1 exerts any significant inhibitory effect on ENaC under these conditions.…”

Section: Resultsmentioning

confidence: 97%

“…In normal airways, SPLUNC1 is highly expressed in submucosal glands with moderate expression in surface epithelium of the proximal airways with little expression in the distal airways (38). Thus, we propose that SPLUNC1 is secreted from glands and surface epithelium where it serves as a reporter molecule whose dilution or concentration can adjust ENaC activity to regulate airways hydration and mucus clearance.…”

Section: Resultsmentioning

confidence: 97%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

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

View full text Add to dashboard Cite

show abstract

“…This raises the possibility that the pattern recognition receptor-induced inhibition of SPLUNC1 is mediated by cytokines. TNF-a and IL-1b, common cytokines induced downstream from TLR4, did not inhibit SPLUNC1 in vitro when tested on cultured human tracheal epithelial cells (9), indicating that SPLUNC1 inhibition is not a universal response to inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Short PLUNC 1 (SPLUNC1) is a 25-kD protein secreted by epithelial cells in the upper airway and proximal lower respiratory tract (3,(6)(7)(8)(9)(10). SPLUNC1 is readily detected in human saliva and in nasal and bronchial epithelial washings at concentrations ranging from 34.7 ng/ml to 13.8 mg/ml (6,(10)(11)(12).…”

mentioning

confidence: 99%

Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive Immunity

Britto

Liu

Curran

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Short palate, lung, and nasal epithelial clone-1 (SPLUNC1) is a protein abundantly expressed by the respiratory epithelium of the proximal lower respiratory tract, a site of great environmental exposure. Previous studies showed that SPLUNC1 exerts antimicrobial effects, regulates airway surface liquid and mucociliary clearance, and suppresses allergic airway inflammation. We studied SPLUNC1 to gain insights into its role in host defense. In the lower respiratory tract, concentrations of SPLUNC1 are high under basal conditions. In models of pneumonia caused by common respiratory pathogens, and in Th1-induced and Th2-induced airway inflammation, SPLUNC1 secretion is markedly reduced. Pathogen-associated molecular patterns and IFN-g act directly on airway epithelial cells to inhibit SPLUNC1 mRNA expression. Thus, SPLUNC1 is quickly suppressed during infection, in response to an insult on the epithelial surface. These experiments highlight the finely tuned fluctuations of SPLUNC1 in response to exposures in the respiratory tract, and suggest that the loss of SPLUNC1 is a crucial feature of host defense across airbreathing animal species.Keywords: SPLUNC1; inflammation; innate; immunity; mucosaThe respiratory tract continuously interacts with environmental irritants and pathogens. These stimuli constitute part of an intricate network of signals that activate host defenses. Airway epithelial cells participate actively in this process by producing antimicrobial and immune mediators that maintain homeostasis during steady-state conditions, and promote inflammation during injury.The palate, lung, and nasal epithelial clone (PLUNC) genes are members of the bactericidal permeability-increasing protein foldcontaining (BPIF)/PLUNC protein family (1, 2). These genes are focally expressed by epithelial cells throughout the respiratory tracts of multiple air-breathing vertebrates (3). In total, 11 human genes and 14 murine genes have been described to date, located within a single locus on chromosome 20 and chromosome 2, respectively (4, 5). These genes code for the PLUNC proteins, which are classified into six short and eight long PLUNCs, based on their lengths.Short PLUNC 1 (SPLUNC1) is a 25-kD protein secreted by epithelial cells in the upper airway and proximal lower respiratory tract (3, 6-10). SPLUNC1 is readily detected in human saliva and in nasal and bronchial epithelial washings at concentrations ranging from 34.7 ng/ml to 13.8 mg/ml (6, 10-12). In tracheal epithelial-cell supernatants SPLUNC1 constituted 10% of the total soluble protein, making it one of the most highly expressed proteins produced by airway epithelial cells (7).SPLUNC1 shares structural similarities with the immunomodulatory proteins bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (4, 13-15). It was initially hypothesized to express antimicrobial functions, and has been shown to inhibit the growth of multiple pathogens (16-19), inhibit biofilm formation, and possess surfactant properties (20,21). Although mos...

show abstract

“…A number of previous studies have demonstrated that BPIFA1 is involved in various physiological and pathological processes (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). It is considered to be involved in inflammatory responses to irritants in the upper airway (2-7).…”

Section: Introductionmentioning

confidence: 99%

Increased expression of BPI fold-containing family A member 1 is associated with metastasis and poor prognosis in human colorectal carcinoma

Wang

Jiang

et al. 2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Bactericidal or permeability-increasing protein fold-containing family A member 1 (BPIFA1) has been demonstrated to be involved in inflammatory responses in the upper airway and the progression of non-small cell lung cancer. However, the expression levels of BPIFA1 and its clinical prognostic significance in colorectal carcinoma (CRC) has not yet been elucidated. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to analyze the expression levels of BPIFA1 in CRC and normal mucosal tissues. The associations between BPIFA1 expression levels and clinicopathological characteristics, and its predictive value for prognosis in CRC, were statistically evaluated as appropriate. The expression levels of BPIFA1 were revealed to be upregulated at the transcriptional and translational levels in CRC tissues, compared with in normal mucosal tissues. A high expression level of BPIFA1 is significantly associated with invasion depth (P=0.040), lymph node metastasis (P=0.035) and distant metastasis (P=0.010). Furthermore, Kaplan-Meier analysis indicated that BIPFA1 overexpression is associated with short survival time, and the Cox proportional hazards model of risk analysis indicated that BPIFA1 is an independent prognostic factor for patients with CRC. The results of the present study suggested that BPIFA1 expression is upregulated in CRC tissues, and that an increased expression level of BPIFA1 is associated with tumor invasion, metastasis and poor prognosis, indicating that BPIFA1 may be a potential clinical prognostic predictor and therapeutic target for patients with CRC. IntroductionColorectal carcinoma (CRC) is the one of the most common types of cancer, and is the fifth leading cause of cancer-associated mortalities worldwide (1). Despite recent advancements in the surgical techniques, radiotherapy and chemotherapy available to patients diagnosed with CRC over the past several decades, the overall survival rate has not significantly improved. The existence of numerous known carcinogens and varying genetic backgrounds makes it difficult to determine which factors are most important in the development of CRC. Thus, there is a requirement to further understand the underlying molecular mechanisms and identify novel prognostic biomarkers and therapeutic targets to provide improved treatment strategies for CRC.Bactericidal or permeability-increasing protein fold-containing family A member 1 (BPIFA1) is a protein-coding gene specifically expressed in the upper airways and nasopharyngeal regions. A number of previous studies have demonstrated that BPIFA1 is involved in various physiological and pathological processes (2-19). It is considered to be involved in inflammatory responses to irritants in the upper airway (2-7). BPIFA1 may decrease mycoplasma pneumonia expression levels and inhibit interleukin 8 (8). BPIFA1 protein was also revealed to have antibacterial activity against gram-negative bacteria (9,10). The anti-inflammatory function has been associated with the regulation of macro...

show abstract

Differential epithelial expression of the putative innate immune molecule SPLUNC1 in Cystic Fibrosis

Cited by 53 publications

References 36 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

Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive Immunity

Increased expression of BPI fold-containing family A member 1 is associated with metastasis and poor prognosis in human colorectal carcinoma

Contact Info

Product

Resources

About