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Spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.

ABSTRACT: Background:Spliceosome-associated protein 130 (SAP130), a novel danger-associated molecular pattern (DAMP), is involved in inflammatory disease. However, no data are available about SAP130 in idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate SAP130 in the serum and lung tissue of patients with IPF and to determine its clinical significance. Methods:SAP130 levels in the serum of 83 IPF patients and 38 healthy subjects were measured. Additionally, immunohistochemical staining for SAP130 was performed in lung specimens of IPF patients and control subjects. Correlation between serum SAP130 levels and clinical parameters were investigated. Results:Serum SAP130 levels were elevated in IPF patients compared with healthy controls. In parallel, the expression of SAP130 in lung tissue was elevated in IPF. SAP130 levels were higher in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) than patients with stable IPF (P=0.0144). The area under curve (AUC) of the ROC curve for the diagnosis of IPF was 0.944 (95% CI, 0.810-0.997) for SAP130. The sensitivity (92.1%) and specificity (69.9%) were obtained for the cutoff value of 643.87 pg/mL. In patients with stable IPF, the SAP130 level correlated positively with fibrosis on high-resolution CT (HRCT) (r=0.4164, P=0.0029) and serum KL-6 (r=0.4564, P=0.0010), and inversely with FEV1 (r=-0.3562, P=0.0120) and DLCO (r=-0.5550, P<0.0001). In patients with AE-IPF, the SAP130 level correlated positively with fibrosis (r=0.3735, P=0.0296) and ground-glass opacity (r=0.4697, P=0.0051) on HRCT and serum Krebs von den Lungen 6 (KL-6) (r=0.5470, P= 0.0008). Conclusions:The study suggested that SAP130 was a potential noninvasive biomarker that correlates well with disease severity of IPF. A prospective, multicentre study is required to validate the clinical and pathophysiological utility of SAP130 in IPF.

SUBMITTER: Liu K

PROVIDER: S-EPMC7475450 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.

Liu Kaixiong K Liu Dong D Feng Yun Y Zhang Hongying H Zeng Dunhuan D Liu Qinhua Q Qu Jieming J

Annals of translational medicine 20200801 16

<h4>Background</h4>Spliceosome-associated protein 130 (SAP130), a novel danger-associated molecular pattern (DAMP), is involved in inflammatory disease. However, no data are available about SAP130 in idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate SAP130 in the serum and lung tissue of patients with IPF and to determine its clinical significance.<h4>Methods</h4>SAP130 levels in the serum of 83 IPF patients and 38 healthy subjects were measured. Additionally, immunohistochemic ...[more]

PMID: 32953786

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Project description:Idiopathic pulmonary fibrosis is a chronic, fibrosing interstitial pneumonia that presents with various clinical courses and progression ranging from rapid to slow. To identify novel biomarkers that can support the diagnosis and/or prognostic prediction of idiopathic pulmonary fibrosis, we performed gene expression analysis, and the mRNA of interleukin-18 binding protein was increasingly expressed in patients with idiopathic pulmonary fibrosis compared with healthy controls. Therefore, we hypothesized that the interleukin-18 binding protein can serve as a diagnostic and/or prognostic biomarker for idiopathic pulmonary fibrosis. We investigated the expression of interleukin-18 binding protein in lung tissue, bronchoalveolar lavage fluid, and serum. Additionally, the correlation between interleukin-18 binding protein expression levels and the extent of fibrosis was investigated using mouse models of lung fibrosis induced by subcutaneous bleomycin injections. Serum interleukin-18 binding protein levels were significantly higher in idiopathic pulmonary fibrosis patients (5.06 ng/mL, interquartile range [IQR]: 4.20-6.35) than in healthy volunteers (3.31 ng/mL, IQR: 2.84-3.99) (p < 0.001). Multivariate logistic regression models revealed that the correlation between serum interleukin-18 binding protein levels and idiopathic pulmonary fibrosis was statistically independent after adjustment for age, sex, and smoking status. Multivariate Cox proportional hazard models revealed that serum interleukin-18 binding protein levels were predictive of idiopathic pulmonary fibrosis disease prognosis independent of other covariate factors (hazard ratio: 1.655, 95% confidence interval: 1.224-2.237, p = 0.001). We also demonstrated a significant positive correlation between lung hydroxyproline expression levels and interleukin-18 binding protein levels in bronchoalveolar lavage fluid from bleomycin-treated mice (Spearman r = 0.509, p = 0.004). These results indicate the utility of interleukin-18 binding protein as a novel prognostic biomarker for idiopathic pulmonary fibrosis.

Project description:Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).To assess the expression and function of FKBP10 in IPF.We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-?1, was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68(+) macrophages. Transforming growth factor-?1, but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and ?-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.FKBP10 might be a novel drug target for IPF.

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Spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.

Publications

Spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.

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