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.

Keywords: Idiopathic pulmonary fibrosis (IPF); acute exacerbation; biomarkers; spliceosome-associated protein 130 (SAP130).

Figure 1

Baseline serum SAP130 levels. (A) Distribution of serum levels of SAP130 in IPF patients and control subjects. IPF patients showed significantly higher serum SAP130 levels than normal control subjects (P<0.0001). (B) Distribution of serum levels of SAP130 in patients with stable IPF and patients with AE-IPF. AE-IPF patients showed significantly higher serum SAP130 levels than stable IPF patients (P=0.0144). Scatter plots showing the baseline distribution. SAP130, spliceosome-associated protein 130; AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis.

Figure 2

Expression of SAP130 in lung tissue of IPF patients and control subjects (IHC staining). (A) Representative image of control lung tissues (scale bar: 50 µm) showed SAP130 protein is expressed sparsely in normal alveolar structures. (B) Representative image of lung tissues of an IPF patient (scale bar: 50 µm) showed SAP130 protein is dramatically increased in IPF compared to control. SAP130 localizes diffusely to alveolar epithelial cells adjacent to the areas of mature fibrosis. SAP130, spliceosome-associated protein 130; IPF, idiopathic pulmonary fibrosis; IHC, immunohistochemistry.

Figure 3

ROC curve analysis of biomarker SAP130. (A) The derived area under the ROC (AUC) curve between IPF patients and healthy control subjects was 0.944 (95% CI, 0.810–0.997; cut-off 643.87 pg/mL; 92.1% sensitivity; 69.9% specificity). (B) The AUC of the ROC curve for the diagnosis of stable IPF versus AE-IPF diagnoses was 0.694 (95% CI, 0.580–0.809) for SAP130 (95% CI, 0.81–0.997; cut-off 741.46 pg/mL; 63.3% sensitivity; 67.6% specificity). SAP130, spliceosome-associated protein 130; ROC, receiver operating characteristic curve; AUC, area under curve; AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis.

Figure 4

Correlations between serum SAP130 levels and clinical variables in patients with stable IPF. Correlations between serum SAP130 levels and (A) FEV1 (% predicted); (B) FVC (% predicted); (C) DLCO (% predicted); (D) 6MWD; (E) Fibrosis Score (%); (F) GGO Score (%); (G) serum KL-6 were shown. SAP130, spliceosome-associated protein 130; IPF, idiopathic pulmonary fibrosis; FEV1, forced expiratory volume in 1; FVC, forced vital capacity; DLCO, carbon monoxide diffusing capacity; 6MWD, 6-minute walk distance; GGO, ground glass opacification; KL-6, Krebs von den Lungen 6.

Figure 5

Correlations between serum SAP130 levels and clinical variables in patients with AE-IPF. Correlations between serum SAP130 levels and (A) Fibrosis Score (%); (B) GGO Score (%); (C) serum KL-6 were shown. SAP130, spliceosome-associated protein 130; AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; GGO, ground glass opacification; KL-6, Krebs von den Lungen 6.

Figure S1

Expression of SAP130 in lung tissue of IPF patients and control subjects (IHC staining). (A) Representative image of control lung tissues (scale bar: 100 µm) showed SAP130 protein is expressed sparsely in normal alveolar structures. (B) Representative image of lung tissues of an IPF patient (scale bar: 100 µm) showed SAP130 protein is dramatically increased in IPF compared to control. SAP130, spliceosome-associated protein 130; IPF, idiopathic pulmonary fibrosis; IHC, immunohistochemistry.