Abstract
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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrosing interstitial pneumonia of unknown cause, characterized by persistently progressive fibrosis of the lung interstitium that results in irreversible destruction of the alveolar structure [1]
To further assesses the clinical usefulness of interleukin-18 binding protein (IL-18BP) as a biomarker, we investigated serum IL-18 levels, which had previously been reported to be useful as a clinical biomarker for IPF [16], in both IPF patients and healthy volunteers (HVs)
Receiver operating characteristic (ROC) curve analysis revealed that the area under the ROC curve (AUC) value of serum IL-18BP was significantly larger than that of serum IL-18 for discriminating IPF patients from HVs (Fig 2B, p < 0.001)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrosing interstitial pneumonia of unknown cause, characterized by persistently progressive fibrosis of the lung interstitium that results in irreversible destruction of the alveolar structure [1]. The median survival of IPF patients has been reported to be approximately 3 years [1]. With no available treatment option that can restore the deteriorated pulmonary function, early diagnosis of IPF as well as accurate prediction of disease progression are quite important for the clinical management of IPF [8, 9]. For the reasons described above, substantial efforts have been made to identify a biomarker for IPF that can support the diagnosis, prognosis prediction, and the assessment of response to treatment [11]. IL-18 was upregulated in patients with IPF and the lungs of bleomycin (BLM)injured mice [14,15,16], but the role of IL-18BP, which is a natural antagonist of IL-18, is still unknown. The present study was conducted to clarify whether IL-18BP can serve as a diagnostic and/or prognostic biomarker for IPF
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