Gremlin-1 for the Differential Diagnosis of Idiopathic Pulmonary Fibrosis Versus Other Interstitial Lung Diseases: A Clinical and Pathophysiological Analysis

Yoichiro Aoshima,Hideya Kawasaki,Noriyuki Enomoto,Tomoyuki Fujisawa,Takafumi Suda,Yasunori Enomoto,Shigeki Muto,Yutaro Nakamura,Shiori Meguro,Isao Kosugi,Toshihide Iwashita,Naoki Inui

doi:10.1007/s00408-021-00440-y

Abstract

PurposeThe differential diagnosis of interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF) versus other non-IPF ILDs, is important for selecting the appropriate treatment. This retrospective study aimed to explore the utility of gremlin-1 for the differential diagnosis.MethodsSerum gremlin-1 concentrations were measured using an ELISA in 50 patients with IPF, 42 patients with non-IPF ILD, and 30 healthy controls. The baseline clinical data, including pulmonary functions, prognosis, and three serum biomarkers (Krebs von den Lungen-6 [KL6], surfactant protein-D [SP-D], and lactate dehydrogenase [LDH]), were obtained through a medical record review for analyzing their associations with serum gremlin-1 concentrations. To evaluate the origin of gremlin-1, we performed immunostaining on lung sections.ResultsSerum gremlin-1 concentrations were significantly higher in patients with IPF (mean concentration, 14.4 ng/mL), followed by those with non-IPF ILD (8.8 ng/mL) and healthy controls (1.6 ng/mL). The area under the curve for IPF versus non-IPF ILDs was 0.759 (95% confidence interval, 0.661–0.857), which was superior to that of KL6/SP-D/LDH. The sensitivity and specificity for gremlin-1 (cutoff, 10.4 ng/mL) was 72 and 69%, respectively. By contrast, serum gremlin-1 concentrations were not associated with the pulmonary functions nor the prognosis in all patients with ILDs. In immunostaining, the gremlin-1 was broadly upregulated in IPF lungs, particularly at myofibroblasts, bronchiolar/alveolar epithelium, and CD163-positive M2-like macrophages.ConclusionsGremlin-1 may be a useful biomarker to improve the diagnostic accuracy for IPF compared to non-IPF ILDs, suggesting a role of this molecule in the pathogenesis of IPF.

Highlights

Interstitial lung disease (ILD) is a heterogeneous disease in terms of its variety, in regard to its clinical course and treatment [1]
As several researchers have pointed out, this molecule is more suitable for evaluating disease behavior and prognosis than differentiating ILDs [8, 9], which suggests a need for another biomarker for the purpose of differential diagnosis
According to our published mouse microarray dataset (GSE111043), gremlin-1 mRNA (Grem1) was significantly upregulated, while bone morphogenetic protein-4 (BMP4) mRNA was downregulated in bleomycin-induced lung myofibroblasts compared with steady-state fibroblasts (Fig. 2a), which is consistent with previous human data comparing idiopathic pulmonary fibrosis (IPF) fibroblasts with normal fibroblasts [11]

Summary

Introduction

Interstitial lung disease (ILD) is a heterogeneous disease in terms of its variety, in regard to its clinical course and treatment [1]. Consistent with our data, previous studies have suggested that gremlin-1 is upregulated in human lungs with ILDs, IPF [11, 12].

Results

Conclusion