Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis

Background.Recent reports indicate that matrix metalloproteinase-7 (MMP-7) and CC-chemokine ligand 18 (CCL18) are potential disease markers of idiopathic pulmonary fibrosis (IPF). The objective of this study was to perform direct comparisons of these two biomarkers with three well-investigated serum markers of IPF, Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), and SP-D.Methods.The serum levels of MMP-7, CCL18, KL-6, SP-A, and SP-D were evaluated in 65 patients with IPF, 31 patients with bacterial pneumonia, and 101 healthy controls. The prognostic performance of these five biomarkers was evaluated in patients with IPF.Results.The serum levels of MMP-7, KL-6, and SP-D in patients with IPF were significantly elevated compared to those in patients with bacterial pneumonia and in the healthy controls. Multivariate survival analysis showed that serum MMP-7 and KL-6 levels were independent predictors in IPF patients. Moreover, elevated levels of both KL-6 and MMP-7 were associated with poorer survival rates in IPF patients, and the combination of both markers provided the best risk discrimination using the C statistic.Conclusions.The present results indicated that MMP-7 and KL-6 were promising prognostic markers of IPF, and the combination of the two markers might improve survival prediction in patients with IPF.

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Increased Surfactant Protein-A Levels in Patients With Newly Diagnosed Idiopathic Pulmonary Fibrosis

CHEST Journal ◽

10.1378/chest.125.2.617 ◽

2004 ◽

Vol 125 (2) ◽

pp. 617-625 ◽

Cited By ~ 27

Author(s):

David S. Phelps ◽

Todd M. Umstead ◽

Mayra Mejia ◽

Guillermo Carrillo ◽

Annie Pardo ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Newly Diagnosed

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Elevated Levels of Lung Surfactant Protein A in Sera from Patients with Idiopathic Pulmonary Fibrosis and Pulmonary Alveolar Proteinosis

American Review of Respiratory Disease ◽

10.1164/ajrccm/147.3.723 ◽

1993 ◽

Vol 147 (3) ◽

pp. 723-729 ◽

Cited By ~ 109

Author(s):

Yoshio Kuroki ◽

Shin Tsutahara ◽

Noriharu Shijubo ◽

Hiroki Takahashi ◽

Masanori Shiratori ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Pulmonary Alveolar Proteinosis ◽

Lung Surfactant ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Alveolar Proteinosis ◽

Lung Surfactant Protein

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Surfactant protein A predicts survival in idiopathic pulmonary fibrosis.

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/ajrccm.154.3.8810629 ◽

1996 ◽

Vol 154 (3) ◽

pp. 825-826 ◽

Cited By ~ 3

Author(s):

R G McFadden

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A

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Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

Journal of Clinical Medicine ◽

10.3390/jcm9061940 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1940 ◽

Cited By ~ 2

Author(s):

Ivo A. Wiertz ◽

Sofia A. Moll ◽

Benjamin Seeliger ◽

Nicole P. Barlo ◽

Joanne J. van der Vis ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Mrna Expression ◽

Mononuclear Cells ◽

Serum Levels ◽

High Serum ◽

Lung Fibroblasts ◽

Healthy Controls ◽

Peripheral Blood Mononuclear ◽

Matrix Deposition

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p < 0.001). Both in IPF patients and HCs, serum CCL18 levels were influenced by rs2015086 C > T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF.

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Serum calprotectin as new biomarker for disease severity in idiopathic pulmonary fibrosis: a cross-sectional study in two independent cohorts

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2020-000827 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000827 ◽

Cited By ~ 1

Author(s):

Carlos Machahua ◽

Sabina A. Guler ◽

Michael P. Horn ◽

Lurdes Planas-Cerezales ◽

Ana Montes-Worboys ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Severity ◽

Validation Cohort ◽

Serum Levels ◽

Cross Sectional Study ◽

Healthy Controls ◽

Sectional Study ◽

Cross Sectional ◽

Derivation Cohort

BackgroundNon-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF pathogenesis. Calprotectin is a well-established biomarker in inflammatory bowel diseases. In this cross-sectional study, we aimed to establish the potential role of calprotectin as a biomarker in IPF. Specifically, we hypothesised that patients with IPF have higher serum calprotectin levels compared with healthy controls, and that calprotectin levels are associated with disease severity.MethodsBlood samples were obtained from healthy volunteers (n=26) and from two independent IPF cohorts (derivation cohort n=26, validation cohort n=66). Serum calprotectin levels were measured with a commercial kit adapted for that purpose and compared between healthy controls and patients with IPF. Clinical parameters, including forced vital capacity, diffusing capacity for carbon monoxide (DLCO) and the Composite Physiologic Index (CPI), were correlated with calprotectin serum levels.ResultsThe IPF derivation cohort showed increased serum calprotectin levels compared with healthy controls (2.47±1.67 vs 0.97±0.53 µg/mL, p<0.001). In addition, serum calprotectin levels correlated with DLCO% predicted (r=−0.53, p=0.007) and with CPI (r=0.66, p=0.007). These findings were confirmed in an independent IPF validation cohort.ConclusionSerum calprotectin levels are significantly increased in patients with IPF compared with healthy controls and correlate with DLCO and CPI. Calprotectin might be a potential new biomarker for disease severity in IPF.

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Serum Biomarkers in Differential Diagnosis of Idiopathic Pulmonary Fibrosis and Connective Tissue Disease-Associated Interstitial Lung Disease

Journal of Clinical Medicine ◽

10.3390/jcm10143167 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3167

Author(s):

Eva Cabrera Cesar ◽

Lidia Lopez-Lopez ◽

Estrella Lara ◽

M. Victoria Hidalgo-San Juan ◽

Concepcion Parrado Romero ◽

...

Keyword(s):

Differential Diagnosis ◽

Interstitial Lung Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Connective Tissue ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Connective Tissue Disease ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls

Introduction: The goal of this study is to determine whether Advanced glycosylated end-products (AGE), Advanced oxidation protein products (AOPP) and Matrix metalloproteinase 7 (MMP7) could be used as differential biomarkers for idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD). Method: Seventy-three patients were enrolled: 29 with IPF, 14 with CTD-ILD, and 30 healthy controls. The study included a single visit by participants. A blood sample was drawn and serum was analysed for AGE using spectrofluorimetry, AOPP by spectrophotometry, and MMP7 using sandwich-type enzyme-linked immunosorbent assay. Results: AGE, AOPP and MMP7 serum levels were significantly higher in both IPF and CTD-ILD patients versus healthy controls; and AGE was also significantly elevated in CTD-ILD compared to the IPF group. AGE plasma levels clearly distinguished CTD-ILD patients from healthy participants (AUC = 0.95; 95% IC 0.86–1), whereas in IPF patients, the distinction was moderate (AUC = 0.78; 95% IC 0.60–0.97). Conclusion: In summary, our results provide support for the potential value of serum AGE, AOPP and MMP7 concentrations as diagnostic biomarkers in IPF and CTD-ILD to differentiate between ILD patients and healthy controls. Furthermore, this study provides evidence, for the first time, for the possible use of AGE as a differential diagnostic biomarker to distinguish between IPF and CTD-ILD. The value of these biomarkers as additional tools in a multidisciplinary approach to IPF and CTD-ILD diagnosis needs to be considered and further explored. Multicentre studies are necessary to understand the role of AGE in differential diagnosis.

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