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.

[1]  Brandon D Gallas,et al.  Comparing two correlated C indices with right‐censored survival outcome: a one‐shot nonparametric approach , 2015, Statistics in medicine.

[2]  N. Kohno,et al.  Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. , 2014, Respiratory medicine.

[3]  F. Bonella,et al.  CCL18 in serum, BAL fluid and alveolar macrophage culture supernatant in interstitial lung diseases. , 2013, Respiratory medicine.

[4]  T. Colby,et al.  Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. , 2013, Chest.

[5]  N. Kaminski,et al.  Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. , 2012, American journal of respiratory and critical care medicine.

[6]  T. Shiomi,et al.  Production and activation of matrix metalloproteinase 7 (matrilysin 1) in the lungs of patients with idiopathic pulmonary fibrosis. , 2010, Archives of pathology & laboratory medicine.

[7]  G. Raghu,et al.  Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. , 2010, American journal of respiratory and critical care medicine.

[8]  M. Olschewski,et al.  Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. , 2009, American journal of respiratory and critical care medicine.

[9]  L. Fabbri,et al.  Mycobacterium tuberculosis Induces CCL18 Expression in Human Macrophages , 2008, Scandinavian journal of immunology.

[10]  N. Kaminski,et al.  Approaching the degradome in idiopathic pulmonary fibrosis. , 2008, The international journal of biochemistry & cell biology.

[11]  Naftali Kaminski,et al.  MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis , 2008, PLoS medicine.

[12]  N. Todd,et al.  Complex regulation of pulmonary inflammation and fibrosis by CCL18. , 2007, The American journal of pathology.

[13]  E. Kita,et al.  Roxithromycin Favorably Modifies the Initial Phase of Resistance against Infection with Macrolide-Resistant Streptococcus pneumoniae in a Murine Pneumonia Model , 2007, Antimicrobial Agents and Chemotherapy.

[14]  H. Satoh,et al.  Increased levels of KL‐6 and subsequent mortality in patients with interstitial lung diseases , 2006, Journal of internal medicine.

[15]  M. Nishimura,et al.  Prognostic value of circulating KL‐6 in idiopathic pulmonary fibrosis , 2006, Respirology.

[16]  S. Abe,et al.  Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D , 2006, Respirology.

[17]  N. Kohno,et al.  KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. , 2005, Biochemical and biophysical research communications.

[18]  J. Hankinson,et al.  General considerations for lung function testing , 2005, European Respiratory Journal.

[19]  S. Jimenez,et al.  Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts. , 2003, American journal of respiratory cell and molecular biology.

[20]  H. Mukae,et al.  High serum concentrations of surfactant protein A in usual interstitial pneumonia compared with non-specific interstitial pneumonia , 2003, Thorax.

[21]  Naftali Kaminski,et al.  Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  N. Kohno,et al.  Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. , 2002, American journal of respiratory and critical care medicine.

[23]  G. Opdenakker,et al.  Selective induction of CCL18/PARC by staphylococcal enterotoxins in mononuclear cells and enhanced levels in septic and rheumatoid arthritis , 2001, European journal of immunology.

[24]  J. Tooze,et al.  Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. , 2001, American journal of respiratory and critical care medicine.

[25]  G. Riet,et al.  Systematic reviews of evaluations of diagnostic and screening tests , 2001, BMJ : British Medical Journal.

[26]  J. Deeks.  Systematic reviews of evaluations of diagnostic and screening tests , 2001, BMJ : British Medical Journal.

[27]  Y. Kuroki,et al.  Surfactant proteins A and D: disease markers. , 1998, Biochimica et biophysica acta.

[28]  Eric R. Ziegel,et al.  A Handbook of Statistical Analysis Using R , 1997, Technometrics.

[29]  N. Kohno,et al.  KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. , 1997, American journal of respiratory cell and molecular biology.

[30]  D. Schwartz,et al.  Determinants of survival in idiopathic pulmonary fibrosis. , 1994, American journal of respiratory and critical care medicine.

[31]  N. Kohno,et al.  KL-6, a mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial lung disease. , 1993, The American review of respiratory disease.

[32]  N. Kohno,et al.  New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. , 1989, Chest.

[33]  Takeshi Johkoh,et al.  American Thoracic Society Documents An Official ATS / ERS / JRS / ALAT Statement : Idiopathic Pulmonary Fibrosis : Evidence-based Guidelines for Diagnosis and Management , 2011 .

[34]  F. Sciurba,et al.  MMP 1 and MMP 7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis , 2008 .