Peripheral Blood Proteins Predict Mortality in Idiopathic Pulmonary Fibrosis

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. Objectives: The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. Methods: Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex beadbased immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. Measurements and Main Results: High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. Conclusions: Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression

“…Future studies should also consider whether sLOXL2, along with other promising prognostic IPF biomarkers (e.g. matrix metalloproteinase (MMP)1, MMP7, KL-6, periostin, surfactant protein-A and D, CC chemokine ligand 18, vascular endothelial growth factor and YKL-40) [19][20][21][22][23][24][25][26][27][28][29], as well as prognostic scores [30,31] and radiological modalities [32], might have prognostic value for helping physicians and patients anticipate the patient's IPF disease progression. This might include evaluation of serially collected sLOXL2 levels and their relationship to IPF acute exacerbations, which represent a terminal event for many IPF patients [33].…”

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

“…Effects of age and gender on serum CCL2 and CXCL8 concentrations were not significant. In humans, both CXCL8 and CCL2 concentrations were found to be increased in blood (Ziegenhagen et al, 1998a;Suga et al, 1999;Fujiwara et al, 2012) and bronchoalveolar lavage fluid (BALF) (Capelli et al, 2005;Antoniou et al, 2006;Baran et al, 2007) of IPF patients compared with healthy volunteers and correlated with lung function (Capelli et al, 2005;Emad and Emad, 2007;Martina et al, 2009;Vasakova et al, 2009), disease progression (Ziegenhagen et al, 1998b;Totani et al, 2002), and outcome (Shinoda et al, 2009;Richards et al, 2012). Furthermore, several studies suggested an involvement of the chemokine CCL2 in the pathogenesis of IPF, notably through its action on resident pulmonary fibroblast and circulating fibrocytes, promoting the generation of abundant extracellular matrix in the lungs (Gharaee-Kermani et al, 1996;Phillips et al, 2004;Moore et al, 2005;Inomata et al, 2014).…”

Staging of idiopathic pulmonary fibrosis: past, present and future

“…Aggressive development of molecular and other biological biomarkers is just beginning, and additional work in this area is greatly needed. Markers being investigated include serum markers, such as KL-6, surfactant protein (SP)-A/D, CCL18, brain natriuretic peptide and matrix metalloproteinase-7, and markers from bronchoalveolar lavage, such as SP-A and neutrophilia [25,26].…”