Associations of Serological Biomarkers of sICAM-1, IL-1β, MIF, and su-PAR with 3-Month Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Objective. To investigate prognostic values of serum biomarkers of soluble intercellular adhesion molecule 1 (sICAM-1), macrophage migration inhibitor factor (MIF), interleukin 1β (IL-1β), and soluble urokinase plasminogen activator receptor (su-PAR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods. From August 2017 to November 2019, 122 consecutive IPF patients treated in our center were classified as stable IPF and AE-IPF based on the newly published international guidelines. Serum levels of four biomarkers at admission were measured by the enzyme-linked immunosorbent assay (ELISA). The primary endpoint was 3-month mortality. The log-rank test and logistic regression analysis were used to evaluate the effects of these biomarkers for survival in patients with AE-IPF. Cox proportional hazards analysis was performed to evaluate the prognostic values of serological biomarkers and clinical data. Results. Eighty-one patients were diagnosed with stable IPF, and 41 AE-IPF patients were enrolled in the study. Serum levels of sICAM-1 (p<0.001), IL-1β (p<0.001), MIF (p<0.001), and su-PAR (p<0.001) in patients with IPF were significantly increased compared to those in healthy controls. All the four biomarkers were elevated in patients with AE-IPF compared to those with stable IPF. The 3-month mortality in AE-IPF was 56.1% (23/41). Increased levels of MIF (p=0.01) and IL-1β (>5 pg/mL, p=0.033) were independent risk factors for 3-month mortality in patients with AE-IPF. Conclusions. We showed the higher serum levels of IL-1β, and MIF had prognostic values for 3-month mortality in AE-IPF. This study provided a clue to promote our understanding in the pathogenesis of the disease.

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The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis

BMC Pulmonary Medicine ◽

10.1186/s12890-019-1032-2 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Tetsuya Hanaka ◽

Takashi Kido ◽

Shingo Noguchi ◽

Sohsuke Yamada ◽

Hirotsugu Noguchi ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Healthy Volunteers ◽

Area Under The Curve ◽

Serum Levels ◽

Lung Epithelial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Surfactant Protein D ◽

Intratracheal Administration ◽

Inflammatory Changes

Abstract Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear. Methods Serum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration. Results Serum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice. Conclusions PRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

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Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

Journal of Clinical Medicine ◽

10.3390/jcm9061993 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1993

Author(s):

Canay Caliskan ◽

Benjamin Seeliger ◽

Benedikt Jäger ◽

Jan Fuge ◽

Tobias Welte ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Progressive Disease ◽

Progression Free Survival ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Free Survival ◽

Antifibrotic Therapy ◽

Level Measurement ◽

Chemokine Ligand

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts.

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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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Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis

European Respiratory Journal ◽

10.1183/13993003.01339-2016 ◽

2017 ◽

Vol 49 (5) ◽

pp. 1601339 ◽

Cited By ~ 62

Author(s):

Harold R. Collard ◽

Luca Richeldi ◽

Dong Soon Kim ◽

Hiroyuki Taniguchi ◽

Inga Tschoepe ◽

...

Keyword(s):

Risk Factors ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Acute Exacerbation ◽

Supplemental Oxygen ◽

Rank Test ◽

Risk Of Mortality ◽

Acute Exacerbations ◽

The Impact ◽

Similar Risk

Time to first investigator-reported acute exacerbation was a key secondary end-point in the INPULSIS trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF).We used the INPULSIS trial data to investigate risk factors for acute exacerbation of IPF and to explore the impact of nintedanib on risk and outcome of investigator-reported and adjudicated confirmed/suspected acute exacerbations. Mortality following these events and events adjudicated as not acute exacerbations was analysed using the log rank test.Risk of acute exacerbations was most strongly associated with the following variables: baseline forced vital capacity (higher risk with lower value), baseline supplemental oxygen (higher risk with use), baseline antacid medication (higher risk with use), treatment (higher risk with placebo), and for confirmed/suspected acute exacerbations, cigarette smoking. Mortality was similar following investigator-reported and adjudicated confirmed/suspected acute exacerbations. Nintedanib had no significant effect on risk of mortality post-exacerbation.Investigator-reported acute exacerbations of IPF are associated with similar risk factors and outcomes as adjudicated confirmed/suspected acute exacerbations.

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