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Original Research: Genetic and Developmental Disorders |

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

Béla Nagy, Jr., MD, PhD; Béla Nagy, MD, PhD; Libor Fila, MD; Luka A. Clarke, PhD; Ferenc Gönczy, MD; Olga Bede, MD, PhD; Dóra Nagy, MD; Rita Újhelyi, MD, PhD; Ágnes Szabó, MD; Andrea Anghelyi, MD; Miklós Major, MD; Zsolt Bene, MD; Zsolt Fejes, MSc; Péter Antal-Szalmás, MD, PhD; Harjit Pal Bhattoa, MD, PhD; György Balla, MD, PhD; János Kappelmayer, MD, PhD; Margarida D. Amaral, PhD; Milan Macek, Jr., MD, PhD; István Balogh, PhD
Author and Funding Information

FUNDING/SUPPORT: This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-11/1-2012-0001 National Excellence Program and the TÁMOP-4.2.2.A-11/1/KONV-2012-0045 project. It was also supported by the Hungarian Research Fund (K109076 to I. B.) and the Czech Ministry of Health Conceptual Development of Research Organization (00064203), European Regional Development Fund Prague (CZ.2.16/3.1.00/24022OPPK), LM2015091, 15-30880A, Norway Grants (NF-CZ11-PDP-3-003-2014) and COST-LD14073 to M. Macek Jr. The LAC/MDA laboratory was supported by UID/MULTI/04046/2013 center grant (to BioISI) and a research grant (to M. D. A.), FCT/MCTES (PTDC/BIM-MEC/2131/2014), Portugal.

CFBE 41o– was a gift from Dr J. P. Clancy, Department of Pediatrics, Cincinnati Children’s Hospital.

aDepartment of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

bDivision of Clinical Genetics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

cInstitute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

dDepartment of Pulmonology, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic

eUniversity of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Lisboa, Portugal

fKenézy Gyula County Hospital, Debrecen, Hungary

gDepartment of Pediatrics, Szent-Györgyi Albert Medical University, Szeged, Hungary

hHeim Pál Children’s Hospital, Budapest, Hungary

iPetz Aladár County Hospital, Győr, Hungary

jMarkusovszky Lajos County Hospital, Szombathely, Hungary

kDepartment of Biology and Medical Genetics, Motol University Hospital, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

CORRESPONDENCE TO: Béla Nagy Jr, MD, PhD, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., H-4032 Debrecen, Hungary


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(3):661-672. doi:10.1016/j.chest.2016.04.006
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Background  Increased expression of the human epididymis protein 4 (HE4) was previously described in lung biopsy samples from patients with cystic fibrosis (CF). It remains unknown, however, whether serum HE4 concentrations are elevated in CF.

Methods  Seventy-seven children with CF from six Hungarian CF centers and 57 adult patients with CF from a Czech center were enrolled. In addition, 94 individuals with non-CF lung diseases and 117 normal control subjects with no pulmonary disorders were analyzed. Serum HE4 levels were measured by using an immunoassay, and their expression was further investigated via the quantification of HE4 messenger RNA by using quantitative reverse transcription polymerase chain reaction in CF vs non-CF respiratory epithelium biopsy specimens. The expression of the potential regulator miR-140-5p was analyzed by using an UPL-based quantitative reverse transcription polymerase chain reaction assay. HE4 was measured in the supernatants from unpolarized and polarized cystic fibrosis bronchial epithelial cells expressing wild-type or F508del-CFTR.

Results  Median serum HE4 levels were significantly elevated in children with CF (99.5 [73.1-128.9] pmol/L) compared with control subjects (36.3 [31.1-43.4] pmol/L; P < .0001). This observation was replicated in adults with CF (115.7 [77.8-148.7] pmol/L; P < .0001). In contrast, abnormal but lower HE4 concentrations were found in cases of severe bronchitis, asthma, pneumonia, and bronchiectasis. In patients with CF, the concentrations of HE4 were positively correlated with overall disease severity and C-reactive protein concentrations, whereas a significant inverse relationship was found between HE4 and the spirometric FEV1 value. Relative HE4 mRNA levels were significantly upregulated (P = .011) with a decreased miR-140-5p expression (P = .020) in the CF vs non-CF airway biopsy specimens. Twofold higher HE4 concentrations were recorded in the supernatant of polarized F508del-CF transmembrane conductance regulator/bronchial epithelial cells compared with wild-type cells.

Conclusions  HE4 serum levels positively correlate with the overall severity of CF and the degree of pulmonary dysfunction. HE4 may thus be used as a novel inflammatory biomarker and possibly also as a measure of treatment efficacy in CF lung disease.

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