Béla Nagy2, Béla Nagy2, Libor Fila3, Luka A Clarke4, Ferenc Gönczy5, Olga Bede6, Dóra Nagy6, Rita Újhelyi7, Ágnes Szabó6, Andrea Anghelyi8, Miklós Major9, Zsolt Bene2, Zsolt Fejes10, Péter Antal-Szalmás10, Harjit Pal Bhattoa10, György Balla2, János Kappelmayer10, Margarida D Amaral4, Milan Macek11, István Balogh12. 1. Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. Electronic address: nagyb80@gmail.com. 2. Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 3. Department of Pulmonology, Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic. 4. University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Lisboa, Portugal. 5. Kenézy Gyula County Hospital, Debrecen, Hungary. 6. Department of Pediatrics, Szent-Györgyi Albert Medical University, Szeged, Hungary. 7. Heim Pál Children's Hospital, Budapest, Hungary. 8. Petz Aladár County Hospital, Győr, Hungary. 9. Markusovszky Lajos County Hospital, Szombathely, Hungary. 10. Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 11. Department of Biology and Medical Genetics, Motol University Hospital, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. 12. Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Division of Clinical Genetics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Abstract
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.
BACKGROUND: Increased expression of the humanepididymis 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.
Authors: Zsolt Bene; Zsolt Fejes; Tibor Gabor Szanto; Ferenc Fenyvesi; Judit Váradi; Luka A Clarke; Gyorgy Panyi; Milan Macek; Margarida D Amaral; István Balogh; Béla Nagy Journal: Front Pharmacol Date: 2021-05-14 Impact factor: 5.810