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

BACKGROUND: Increased expression of the human epididymis protein 4 (HE4) was previouslydescribed 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 patientswith CF from a Czech center were enrolled. In addition, 94 individuals with non-CF lung diseasesand 117 normal control subjects with no pulmonary disorders were analyzed. Serum HE4 levelswere measured by using an immunoassay, and their expression was further investigated via thequantification of HE4messengerRNAby using quantitative reverse transcription polymerase chainreaction in CF vs non-CF respiratory epithelium biopsy specimens. The expression of the potentialregulator miR-140-5p was analyzed by using an UPL-based quantitative reverse transcription polymerasechain reaction assay. HE4 was measured in the supernatants from unpolarized andpolarized 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). Thisobservation 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 positivelycorrelated with overall disease severity and C-reactive protein concentrations, whereas a significantinverse relationship was found between HE4 and the spirometric FEV1 value. RelativeHE4 mRNA levels were significantly upregulated (P ¼ .011) with a decreased miR-140-5pexpression (P ¼ .020) in the CF vs non-CF airway biopsy specimens. Twofold higher HE4concentrations were recorded in the supernatant of polarized F508del-CF transmembraneconductance regulator/bronchial epithelial cells compared with wild-type cells.CONCLUSIONS: HE4 serum levels positively correlate with the overall severity of CF and thedegree of pulmonary dysfunction. HE4 may thus be used as a novel inflammatory biomarkerand possibly also as a measure of treatment efficacy in CF lung disease