Human Epididymis Protein 4 (HE4): more than a marker for lung injury?

Background: Human Epididymis Protein 4 (HE4), a biomarker in ovarian cancer, is increased in pulmonary fibrosis. Hypoxia, a typical feature of interstitial lung disease (ILD), induces HE4. The anti-diabetic drug dapagliflozin might counteract the effects of HE4.

Aims: Assess fibrogenic and inflammatory effects of HE4 from hypoxia-stimulated epithelial cells on pulmonary fibroblasts and determine the potential role of dapagliflozin in inhibiting HE4 action.

Methods: Bronchial epithelial cells (16HBE14o-, HBE) were exposed to hypoxia (6h 1%O2) in the presence/absence of HE4 siRNA (siHE4) or dapagliflozin (0-10µM) and the conditioned medium (CM) collected. Pulmonary fibroblasts (CCD11-Lu) were exposed to recombinant huHE4 (rHE4) or CM (10%). HE4, IL-8/6 and collagen were assessed by ELISA and Sirius Red staining, respectively.

Results: A systematic review with meta-analysis of 22 studies (n = 2049) showed significantly increased HE4 gene expression in ILDs compared to non-fibrotic lung diseases (SMD 0.79 (0.57,1.00), p<0.00001). rHE4 and hypoxia CM induced collagen deposition and cytokine secretion from fibroblasts. HBE siHE4-CM did not show differences in IL8/6, but increased collagen deposition from CM-exposed fibroblasts. Dapagliflozin dose-dependently reduced hypoxia-induced HE4 and IL-8 release from HBE and the collagen deposition and IL-8 release from fibroblasts.

Conclusions: HE4 is upregulated in ILDs and has an important role in regulating fibrosis and inflammation. Compared to siRNA, reducing HE4 by dapagliflozin has additional anti-inflammatory effects that may contribute to its antifibrotic effect in our model of lung fibrosis. Future studies need to determine the suitability of HE4 as a therapeutic target.