ArticleRespiratory research2022
Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease.
Article in Respiratory research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 30 citations in OpenAlex.
- Plasma proteomic biomarkers as mediators for the associations between frailty phenotypes and chronic respiratory diseases.GeroScience · 2026Article
- Serum human epididymis protein 4 and long-term mortality in U.S. women: a nationally representative cohort study.Clinics (Sao Paulo, Brazil) · 2026Article
- Spatial transcriptomics reveals compartment-specific cytotoxic T cell crosstalk with AT2 and goblet cells in advanced COPD.Biomarker research · 2026Article
- Serum Human epididymal protein 4 as a predictor of adverse events in acute ischemic stroke patients receiving antiplatelet therapy.BMC cardiovascular disorders · 2026Article
- Plasma level of human epididymis protein 4 is associated with risk of future venous thromboembolism-the Trøndelag Health study.Journal of thrombosis and haemostasis : JTH · 2026Article
- Article
- Macrophage membrane-biomimetic bimetallic manganese-platinum nanozymes ameliorate intrapulmonary oxidative stress and inflammation in experimental COPD.Journal of nanobiotechnology · 2026Article
- Proteomic Profiling of Pulmonary Function and Cardiovascular Disease Risk in the Atherosclerosis Risk in Communities Study.Journal of the American Heart Association · 2026Observational
- Plasma Level of Human Epididymis Protein 4 and Risk of Recurrence after First Venous Thromboembolism: The HUNT Study.TH open : companion journal to thrombosis and haemostasis · 2026Article
- Polydopamine-polyethylene glycol-liproxstatin-1 nanoparticles inhibit ferroptosis for enhanced treatment of neutrophilic asthma.Frontiers in pharmacology · 2026Article
- Pre-diagnostic plasma proteomics profile uncovers new biomarkers and mechanistic insights for incident kidney cancer.International journal of surgery (London, England) · 2026Article
- Article
- Inflammatory Markers and Microbiome Dysbiosis in Hematopoietic Cell Transplant Recipients with Lung Graft-versus-Host Disease.Transplantation and cellular therapy · 2025Article
- Exploratory Study of Prognostic Plasma Biomarkers in Patients with Pulmonary Arterial Hypertension.The American journal of pathology · 2025Article
- Article
- Identification and validation of USP15 and CUL2 as ubiquitination related biomarker in chronic obstructive pulmonary disease.Hereditas · 2025Article
- DNA hypomethylation-mediated upregulation of GADD45B facilitates airway inflammation and epithelial cell senescence in COPD.Journal of advanced research · 2025Article
- Human epididymis protein 4-annexin II binding promotes aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis.Communications biology · 2025Article
- Overexpression of HE4/WFDC2 gene in mice leads to keratitis and corneal opacity.Open life sciences · 2025Article
- HE4 Might Participate in Extracellular Matrix Remodeling in Ovarian Cancer via Activation of Fibroblasts.Oncology research · 2025Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundChronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.
methodsHE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2'-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).
resultsHE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NFκB-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and α-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H
conclusionsOur study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NFκB-p65, and sHE4 promotes fibroblastic differentiation and proliferation.
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