Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interstitial Lung Disease in Rheumatoid Arthritis

Liu, Liang; Chen, Jiali; Di, Chun; Zhan, Minghua; Bao, Huizhang; Xia, Changsheng; Fan, Chunhong; Liu, Yudong

doi:10.3389/fmed.2021.755268

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…It was reported that HE4 could be used as possible biomarker signifying the extent of disease progress [ 25 , 26 ]. Therefore, we measured the HE4 level in the peripheral blood plasma via ELISA, and found the highest HE4 content in COPD patients, followed by the smokers and non-smokers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease

Zhan

Chen

et al. 2022

Respir Res

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Background Chronic 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. Methods HE4 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). Results HE4 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 H2O2-induced HBE mitigated HE4 expression. Conclusions Our 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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Section: Resultsmentioning

confidence: 99%

Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease

Zhan

Chen

et al. 2022

Respir Res

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“…HE4 is a widely used and high-value biomarker for diverse neoplastic diseases, and recent reports indicate that elevated HE4 levels occur in a variety of autoimmune diseases, including SLE, 11 RA 13 and pSS. 12 Available evidence also indicates that it is closely related to concurrent interstitial lung disease and renal involvement.…”

Section: Discussionmentioning

confidence: 99%

“…Given the increasing risk of cancer in patients with autoimmune diseases,10 neoplastic biomarkers, including HE4, are now being used to estimate cancer risk. Congruently, HE4 was found to be elevated in some autoimmune diseases, including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA), and notably, this increase was greater in patients with SLE with lupus nephritis11 patients with pSS and patients with RA with interstitial lung disease 12 13. HE4 has also been recently recognised as a biomarker for fibrotic disease and is reportedly involved in the aetiopathology of fibrotic diseases because fibroblast-derived HE4 has protease inhibitor activity that can promote the aggregation of collagen and cause fibrosis 14 15.…”

Section: Introductionmentioning

confidence: 99%

Human epididymis protein 4 (HE4) is a novel biomarker for fibrosis in IgG4-related disease and can predict poor prognosis

Yan

Peng

et al. 2022

RMD Open

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ObjectivesIgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder with heterogeneous manifestations. This study aimed to investigate the utility of human epididymis protein 4 (HE4) as a potential clinical biomarker of fibrosis in IgG4-RD.MethodsPlasma HE4 levels were estimated in 136 patients with IgG4-RD and 73 healthy individuals (controls) by electrochemical luminescence. HE4 expression levels and the degree of fibrosis in pancreatic tissues from 15 patients with IgG4-RD and 10 controls were compared using immunohistochemistry and Masson trichrome staining. Correlation between HE4 levels and laboratory parameters was determined, and the efficacy of HE4 as a biomarker of fibrosis and prognosis in IgG4-RD was also evaluated.ResultsPlasma HE4 levels were significantly higher in patients with IgG4-RD compared with controls. Optimal HE4 cut-off value for identifying patients with IgG4-RD was determined to be 50.8 pmol/L with an AUC (area under curve) of 0.791. HE4 levels were positively correlated with diverse laboratory parameters, and indicators of organ function impairment. Additionally, HE4 was highly expressed in the affected organs in patients with IgG4-RD and its plasma levels were closely correlated with degree of fibrosis, indicating the utility of HE4 in assessing internal organ damage and fibrosis. Further analysis showed that patients in the HE4 high expression group had poor prognosis.ConclusionsOur results demonstrate that HE4 can be used as a biomarker for IgG4-RD as it is correlated with diverse baseline clinical features, internal organ damage and degree of fibrosis in affected organs, and can predict poor prognosis.

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“…Changes in KL-6 values over time may predict acute exacerbations of RA-ILD ( 99 ) to make routine tests a putative screening method for ILD in patients with RA ( 100 ). In combination with KL-6, the oncological markers CA 19-9, CA 125, and CEA correlate with the presence and severity of ILD in patients with RA ( 124 ) while serum HE4, a biomarker for ovarian cancer, may identify RA cases at risk for subclinical ILD ( 125 ). It was demonstrated that serum onco-marker CA 15–3 is a valid alternative to KL-6, with comparable sensitivity and specificity in differentiating fibrosing and non-fibrosing ILD ( 126 ).…”

Section: Traditional and Novel Biomarkers In Ra-ildmentioning

confidence: 99%

Unmet needs and perspectives in rheumatoid arthritis-associated interstitial lung disease: A critical review

et al. 2023

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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis as the most common clinical manifestation, and interstitial lung disease (RA-ILD) represents one of the most common and potentially severe extra-articular features. Our current understanding of the mechanisms and predictors of RA-ILD is limited despite the demonstration that an early identification of progressive fibrosing forms is crucial to provide timely treatment with antifibrotic therapies. While high resolution computed tomography is the gold standard technique for the diagnosis and follow-up of RA-ILD, it has been hypothesized that serum biomarkers (including novel and rare autoantibodies), new imaging techniques such as ultrasound of the lung, or the application of innovative radiologic algorithms may help towards predicting and detecting early forms of diseases. Further, while new treatments are becoming available for idiopathic and connective tissue disease-associated forms of lung fibrosis, the treatment of RA-ILD remains anecdotal and largely unexplored. We are convinced that a better understanding of the mechanisms connecting RA with ILD in a subgroup of patients as well as the creation of adequate diagnostic pathways will be mandatory steps for a more effective management of this clinically challenging entity.

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Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interstitial Lung Disease in Rheumatoid Arthritis

Cited by 5 publications

References 22 publications

Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease

Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease

Human epididymis protein 4 (HE4) is a novel biomarker for fibrosis in IgG4-related disease and can predict poor prognosis

Unmet needs and perspectives in rheumatoid arthritis-associated interstitial lung disease: A critical review

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