Serum Syndecan-4 as a Possible Biomarker in Patients With Acute Pneumonia

Nikaido, Takefumi; Tanino, Yoshinori; Wang, Xintao; Sato, Suguru; Misa, Kenichi; Fukuhara, Naoko; Sato, Yuki; Fukuhara, Atsuro; Uematsu, Manabu; Suzuki, Yasuhito; Kojima, Tetsuhito; Tanino, Mishie; Endo, Yuichi; Tsuchiya, Kazuo; Kawamura, Ikuo; Frevert, Charles W.; Munakata, Mitsuru

doi:10.1093/infdis/jiv234

Cited by 32 publications

(50 citation statements)

References 44 publications

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“…We did not observe higher mortality in syndecan-4 KO mice after LPS, as previously reported [25], however the reduced ventricular function was in line with an aggravated response. Similarly, in a model of acute pneumonia, syndecan-4 shedding was elevated in WT mice and syndecan-4 KO mice had increased mortality, suggesting a protective role for syndecan-4 shedding in acute bacterial pneumonia [26].…”

Section: Discussionmentioning

confidence: 90%

Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Strand

Aronsen

Braathen

et al. 2015

Journal of Molecular and Cellular Cardiology

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Inflammation is central to heart failure progression. Innate immune signaling increases expression of the transmembrane proteoglycan syndecan-4 in cardiac myocytes and fibroblasts, followed by shedding of its ectodomain. Circulating shed syndecan-4 is increased in heart failure patients, however the pathophysiological and molecular consequences associated with syndecan-4 shedding remain poorly understood. Here we used lipopolysaccharide (LPS) challenge to investigate the effects of syndecan-4 shedding in the heart. Wild-type mice (10mg/kg, 9h) and cultured neonatal rat cardiomyocytes and fibroblasts were subjected to LPS challenge. LPS increased cardiac syndecan-4 mRNA without altering full-length protein. Elevated levels of shedding fragments in the myocardium and blood from the heart confirmed syndecan-4 shedding in vivo. A parallel upregulation of ADAMTS1, ADAMTS4 and MMP9 mRNA suggested these shedding enzymes to be involved. Echocardiography revealed reduced ejection fraction, diastolic tissue velocity and prolonged QRS duration in mice unable to shed syndecan-4 (syndecan-4 KO) after LPS challenge. In line with syndecan-4 shedding promoting immune cell recruitment, expression of immune cell markers (CD8, CD11a, F4/80) and adhesion receptors (Icam1, Vcam1) were attenuated in syndecan-4 KO hearts after LPS. Cardiomyocytes and fibroblasts exposed to shed heparan sulfate-substituted syndecan-4 ectodomains showed increased Icam1, Vcam1, TNFα and IL-1β expression and NF-κB-activation, suggesting direct regulation of immune cell recruitment pathways. In cardiac fibroblasts, shed ectodomains regulated expression of extracellular matrix constituents associated with collagen synthesis, cross-linking and turnover. Higher syndecan-4 levels in the coronary sinus vs. the radial artery of open heart surgery patients suggested that syndecan-4 is shed from the human heart. Our data demonstrate that shedding of syndecan-4 ectodomains is part of the cardiac innate immune response, promoting immune cell recruitment, extracellular matrix remodeling and mitigating cardiac dysfunction in response to LPS.

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Section: Discussionmentioning

confidence: 90%

Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Strand

Aronsen

Braathen

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…Unsatisfactory results have also been obtained in testing of syndecan-4 (SYN4), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), midregional proatrial natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM) [29]. For the detection of bacterial CAP in adult patients, SYN4, a protein that mediates the activity of several inflammatory factors and rapidly increases in response to bacterial infection [33], has been reported to have an AUC of only 0.54 (95% CI 0.42–0.65), with a sensitivity of 31.1% and a specificity of 86.1%—values lower than those evidenced for CRP [34]. Very low AUC values for bacterial CAP identification have also been reported in adults for sTREM-1, a transmembrane glycoprotein expressed on neutrophils, macrophages, and monocytes, which amplifies the inflammatory response and is increased in tissue infected by bacteria and fungi [35], as well as MR-proANP and MR-proADM, which are peptides that have biological actions affecting the cardiovascular system [36].…”

Section: Differentiation Of Bacterial From Viral Capmentioning

confidence: 99%

Biomarkers in Pediatric Community-Acquired Pneumonia

Principi

Esposito

2017

IJMS

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Community-acquired pneumonia (CAP) is an infectious disease caused by bacteria, viruses, or a combination of these infectious agents. The severity of the clinical manifestations of CAP varies significantly. Consequently, both the differentiation of viral from bacterial CAP cases and the accurate assessment and prediction of disease severity are critical for effectively managing individuals with CAP. To solve questionable cases, several biomarkers indicating the etiology and severity of CAP have been studied. Unfortunately, only a few studies have examined the roles of these biomarkers in pediatric practice. The main aim of this paper is to detail current knowledge regarding the use of biomarkers to diagnose and treat CAP in children, analyzing the most recently published relevant studies. Despite several attempts, the etiologic diagnosis of pediatric CAP and the estimation of the potential outcome remain unsolved problems in most cases. Among traditional biomarkers, procalcitonin (PCT) appears to be the most effective for both selecting bacterial cases and evaluating the severity. However, a precise cut-off separating bacterial from viral and mild from severe cases has not been defined. The three-host protein assay based on C-reactive protein (CRP), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), plasma interferon-γ protein-10 (IP-10), and micro-array-based whole genome expression arrays might offer more advantages in comparison with former biomarkers. However, further studies are needed before the routine use of those presently in development can be recommended.

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“…Syndecan-4 levels were measured as described previously [19] with a commercially available ELISA kit (IBL, Takasaki, Japan) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…We also found higher serum syndecan-4 levels in hospitalized patients with bacterial pneumonia than in healthy subjects, and the syndecan-4 levels tended to increase over the course of pneumonia in those patients with a favorable prognosis [19]. Another effect of syndecan-4 may involve its interaction with the C-X-C motif chemokine ligand 10 (CXCL10), which shows an anti-fibrotic effect upon binding to syndecan-4 in a bleomycin-induced mouse model of pulmonary fibrosis [20].…”

Section: Introductionmentioning

confidence: 95%

Baseline serum syndecan-4 predicts prognosis after the onset of acute exacerbation of idiopathic interstitial pneumonia

et al. 2017

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BackgroundPatients with idiopathic interstitial pneumonia can experience acute respiratory worsening, also known as acute exacerbation, with a large deterioration on prognosis. The precise mechanism remains unclear; however, syndecan-4 may be involved. Syndecan-4, a transmembrane heparan sulfate proteoglycan expressed in a variety of cells (e.g., epithelial cells, macrophages, fibroblasts, etc.), performs various biological roles by binding to several proteins through its heparan sulfate glycosaminoglycan side chains. The goal of this study was to clarify the role of syndecan-4 in acute exacerbation of idiopathic interstitial pneumonia.MethodsPatients with idiopathic interstitial pneumonia who had been sequentially admitted to our hospital due to acute exacerbation were retrospectively analyzed. First, serum syndecan-4 levels in the acute exacerbation and clinically stable phases were compared. Second, the relationship between serum syndecan-4 levels and clinical parameters was analyzed. Third, the relationship between serum syndecan-4 levels and prognosis was evaluated.ResultsSerum syndecan-4 levels were significantly lower in patients with acute exacerbation of idiopathic interstitial pneumonia than in patients in the clinically stable phase. Serum syndecan-4 levels also showed a significant positive correlation with white blood cell count and a weak positive tendency with KL-6 and baseline %VC. Prognosis was significantly worse in patients with idiopathic interstitial pneumonia with high baseline serum syndecan-4 levels than with low baseline levels. Multiple logistic analysis indicated baseline serum syndecan-4 level as the only prognostic predictor following acute exacerbation.ConclusionsBaseline serum syndecan-4 is a possible prognostic biomarker after the onset of acute exacerbation of idiopathic interstitial pneumonia.

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Serum Syndecan-4 as a Possible Biomarker in Patients With Acute Pneumonia

Abstract: These results suggest that syndecan-4 has an anti-inflammatory function in acute pneumonia and could serve as a useful biomarker in these patients.

Cited by 32 publications

References 44 publications

Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice

Biomarkers in Pediatric Community-Acquired Pneumonia

Baseline serum syndecan-4 predicts prognosis after the onset of acute exacerbation of idiopathic interstitial pneumonia

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