Elevated plasma α-defensins in patients with acute exacerbation of fibrotic interstitial pneumonia

Sakamoto, Noriho; Ishimatsu, Yuji; Kakugawa, Tomoyuki; Yura, Hirokazu; Tomonaga, M; Harada, Tatsuhiko; Nakashima, Shota; Hara, Shintaro; Hara, Atsuko; Ishimoto, Hiroshi; Yatera, Kazuhiro; Mukae, Hiroshi; Kohno, Shigeru

doi:10.1016/j.rmed.2014.12.015

Cited by 13 publications

(13 citation statements)

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“…VEGF is expressed by epithelial cells as well as by M. tuberculosis -infected macrophages, and has been implicated in granuloma-associated angiogenesis ( Polena et al, 2016 ). Finally, elevated levels of alpha-defensin are associated with pulmonary fibrosis ( Mukae et al, 2002 , Sakamoto et al, 2015a , Sakamoto et al, 2015b ). Taken together, these data suggest that selected markers measured in serum reflect both the burden of microbial infection and the degree of lung injury.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

et al. 2017

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More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.

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Section: Discussionmentioning

confidence: 99%

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

et al. 2017

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“…We also demonstrated that lot of genes are downregulated in the lung tissue of Japanese IIP patients (Table 3 ). Among them, DEFA 1 and 3 are strongly downregulated; these genes are known to belong to human neutrophil peptides (HNPs) and the serum levels of HNPs have been reported to be elevated in patients with interstitial pneumonia associated with systemic sclerosis [ 40 ] and also in those with acute exacerbation of IIPs [ 41 ]. Our results would support the hypothesis that HNPs play important roles in the pathogenesis of IIPs.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of idiopathic interstitial pneumonias (IIPs): identification of potential diagnostic markers and therapeutic targets

et al. 2017

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BackgroundChronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets.MethodsRNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed.ResultsNinety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung.ConclusionWe identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.

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“…Furthermore, α-defensins were increased in the peripheral blood of patients with AE-IPF, suggesting a potential role as biomarker ( 47 ). In a later study including patients with idiopathic interstitial pneumonia (IIP), elevated plasma levels of α-defensins in AE-IIP compared to stable IIP were also seen, but they were not useful as biomarkers due to a lack of specificity ( 51 ). Therefore, further studies are needed to clarify the role of α-defensins as biomarker.…”

Section: Pathogenesis and Etiologymentioning

confidence: 99%

Acute Exacerbation in Interstitial Lung Disease

2017

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Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has been defined as an acute, clinically significant deterioration that develops within less than 1 month without obvious clinical cause like fluid overload, left heart failure, or pulmonary embolism. Pathophysiologically, damage of the alveoli is the predominant feature of AE-IPF which manifests histopathologically as diffuse alveolar damage and radiologically as diffuse, bilateral ground-glass opacification on high-resolution computed tomography. A growing body of literature now focuses on acute exacerbations of interstitial lung disease (AE-ILD) other than idiopathic pulmonary fibrosis. Based on a shared pathophysiology it is generally accepted that AE-ILD can affect all patients with interstitial lung disease (ILD) but apparently occurs more frequently in patients with an underlying usual interstitial pneumonia pattern. The etiology of AE-ILD is not fully understood, but there are distinct risk factors and triggers like infection, mechanical stress, and microaspiration. In general, AE-ILD has a poor prognosis and is associated with a high mortality within 6–12 months. Although there is a lack of evidence based data, in clinical practice, AE-ILD is often treated with a high dose corticosteroid therapy and antibiotics. This article aims to provide a summary of the clinical features, diagnosis, management, and prognosis of AE-ILD as well as an update on the current developments in the field.

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Elevated plasma α-defensins in patients with acute exacerbation of fibrotic interstitial pneumonia

Abstract: Elevated plasma levels of HNPs were higher in AE-IP than in S-IP, but not specific enough to serve as candidate biomarkers of AE-IP. Further studies are needed to clarify the role of defensins in the pathogenesis of AE-IP.

Cited by 13 publications

References 32 publications

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

Gene expression profiling of idiopathic interstitial pneumonias (IIPs): identification of potential diagnostic markers and therapeutic targets

Acute Exacerbation in Interstitial Lung Disease

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