<i>IL4Rα</i> and <i>ADAM33</i> as genetic markers in asthma exacerbations and type‐2 inflammatory endotype

Sunadome, Hironobu; Matsumoto, Hisako; Petrova, Guergana; Kanemitsu, Yoshihiro; Tohda, Yuji; Horiguchi, T.; Kita, Hideo; Kuwabara, Kazunobu; Tomii, Keisuke; Otsuka, Kojiro; Fujimura, Masaki; Ohkura, Noriyuki; Tomita, Katsuyuki; Yokoyama, Akihito; Ohnishi, Hiroshi; Nakano, Yasutaka; Oguma, Tsuyoshi; Hozawa, Soichiro; Nagasaki, Tadao; Ito, Isao; Inoue, Hideki; Tajiri, Tomoko; Iwata, Toshiyuki; Izuhara, Yumi; Ono, Jyunya; Hirota, Tomomitsu; Tamari, Mayumi; Yokoyama, Tetsuji; Izuhara, Kenji; Mishima, Michiaki

doi:10.1111/cea.12927

Cited by 19 publications

(19 citation statements)

References 47 publications

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“…Periostin is secreted as a 93.3-kDa extracellular matrix protein [11]. Consistent with previous studies on patients with asthma and the general population [12][13][14][15][16], the present study showed that the serum periostin level was negatively associated with BMI, albeit marginally. This precluded us from using serum periostin as a simple marker to predict severe OSA.…”

Section: Discussionsupporting

confidence: 91%

“…Serum periostin, which is an extracellular matrix protein, is a robust marker of T helper type 2 (Th2) inflammation, particularly in asthma [10][11][12]. Interestingly, several recent studies on asthma and the general population have revealed that serum periostin was negatively associated with body mass index (BMI) [12][13][14][15][16] and serum leptin [15]. In addition to Th2 inflammation, periostin has been shown by in vitro studies to be upregulated under several stimulations, including mechanical stress [17] and hypoxic stimulation [18], which are major features of OSA [19].…”

Section: Introductionmentioning

confidence: 99%

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Role of serum periostin in severe obstructive sleep apnea with albuminuria: an observational study

et al. 2020

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Background: Periostin is a matricellular protein and is a useful marker in respiratory diseases. However, the roles of periostin in patients with obstructive sleep apnea (OSA) remain unclear. Several in vitro studies have suggested that mechanical stress, hypoxia, impaired metabolism, and kidney injury, which often accompany OSA, may upregulate the expression of periostin. Meanwhile, serum periostin level has been negatively associated with body mass index (BMI) in the general population. In this study, we hypothesized that a high level of serum periostin despite being overweight/ obese may discriminate severe OSA or OSA with comorbidities from mild OSA with obesity alone. We aimed to clarify the roles of periostin in patients with OSA to assist in elucidating the heterogeneity of OSA with comorbidities. Methods: Among patients diagnosed as OSA, we examined the associations between serum periostin levels and clinical indices, including the severity of OSA, BMI, and comorbidities, using a multifaceted approach. The serum periostin levels and clinical indices were assessed after 3 months of continuous positive airway pressure (CPAP) treatment. Results: In 96 patients with OSA, serum periostin level was negatively correlated with BMI, albeit marginally, and tended to be higher in severe OSA than in others when adjusted for BMI. Cluster analysis identified four clusters, including two severe OSA clusters, one of which was characterized by high serum periostin levels and the presence of comorbidities, including albuminuria. In a comparative analysis of severe OSA cases (n = 53), the level of serum-free fatty acids and the frequency of albuminuria were higher in patients with high serum periostin level of ≥87 ng/mL, which was the highest quintile among all participants, than in those with low serum periostin levels (< 87 ng/mL, n = 41). In patients with severe OSA and high serum periostin levels, the levels of serum periostin and urinary albumin significantly decreased after 3 months of CPAP treatment. Conclusions: Elevated serum periostin in patients with OSA despite being overweight/obese may be an indicator of severe OSA with comorbidities, particularly albuminuria.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Role of serum periostin in severe obstructive sleep apnea with albuminuria: an observational study

et al. 2020

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“…As the miR‐146a level was reduced in the airway epithelial cells from patients with asthma, we next analyzed mRNA expression of miR‐146a indirect (CXCL1 and IL‐8) [26, 28 ] and direct (IRAK1) [27 ] target genes in the same samples. In addition, to evaluate the relevance of our findings, we assessed the expression of genes previously associated with Th2 type immune responses, including IL‐33 [32 ] and IL‐4 receptor (IL‐4R) [33 ], and the interferon‐response genes associated with Th1 type immune responses, such as interferon regulatory factor 1 (IRF1) and IFITM1. Among these genes, only the expression of IL‐33 was detected to be increased when all asthma patient samples were included to analysis (Additional file 1 : Figure S1D).…”

Section: Resultsmentioning

confidence: 99%

Reduced expression of miR-146a in human bronchial epithelial cells alters neutrophil migration

Kivihall

Aab

Soja

et al. 2019

Clin Transl Allergy

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BackgroundThe role of miRNAs in the pathogenesis and determining the phenotypes of asthma is not fully elucidated. miR-146a has been previously shown to suppress inflammatory responses in different cells. In this study, we investigated the functions of miR-146a in human bronchial epithelial cells (HBECs) in association with neutrophilic, eosinophilic, and paucigranulocytic phenotypes of asthma.MethodsBronchial brushing specimens and brochial mucosal biopsy samples were collected from adult patients with asthma and from age- and gender-matched non-asthmatic individuals. The expression of miR-146a in bronchial brushing specimens, bronchial biopsy tissue sections or cultured primary bronchial epithelial cells was analyzed by RT-qPCR or by in situ hybridization. The expression of direct and indirect miR-146a target genes was determined by RT-qPCR or ELISA. The migration of neutrophils was studied by neutrophil chemotaxis assay and flow cytometry. For statistical analysis, unpaired two-way Student’s t test, one-way ANOVA or linear regression analysis were used.ResultsReduced expression of miR-146a was found in bronchial brushing specimens from asthma patients as compared to non-asthmatics and irrespective of the phenotype of asthma. In the same samples, the neutrophil attracting chemokines IL-8 and CXCL1 showed increased expression in patients with neutrophilic asthma and increased IL-33 expression was found in patients with eosinophilic asthma. Linear regression analysis revealed a significant negative association between the expression of miR-146a in bronchial brushings and neutrophil cell counts in bronchoalveolar lavage fluid of patients with asthma. In bronchial biopsy specimens, the level of miR-146a was highest in the epithelium as determined with in situ hybridization. In primary conventional HBEC culture, the expression of miR-146a was induced in response to the stimulation with IL-17A, TNF-α, and IL-4. The mRNA expression and secretion of IL-8 and CXCL1 was inhibited in both stimulated and unstimulated HBECs transfected with miR-146a mimics. Supernatants from HBECs transfected with miR-146a had reduced capability of supporting neutrophil migration in neutrophil chemotaxis assay.ConclusionOur results suggest that decreased level of miR-146a in HBECs from patients with asthma may contribute to the development of neutrophilic phenotype of asthma.

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“…A previous study revealed that the expression levels of ADAM33 were upregulated in the lung tissues of asthma patients (12). In another study, in situ hybridization and immunohistochemistry were used to determine the mRNA and protein expression levels of ADAM33 in human bronchial biopsy specimens, and the results indicated that ADAM33 was significantly overexpressed in tissues from asthmatic patients compared with those from normal subjects (13).…”

Section: Discussionmentioning

confidence: 96%

TGF-β1 stimulates epithelial‑mesenchymal transition mediated by ADAM33

Fang

Huang

et al. 2017

Exp Ther Med

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The present study aimed to determine the effects of transforming growth factor (TGF)-β1 on disintegrin and metalloproteinase domain-containing protein 33 (ADAM33) expression in airway epithelial cells in order to investigate the association between ADAM33 expression and TGF-β1-induced epithelial to mesenchymal transition (EMT), and to further explore the mechanisms underlying the role of ADAM33 in airway remodeling in asthma. The human bronchial epithelial cell line HBE was transfected with small interfering RNA targeting ADAM33 (siADAM33) and treated with different concentrations of TGF-β1 (10, 20 or 30 ng/ml), while untransfected cells were used as controls. At 72 h after treatment, cellular morphology and immunohistochemical staining were observed under a microscope. The protein and mRNA expression levels of ADAM33 and the EMT markers E-cadherin and vimentin were detected by western blot analysis and reverse-transcription quantitative polymerase chain reaction, respectively. In addition, a correlation analysis of ADAM33 expression and E-cadherin/vimentin expression was performed. A wound healing migration assay and a cell invasion assay were also performed. The results of the cellular morphology, migration and invasion studies suggested that TGF-β1 treatment induced typical EMT changes in HBE cells. In addition, treatment with various concentrations of TGF-β1 significantly increased the protein and mRNA expression levels of ADAM33 and vimentin compared with those in untreated cells. TGF-β1 treatment also decreased the protein and mRNA expression levels of E-cadherin in a dose-dependent manner. By contrast, transfection with siADAM33 promoted the protein expression of E-cadherin and decreased the protein expression of vimentin. Furthermore, ADAM33 and E-cadherin expression levels exhibited a significant negative correlation, whereas ADAM33 and vimentin were positively correlated. In conclusion, the results suggested that TGF-β1 enhances ADAM33 expression in airway epithelial cells, and that ADAM33 induces the EMT of airway epithelial cells, thus participating in airway remodeling in asthma.

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IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type‐2 inflammatory endotype

Abstract: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Cited by 19 publications

References 47 publications

Role of serum periostin in severe obstructive sleep apnea with albuminuria: an observational study

Role of serum periostin in severe obstructive sleep apnea with albuminuria: an observational study

Reduced expression of miR-146a in human bronchial epithelial cells alters neutrophil migration

TGF-β1 stimulates epithelial‑mesenchymal transition mediated by ADAM33

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