The non-antibiotic macrolide EM900 attenuates HDM and poly(I:C)-induced airway inflammation with inhibition of macrophages in a mouse model

Sadamatsu, Hironori; Takahashi, Koichiro; Tashiro, Hiroki; Kato, Go; Noguchi, Yoshihiko; Kurata, Kunio; Ōmura, Satoshi; Kimura, Shinya; Sunazuka, Toshiaki; Sueoka‐Aragane, Naoko

doi:10.1007/s00011-019-01302-3

Cited by 21 publications

(11 citation statements)

References 51 publications

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“…RANTES/CCL5, which is upregulated in adipose tissue of obese individuals 16 and associated with obesity-induced pathophysiology, such as atherosclerosis and sleep apnea syndrome, 17,18 was significantly higher in overweight asthma patients than in non-overweight asthma patients. RANTES/CCL5 is also associated with airway inflammation and airway hyperresponsiveness, as we and others previously reported, 19,20 which is also supported by the present results. Interestingly, a high level of VEGF-A, which is correlated with decreased pulmonary function, 21 was also significantly more common in overweight patients with asthma, supporting the lower FVC and FEV1, compared to non-overweight asthma patients.…”

Section: Discussionsupporting

confidence: 93%

<p>Biomarkers for Overweight in Adult-Onset Asthma</p>

Tashiro

Takahashi

Sadamatsu

et al. 2020

JAA

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Overweight and obesity are associated with one of the severe phenotypes of asthma, with an increased rate of exacerbations, low level of lung function, and reduced response to corticosteroid therapy. The present study focused on identifying useful biomarkers of severity in overweight patients with adult-onset asthma using real-world data. Patients and Methods: A total of 56 patients with adult-onset asthma who visited Saga University Hospital between 2018 and 2019 were retrospectively reviewed. Overweight was defined as a body mass index (BMI) greater than 25 kg/m 2. Blood eosinophils, cytokines, and chemokines were compared between non-overweight asthma and overweight asthma patients. Results: Overweight asthma patients had a higher annual exacerbation rate, lower pulmonary function even when treated frequently with high-dose inhaled corticosteroids, and a significantly lower percentage of eosinophils and lower eosinophil count compared to nonoverweight asthma patients (p<0.01, p=0.03). Moreover, the percentage of eosinophils was significantly negatively correlated with BMI (ρ=−0.38, p<0.01) (Figure 1). On serum cytokine and chemokine analyses, the overweight asthma group included significantly more patients with a lower level of tissue growth factor α (TGF-α) (1.1 pg/mL) and higher levels of hsIL-6 (2.5 pg/mL), RANTES/CCL5 (298.5 pg/mL), and vascular endothelial growth factor A (VEGF-A) (63.7 pg/mL), than the non-overweight asthma group (p=0.02, p<0.01, p=0.02, p=0.01, respectively). Conclusion: The present study showed that overweight patients with adult-onset asthma were characterized by a higher rate of annual exacerbations and worse lung function despite treatment with high-dose inhaled corticosteroids and lower blood eosinophil counts than nonoverweight patients with asthma. On blood cytokine and chemokine analyses, a low level of TGF-α and high levels of hsIL-6, RANTES/CCL5, and VEGF-A might be biomarkers reflecting the pathophysiology in overweight patients with asthma.

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Section: Discussionsupporting

confidence: 93%

<p>Biomarkers for Overweight in Adult-Onset Asthma</p>

Tashiro

Takahashi

Sadamatsu

et al. 2020

JAA

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“…We previously reported the mechanisms underlying the involvement of monocytes or macrophages in a mouse model of airway inflammation. In the previous studies, saturated fatty acids increased the recruitment of lung macrophages and augmented HDM-induced airway inflammation in obese mice, and EM900 suppressed the recruitment of lung macrophages in a virus-induced asthma exacerbation model [23, 28]. In the present study, the number of interstitial macrophages (defined as CD45 + , CD11c low , CD11b + , and Ly6c − cells) was significantly decreased by EM900 in an obesity-associated mouse asthma model.…”

Section: Discussionsupporting

confidence: 69%

“…EM900 is a 12-membered nonantibiotic macrolide derived from erythromycin that has been found to exert potent anti-inflammatory and immunomodulatory effects [22]. We previously reported that the nonantibiotic macrolide EM900 has the potential to inhibit virus-associated asthma exacerbation in mice [23]. The present study investigated the effects and mechanisms of activity of EM900 in type 2-low airway inflammation related to obesity in mice.…”

Section: Introductionmentioning

confidence: 99%

The Nonantibiotic Macrolide EM900 Attenuates House Dust Mite-Induced Airway Inflammation in a Mouse Model of Obesity-Associated Asthma

Sadamatsu

Takahashi

Tashiro

et al. 2020

Int Arch Allergy Immunol

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Introduction: Obesity-associated asthma is characterized by type 2-low airway inflammation. We previously showed that EM900, which is a 12-membered nonantibiotic macrolide, suppressed airway inflammation in a mouse model of asthma exacerbation. The aim of this study was to clarify the effects of EM900 in obesity-associated asthma. Methods: BALB/c mice were fed a low-fat diet (LFD) or high-fat diet (HFD). Mice were intranasally sensitized and challenged with house dust mites (HDMs) and were orally administered EM900. Airway inflammation was assessed using inflammatory cells in bronchoalveolar lavage (BALF). Cytokines were examined by ELISA in lung tissues. Lung interstitial macrophages (CD45 + , CD11c low , CD11b + , and Ly6c −) were counted by flow cytometry in single cells from lung tissues. Results: Body weight increased significantly in the HFD compared with the LFD group. The total cell count and numbers of neutrophils and eosinophils in BALF were significantly suppressed by EM900 administration in the HFD-HDM group. The levels of interleukin (IL)-17A were increased in the HFD-HDM group compared with the LFD-HDM group, although the difference did not reach statistical significance. The levels of IL-17A, macrophage inflammatory protein 2, IL-1β, IL-5, and regulated on activation, normal T cell expressed and secreted in lung tissue were significantly suppressed by EM900 administration in the HFD-HDM group. The percentage of interstitial macrophages in lungs was significantly decreased by EM900 administration in the HFD-HDM group. Conclusion: Both type 2 and type 2-low airway inflammation were attenuated by EM900 in this obesity-associated asthma model. These results show that EM900 might be a candidate agent for the treatment of obesity-associated asthma.

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“…Asthma-like eosinophilic airway inflammation can be modeled by adjuvant-driven immunization [15,[18][19][20][21], chronic antigen administration [19,22], and transfer of antigen-pulsed cells [18,19,23]. Asthma-like neutrophilic airway inflammation can be induced in mice by subcutaneous administration of either CFA [21,24], LPS [14,25], or poly(I:C) [26], along with a model antigen, like ovalbumin (OVA). For severe non-type 2 asthma, there is still a significant gap between disease-associated pathological features and a particular clinical outcome or treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Macrophage and dendritic cell subset composition can distinguish endotypes in adjuvant-induced asthma mouse models

Özkan

Eskiocak²,

Wingender

2021

PLoS ONE

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Asthma is a heterogeneous disease with neutrophilic and eosinophilic asthma as the main endotypes that are distinguished according to the cells recruited to the airways and the related pathology. Eosinophilic asthma is the treatment-responsive endotype, which is mainly associated with allergic asthma. Neutrophilic asthma is a treatment-resistant endotype, affecting 5–10% of asthmatics. Although eosinophilic asthma is well-studied, a clear understanding of the endotypes is essential to devise effective diagnosis and treatment approaches for neutrophilic asthma. To this end, we directly compared adjuvant-induced mouse models of neutrophilic (CFA/OVA) and eosinophilic (Alum/OVA) asthma side-by-side. The immune response in the inflamed lung was analyzed by multi-parametric flow cytometry and immunofluorescence. We found that eosinophilic asthma was characterized by a preferential recruitment of interstitial macrophages and myeloid dendritic cells, whereas in neutrophilic asthma plasmacytoid dendritic cells, exudate macrophages, and GL7+ activated B cells predominated. This differential distribution of macrophage and dendritic cell subsets reveals important aspects of the pathophysiology of asthma and holds the promise to be used as biomarkers to diagnose asthma endotypes.

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The non-antibiotic macrolide EM900 attenuates HDM and poly(I:C)-induced airway inflammation with inhibition of macrophages in a mouse model

Cited by 21 publications

References 51 publications

<p>Biomarkers for Overweight in Adult-Onset Asthma</p>

<p>Biomarkers for Overweight in Adult-Onset Asthma</p>

The Nonantibiotic Macrolide EM900 Attenuates House Dust Mite-Induced Airway Inflammation in a Mouse Model of Obesity-Associated Asthma

Macrophage and dendritic cell subset composition can distinguish endotypes in adjuvant-induced asthma mouse models

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