TLR4 antagonist suppresses airway remodeling in asthma by inhibiting the T-helper 2 response

Li, Ming; Wang, Zhao‐Ni; Yang, Lei; Yan, Yan; Cai, Liang‐Ming; Li, Ya‐Ting; Qiao, Yong‐Kang; Chen, Zhuang‐Gui

doi:10.3892/etm.2017.4898

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…In contrast, the increase in neutrophils was only 3-fold in the 4 HDM models compared to Saline controls. Our observations in the 4- and 8-week HDM groups are consistent with previously reported 5-week models 19 , 20 , 25 , where robust increases in eosinophils were also accompanied by significant increases in the BAL neutrophil cell counts, with the overall absolute neutrophil counts ~10-fold higher than the absolute eosinophils.…”

Section: Discussionsupporting

confidence: 92%

“…Reversible airflow obstruction, airways inflammation, AHR to contractile agonists (spasmogens, such as methacholine or histamine) and airway remodeling are defining features of asthma 7 , 10 . Airways inflammation and enhanced MCh-responsiveness are observed in virtually all experimental models of allergic airways inflammation currently used 12 , 17 , 20 – 23 , 25 , 26 , with varying degrees depending on the dose, frequency, duration and type of allergen exposure 11 , 19 . Although goblet cell hyperplasia is observed as early as day 12 in our model (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling

Woo

Guo

Wang

et al. 2018

Sci Rep

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Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5–12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 µg and 25 µg) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 µg in 35 µl saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5–12 weeks) to develop.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling

Woo

Guo

Wang

et al. 2018

Sci Rep

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“…Several studies have shown that TLR4-signaling inhibition or HMGB1 neutralization reduces the pathologic features of asthma. For example, treatment of TAK242 in an HDM-induced asthma animal model suppresses airway remodeling in asthma by inhibiting the T-helper 2 response, 31 ameliorates combined allergic rhinitis and asthma syndrome (CARAS) by reducing inflammatory monocytes infiltration in mice model. 32 Moreover, HMGB1 neutralization attenuation of neutrophilic airway inflammation in asthma by suppressing Th17 polarization.…”

Section: Discussionmentioning

confidence: 99%

Inhibitions of HMGB1 and TLR4 alleviate DINP-induced asthma in mice

Hwang

Lee

Paik

et al. 2019

Toxicology Research

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We studied the effects of high mobility group box chromosomal protein 1 (HMGB1) and toll-like receptor (TLR4) in diisonoyl phthalate (DINP)-induced asthma. Mice with DINP-induced asthma were treated with a TLR4-signaling inhibitor or anti-HMGB1 antibody, and various markers of asthma were measured 24 h later. DINP increased airway hyperresponsiveness, numbers of cells in BALF, numbers of inflammatory cells (leukocytes, lymphocytes, monocytes, eosinophils, neutrophils, basophils) in blood, mucus production, pulmonary fibrosis, Th2 type cytokine levels in BALF, and lung cell apoptosis. On the other hand, administrations of TLR4-signaling inhibitors (TAK-242) or anti-HMGB1 antibodies to a mouse model of DINP-induced asthma reduced biological markers of asthma. These results show TLR4 and HMGB1 both contribute to DINP-induced asthma, and that the inhibitions of TLR4 or HMGB1 offer potential means of treating asthma induced by phthalates like DINP.

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“…This beneficial activity of soya PC may be due to inhibition of TLR4 signaling‐mediated inflammatory responses and airway remodeling. It is well reported that activation of the MyD88‐dependent intracellular signaling pathway of TLR4 leads to activation of NF‐κB and increases the gene expression of inflammatory cytokines which drive the activation of mucosal DC cascades and airway remodeling …”

Section: Discussionmentioning

confidence: 99%

An anti‐asthmatic activity of natural Toll‐like receptor‐4 antagonist in OVA‐LPS‐induced asthmatic rats

Thakur

Beladiya

Chaudagar

et al. 2018

Clin Exp Pharma Physio

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Toll-like receptor-4 (TLR4) is a key component of the innate immune system and activation of TLR4 signaling has a significant role in the pathogenesis of asthma. Therefore, our objective was to identify the natural TLR4 antagonist and evaluate its activity in experimentally induced asthma. Soya lecithin origin phosphatidylcholine (soya PC) was identified as a natural TLR4 antagonist by computational study. Based on the computational study, TLR4 antagonist activity of soya PC was confirmed in in vitro lipopolysaccharide (LPS)-induced neutrophil adhesion assay. In the in vivo study, rats were sensitized with ovalbumin (OVA) (100 μg/kg, i.p.) on the 7th, 14th and 21st days and challenged intranasally with OVA (100 μg/100 μL) and LPS (10 ng/100 μL), 4 days/wk for 3 weeks. At the end of the experiment, we performed lung function parameters (respiratory rate, tidal volume, airflow rate), inflammatory cytokines (interleukin [IL]-4, IL-5, IL-13), total and differential leukocytes in blood as well as bronchoalveolar lavage fluid (BALf) and histological examinations. The computational study indicated that TLR4 antagonist activity of soya PC is due to linoleic acid (18:2) fatty acid chain. Soya PC significantly suppressed the LPS-induced neutrophil adhesion in a concentration-dependent manner to 1 μg/mL. The treatment of soya PC (5 and 10 mg/kg, 18 days, i.p.) significantly improved the lung function parameters, total and differential leukocyte counts in blood and BALf in asthmatic rats. This efficacy of soya PC was in extent similar to dexamethasone (2.5 mg/kg, 18 days, i.p.). However, soya PC was superior to dexamethasone in terms of benefits. The protective action of soya PC may be due to TLR4 antagonist activity and linoleic acid composition.

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TLR4 antagonist suppresses airway remodeling in asthma by inhibiting the T-helper 2 response

Cited by 18 publications

References 26 publications

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling

Inhibitions of HMGB1 and TLR4 alleviate DINP-induced asthma in mice

An anti‐asthmatic activity of natural Toll‐like receptor‐4 antagonist in OVA‐LPS‐induced asthmatic rats

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