Role of the protease-activated receptor-2 (PAR2) in the exacerbation of house dust mite-induced murine allergic lung disease by multi-walled carbon nanotubes.

IF 7.2 1区 医学 Q1 TOXICOLOGY Particle and Fibre Toxicology Pub Date : 2023-08-14 DOI:10.1186/s12989-023-00538-6
Ho Young Lee, Dorothy J You, Alexia Taylor-Just, Logan J Tisch, Ryan D Bartone, Hannah M Atkins, Lauren M Ralph, Silvio Antoniak, James C Bonner
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Abstract

Background: Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs.

Methods: Wildtype (WT) male C57BL6 mice and Par2 KO mice were exposed to vehicle, MWCNTs, HDM extract, or both via oropharyngeal aspiration 6 times over a period of 3 weeks and were sacrificed 3-days after the final exposure (day 22). Bronchoalveolar lavage fluid (BALF) was harvested to measure changes in inflammatory cells, total protein, and lactate dehydrogenase (LDH). Lung protein and RNA were assayed for pro-inflammatory or profibrotic mediators, and formalin-fixed lung sections were evaluated for histopathology.

Results: In both WT and Par2 KO mice, co-exposure to MWCNTs synergistically increased lung inflammation assessed by histopathology, and increased BALF cellularity, primarily eosinophils, as well as BALF total protein and LDH in the presence of relatively low doses of HDM extract that alone produced little, if any, lung inflammation. In addition, both WT and par2 KO mice displayed a similar increase in lung Cc1-11 mRNA, which encodes the eosinophil chemokine CCL-11, after co-exposure to MWCNTs and HDM extract. However, Par2 KO mice displayed significantly less airway fibrosis as determined by quantitative morphometry compared to WT mice after co-exposure to MWCNTs and HDM extract. Accordingly, at both protein and mRNA levels, the pro-fibrotic mediator arginase 1 (ARG-1), was downregulated in Par2 KO mice exposed to MWCNTs and HDM. In contrast, phosphorylation of the pro-inflammatory transcription factor NF-κB and the pro-inflammatory cytokine CXCL-1 was increased in Par2 KO mice exposed to MWCNTs and HDM.

Conclusions: Our study indicates that PAR2 mediates airway fibrosis but not eosinophilic lung inflammation induced by co-exposure to MWCNTs and HDM allergens.

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蛋白酶激活受体2(PAR2)在多壁碳纳米管加重屋尘螨诱导的小鼠过敏性肺病中的作用。
背景:据报道,肺暴露于多壁碳纳米管(MWCNTs)在过敏性肺病小鼠模型中具有强烈的促炎和促纤维化佐剂作用。然而,MWCNTs加剧过敏原诱导的肺部疾病的分子机制仍有待阐明。我们假设蛋白酶激活受体2(PAR2)是一种G蛋白偶联受体,先前与包括肺纤维化和哮喘在内的各种疾病的发病机制有关,可能在MWCNTs引起的屋尘螨(HDM)过敏原诱导的肺部疾病的恶化中发挥重要作用,HDM提取物或两者在3周内通过口咽抽吸6次并在最终暴露后3天(第22天)处死。采集支气管肺泡灌洗液(BALF)以测量炎症细胞、总蛋白和乳酸脱氢酶(LDH)的变化。测定肺蛋白和RNA的促炎或促纤维化介质,并评估福尔马林固定肺切片的组织病理学。结果:在WT和Par2 KO小鼠中,共同暴露于MWCNTs协同增加了组织病理学评估的肺部炎症,并增加了BALF细胞数,主要是嗜酸性粒细胞,以及在相对低剂量的HDM提取物存在下的BALF总蛋白和LDH,单独产生的肺部炎症很少(如果有的话)。此外,WT和par2-KO小鼠在共同暴露于MWCNTs和HDM提取物后,肺Cc1-11 mRNA(编码嗜酸性粒细胞趋化因子CCL-11)均显示出类似的增加。然而,与WT小鼠相比,在共同暴露于MWCNTs和HDM提取物后,通过定量形态计量学测定,Par2-KO小鼠显示出显著更少的气道纤维化。因此,在蛋白和mRNA水平上,在暴露于MWCNTs和HDM的Par2-KO小鼠中,促纤维化介质精氨酸酶1(ARG-1)下调。相反,在暴露于MWCNTs和HDM的Par2-KO小鼠中,促炎转录因子NF-κB和促炎细胞因子CXCL-1的磷酸化增加。
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来源期刊
CiteScore
15.90
自引率
4.00%
发文量
69
审稿时长
6 months
期刊介绍: Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.
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