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L-arginine metabolism regulates airways responsiveness in asthma and exacerbation by air pollution.

机译：L-精氨酸代谢可调节哮喘的气道反应性，并通过空气污染加剧病情恶化。

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摘要

Asthma is a chronic respiratory disease with a high prevalence in Western countries, including Canada, and increased exacerbations have been associated with ambient air pollution. The maintenance of airways tone is critically dependent on the endogenous bronchodilator, nitric oxide (NO). The nitric oxide synthase (NOS) isoenzymes produce NO from the amino acid, L-arginine, and competition for substrate with the arginase isoenzymes can limit NO production. Imbalances between these pathways have been implicated in the airways hyperresponsiveness (AHR) of asthma. The overall objective of this work was to determine whether arginase and downstream polyamine metabolites are functionally involved in airways responsiveness in animal models of asthma and the adverse responses of allergic animals to air pollution. To this purpose, the expression profiles of proteins involved in L-arginine metabolism were determined in lung tissues from human asthmatics and murine models of ovalbumin (OVA)-induced airways inflammation. Expression of arginase 1 was increased in human asthma and animal models. Competitive inhibition of arginase attenuated AHR in vivo. The roles of the downstream metabolites of arginase, the polyamines (putrescine, spermidine and spermine) were examined by administering them via inhalation to anaesthetized mice. It was demonstrated that spermine increases methacholine responsiveness in normal and allergic mice. Additionally, inhibition of polyamine synthesis improved AHR in a murine model. Thus, arginase and downstream polyamine metabolites contribute to AHR in asthma. Finally, the potential role of arginase in the exacerbation of asthma by air pollution was investigated. For this purpose, murine sub-acute and chronic murine models of allergic airways inflammation were employed, which exhibit inflammatory cell influx and remodeling/AHR, respectively, to determine the role of arginase in the response to concentrated ambient fine particles plus ozone. Allergic mice that were exposed to air pollution exhibited increased arginase activity and expression, compared to filtered air-exposed controls. Furthermore, inhibition of arginase attenuated the air pollution-induced AHR. Thus, the studies of the arginase pathway and downstream metabolites described in this thesis indicate that arginase inhibition may be a therapeutic target in asthma and may also protect susceptible populations against the adverse health effects of air pollution.
机译：哮喘是一种慢性呼吸道疾病，在包括加拿大在内的西方国家中，其患病率很高，而且加剧的发作与周围的空气污染有关。气道音调的维持主要取决于内源性支气管扩张剂一氧化氮（NO）。一氧化氮合酶（NOS）同工酶从氨基酸L-精氨酸中产生NO，与精氨酸酶同工酶竞争底物会限制NO的产生。这些途径之间的失衡与哮喘的气道高反应性（AHR）有关。这项工作的总体目标是确定在哮喘动物模型中，精氨酸酶和下游多胺代谢产物是否在功能上与气道反应有关，以及过敏性动物对空气污染的不良反应。为此，从人哮喘和卵清蛋白（OVA）诱导的气道炎症的鼠模型中确定了肺组织中L-精氨酸代谢相关蛋白的表达谱。在人类哮喘和动物模型中，精氨酸酶1的表达增加。竞争性抑制精氨酸酶在体内减弱了AHR。通过向麻醉的小鼠吸入给药，检验了精氨酸酶下游代谢产物多胺（氨基乙酸，精胺，亚精胺和亚精胺）的作用。已证明精胺可增加正常小鼠和变态反应小鼠的乙酰甲胆碱反应性。另外，在小鼠模型中，多胺合成的抑制改善了AHR。因此，精氨酸酶和下游多胺代谢产物有助于哮喘的AHR。最后，研究了精氨酸酶在空气污染加剧哮喘中的潜在作用。为了这个目的，使用变应性气道炎症的鼠亚急性和慢性鼠模型，其分别表现出炎性细胞流入和重塑/ AHR，以确定精氨酸酶在对浓缩的环境细颗粒加臭氧的响应中的作用。与过滤后的暴露于空气的对照组相比，暴露于空气污染的变态小鼠表现出更高的精氨酸酶活性和表达。此外，精氨酸酶的抑制减弱了空气污染引起的AHR。因此，本文对精氨酸酶途径和下游代谢产物的研究表明，精氨酸酶抑制可能是哮喘的治疗靶标，也可能保护易感人群免受空气污染的不利健康影响。

著录项

  • 作者

    North, Michelle Leanne.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Immunology.;Toxicology.;Environmental health.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 217 p.
  • 总页数 217
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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