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Attenuation of airway hyperreactivity by gram- negative lipopolysaccharide in a murine model of asthma.

机译：革兰氏阴性脂多糖在哮喘小鼠模型中减轻气道高反应性。

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摘要

Asthma exacerbations due to exposures to air pollution and environmental allergens are common, leading to diminished responses to treatment and increased hospitalizations. Endotoxin or lipopolysaccharide (LPS) is a component of the cell wall of Gram- negative bacteria found throughout the environment. Individually, asthma and inhalation of LPS increases lung inflammation and airway hyperresponsiveness (AHR). Previous studies have shown that LPS exposure modulates both inflammatory and physiological responses in the lungs of asthmatic individuals. The primary focus of this work was to investigate the effects of inhaled LPS exposure on the pathology and physiological responses in the lung of a murine model of ovalbumin (OVA) - induced allergic asthma. Additionally, I investigated potential mechanisms that may underlie the dissociation between airway inflammation and AHR present in allergic mice exposed to LPS (OVALPS). I hypothesized that the attenuation of AHR in OVA-LPS mice was dependent on the upregulation of the gene responsible for nitric oxide production, Nos2, induced by recruited neutrophils. Four specific aims were generated. In aim 1, I studied the relationships between the cellular character and distribution of lung lesions with components of AHR in OVA-LPS mice. To do so, naive and OVA- induced allergic mice were exposed to LPS by intranasal instillation 48 hours following the final saline/OVA challenge. AHR was determined and animals were euthanized to collect tissue samples 24 hours after LPS exposure. There was significant pulmonary inflammation consisting of eosinophils distributed within the central airway compartment composed of perivascular and peribronchiolar regions (OVA group), neutrophils located in central airway and peripheral lung tissue compartments composed of alveolar septa and airspaces (LPS group), and OVA-LPS mice had more severe inflammation combining both cell types distributed in both compartments as well. AHR was increased in both central airways and the peripheral lung tissue in OVA and LPS mice. By comparison, AHR was attenuated in OVA-LPS mice. In aim 2, I hypothesized that recruited airway neutrophils contributed to the attenuation of AHR in OVA-LPS mice. Systemic depletion of neutrophils prior to LPS exposure significantly lowered BALF neutrophils. Compared to neutrophil sufficient mice, neutrophil depletion did not alter AHR in OVA-LPS mice. In aim 3, I hypothesized that LPS activation of the transcription factor, NF-kappaB, attenuated AHR in OVA-LPS mice. Following treatment with a novel NF-eB inhibitor, OVA-LPS mice had significantly decreased BALF macrophages, eosinophils, and lymphocytes but not neutrophils compared to nontreated mice. In spite of the decrease in cellularity, AHR significantly increased suggesting that NF-eB activation contributes to the attenuation of AHR in OVA-LPS mice. In aim 4, I evaluated the relationship between expression of the genes nitric oxide synthase-2 (Nos2) and arginase-1 (Arg1) and the attenuation of AHR in OVA-LPS mice. Following LPS exposure, Nos2 and Arg1 were increased in OVA-LPS mice. Treatment with a NF-kappaB inhibitor significantly blunted the expression of both genes, suggesting that NF-kappaB mediated increased expression of Nos2 potentially contributes to attenuation in AHR, which is reversed with downregulation of NOS2 gene expression.
机译：由于暴露于空气污染和环境过敏原引起的哮喘加重是常见的，导致对治疗的反应减弱和住院增加。内毒素或脂多糖（LPS）是在整个环境中发现的革兰氏阴性细菌细胞壁的组成部分。哮喘和吸入LPS分别会增加肺部炎症和气道高反应性（AHR）。先前的研究表明，LPS暴露可调节哮喘个体肺部的炎症和生理反应。这项工作的主要重点是研究吸入LPS暴露对卵清蛋白（OVA）诱发的过敏性哮喘小鼠模型的肺部病理和生理反应的影响。此外，我研究了潜在的机制，这些机制可能是暴露于LPS（OVALPS）的变态反应小鼠中气道炎症与AHR之间分离的基础。我假设OVA-LPS小鼠中AHR的减弱取决于募集的中性粒细胞诱导的一氧化氮产生基因Nos2的上调。产生了四个具体目标。在目标1中，我研究了OVA-LPS小鼠的肺部病变与AHR成分的细胞特征和分布之间的关系。为此，在最终生理盐水/ OVA攻击后48小时，通过鼻内滴注将天真和OVA诱导的过敏小鼠暴露于LPS。确定AHR并在LPS暴露24小时后对动物实施安乐死以收集组织样品。有明显的肺部炎症，由分布在中央气道隔室内的嗜酸性粒细胞组成（由血管周围和支气管周围区域组成）（OVA组），位于中央气道的中性粒细胞和由肺泡隔和气隙组成的周围肺组织隔室（LPS组）以及OVA-LPS结合两种分布在两个隔室中的细胞类型，小鼠的炎症更加严重。在OVA和LPS小鼠中，中央气道和周围肺组织的AHR均升高。相比之下，在OVA-LPS小鼠中AHR减毒。在目标2中，我假设募集的气道中性粒细胞有助于OVA-LPS小鼠中AHR的减弱。 LPS暴露前中性粒细胞的系统耗竭显着降低了BALF中性粒细胞。与中性粒细胞充足的小鼠相比，中性粒细胞耗竭不会改变OVA-LPS小鼠的AHR。在目标3中，我假设转录因子NF-κB的LPS激活会减弱OVA-LPS小鼠的AHR。与未治疗的小鼠相比，用新型的NF-eB抑制剂治疗后，OVA-LPS小鼠的BALF巨噬细胞，嗜酸性粒细胞和淋巴细胞明显减少，而嗜中性粒细胞则没有。尽管细胞数量减少，但AHR仍显着增加，提示NF-eB激活有助于OVA-LPS小鼠AHR的减弱。在目标4中，我评估了OVA-LPS小鼠中一氧化氮合酶2（Nos2）和精氨酸酶1（Arg1）基因表达与AHR衰减之间的关系。在LPS暴露后，OVA-LPS小鼠的Nos2和Arg1升高。用NF-kappaB抑制剂治疗显着减弱了这两个基因的表达，这表明NF-kappaB介导的Nos2表达增加可能有助于AHR的减弱，这与NOS2基因表达的下调相反。

著录项

  • 作者

    Jackson-Humbles, Daven.;

  • 作者单位

    Michigan State University.;

  • 授予单位 Michigan State University.;
  • 学科 Pathology.;Toxicology.;Physiology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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