Why Are Steroids Ineffective at Suppressing RSV Bronchiolitis

为什么类固醇不能有效抑制 RSV 毛细支气管炎

• 批准号: 8429648
• 负责人: RAYMOND J PICKLES
• 金额: $ 17.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-22 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429648
• 关键词: 2 year old; Acute; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Bronchioles; Bronchiolitis; Cells; Cellular Morphology; Characteristics; Chemotactic Factors; Child; Clinical; Clinical Trials; Columnar Cell; Disease; Distal; Employee Strikes; Engineering; Epithelial Cells; Epithelium; Event; Future; Genes; Genetic; Genetic Models; Goals; Hamsters; Histologic; Histopathology; Hospitalization; Human; Human respiratory syncytial virus; IL8 gene; In Vitro; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Lung; Lung Inflammation; Lung diseases; Mediating; Modeling; Mus; Obstruction; Outcome; Parainfluenza Virus Infections; Patients; Pharmaceutical Preparations; Phenotype; Production; Reagent; Recombinants; Resistance; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Severities; Steroid Resistance; Steroids; Structural Protein; Supportive care; Testing; Therapeutic; Viral; Virus; Virus Diseases; Virus Shedding; airway epithelium; airway inflammation; airway obstruction; efficacy testing; experience; in vivo; in vivo Model; neutrophil; novel; novel therapeutics; parainfluenza virus; pathogen; public health relevance; respiratory virus; treatment strategy

DESCRIPTION (provided by applicant): We have recently discovered expression of the Non-Structural protein 2 of Respiratory Syncytial Virus (RSV) is responsible for hallmark characteristics of RSV infection of human airway epithelium. Using recombinant Parainfluenza Virus (PIV) expressing RSV NS2 and relevant models of human and hamster columnar airway epithelium we show RSV NS2 has a dramatic effect on the fate of PIV-infected cells resulting in a striking shedding of virus-infected epithelial cells into the airway lumen and a hyper-inflammatory phenotype. In hamster distal airways, shedding cells accumulate in the narrow lumens causing acute distal airway obstruction accompanied by exaggerated recruitment of inflammatory cells. These histologic findings are remarkably similar to those found in airways of human infants with RSV bronchiolitis and suggest PIV- mediated RSV NS2 expression in hamster bronchioles represent a novel animal model for investigating early initiating events of bronchiolitis. We are eager to use this model to test therapeutic approaches for reducing the severity of RSV bronchiolitis and envision strategies that lessen the consequences of RSV NS2 expression may provide therapeutic benefit to infants with RSV bronchiolitis. Our first use of this model will be to explore a significant clinical question; why steroids fail to suppress RSV-induced inflammation while effectively suppressing inflammation induced by PIV? Using relevant models of columnar airway epithelium we test whether RSV NS2 expression renders PIV-induced inflammation resistant to steroids in vitro and in vivo. We also test the efficacy of a novel class of non-steroidal anti- inflammatory modulators, the synthetic triterpenoids, to suppress consequences of RSV NS2 expression as these drugs have shown great promise as anti-inflammatory agents but without the adverse effects of steroids and are currently in human clinical trials for non-respiratory indications. Our notion is RSV NS2-induced inflammation, while resistant to steroids, may be suppressed by triterpenoids. Finally, to capitalize on the wealth of mouse genetic models and related reagents we engineer mouse respiratory viruses to express RSV NS2 and test whether infection of mouse airways with these novel chimeric viruses results in distal airway obstruction and exaggerated airway inflammation; thus, providing a useful animal model for future mechanistic studies. RSV bronchiolitis is the single largest cause of hospitalization of infants. Here, we develop animal models in which RSV NS2 expression in distal airways recapitulates hallmark characteristics of RSV bronchiolitis in infants. These studies will provide a novel platform for developing and testing therapeutics for relieving the onset and severity of RSV bronchiolitis in humans.

描述（由申请人提供）：我们最近发现了呼吸综合病毒（RSV）的非结构蛋白2的表达，负责人类气道上皮的RSV感染的标志性特征。使用表达RSV NS2的重组副氟二氮病毒（PIV）以及人和仓鼠柱状气道上皮的相关模型，我们表明RSV NS2对PIV感染的细胞的命运具有巨大的影响，从而导致病毒感染的上皮细胞引起了Airway Pilesial Pulame unfloom and the Arimyflamtial和Fackteact speartial and Fackteact。在仓鼠远端气道中，脱落细胞积聚在狭窄的流明中，导致急性远端气道阻塞，并伴随着夸张的炎症细胞的募集。这些组织学的发现与患有RSV细支气管炎的人类婴儿的气道中发现非常相似，并建议仓鼠支气管中的旋转介导的RSV NS2表达代表了一种新型动物模型，用于研究促进细支气管炎事件的早期引发事件。 我们渴望使用该模型测试治疗方法，以减少RSV细支气管炎的严重程度，并设想降低RSV NS2表达的后果的策略，可能会给RSV支气管炎的婴儿提供治疗益处。 我们对该模型的首次使用将是探索一个重要的临床问题。为什么类固醇无法抑制RSV诱导的炎症，同时有效抑制PIV引起的炎症？使用柱状气道上皮的相关模型，我们测试RSV NS2表达是否会导致PIV诱导的体外和体内抗炎症对类固醇的抗药性。我们还测试了 新型的非甾体类抗炎性调节剂，合成三萜类化合物，以抑制RSV NS2表达的后果，因为这些药物表现出了巨大的希望，作为抗炎剂，但没有类固醇的不良影响，但目前在人类的临床试验中对非呼吸性适应症表示了良好的前景。我们的概念是RSV NS2诱导的炎症，而对类固醇的抗药性可能会被三萜抑制。 最后，利用 小鼠遗传模型和相关试剂我们设计小鼠呼吸道病毒以表达RSV NS2并测试用这些新型嵌合病毒的小鼠气道感染是否导致远端气道阻塞和夸张的气道炎症；因此，为未来的机械研究提供了有用的动物模型。 RSV支气管炎是婴儿住院治疗的单一最大原因。在这里，我们开发了动物模型，其中RSV NS2在远端气道中的表达概括了婴儿RSV细支气管炎的标志性特征。这些研究将为开发和测试治疗剂提供一个新的平台，以减轻人类RSV细支气管炎的发作和严重程度。