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: 8664798
• 负责人: RAYMOND J PICKLES
• 金额: $ 22.8万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664798
• 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）：我们最近发现呼吸道合胞病毒（RSV）的非结构蛋白2的表达与RSV感染人气道上皮的标志性特征有关。利用表达RSV NS2的重组副流感病毒（PIV）和人、仓鼠柱状气道上皮的相关模型，我们发现RSV NS2对PIV感染细胞的命运有显著影响，导致病毒感染的上皮细胞显著脱落到气道腔内，并出现超炎症表型。在仓鼠远端气道中，脱落细胞在狭窄的管腔中积聚，引起急性远端气道阻塞，并伴有炎症细胞的过度募集。这些组织学结果与人类呼吸道感染RSV细支气管炎的婴儿非常相似，表明PIV介导的RSV NS2在仓鼠细支气管炎中的表达为研究细支气管炎早期启动事件提供了一种新的动物模型。我们渴望使用该模型来测试降低RSV细支气管炎严重程度的治疗方法，并设想减轻RSV NS2表达后果的策略，可能为患有RSV细支气管炎的婴儿提供治疗益处。我们第一次使用这个模型是为了探索一个重要的临床问题；为什么类固醇不能抑制rsv诱导的炎症，而能有效抑制PIV诱导的炎症？利用相关的柱状气道上皮模型，我们在体外和体内测试RSV NS2表达是否使piv诱导的炎症对类固醇具有抗性。我们还测试了a的功效