Why Are Steroids Ineffective at Suppressing RSV Bronchiolitis

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的表达是RSV感染人气道上皮的标志性特征的原因。使用表达RSV NS 2的重组副流感病毒（PIV）以及人和仓鼠柱状气道上皮的相关模型，我们显示RSV NS 2对PIV感染细胞的命运具有显著影响，导致病毒感染的上皮细胞显著脱落进入气道腔和高度炎症表型。在仓鼠远端气道中，脱落细胞积聚在狭窄的管腔中，导致急性远端气道阻塞，伴随着过度募集炎性细胞。这些组织学结果与RSV毛细支气管炎人类婴儿气道中发现的结果非常相似，表明仓鼠细支气管中PIV介导的RSV NS 2表达代表了研究毛细支气管炎早期起始事件的新型动物模型。 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 NS 2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将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，而有效地抑制PIV诱导的炎症？使用相关的气道柱状上皮模型，我们测试RSV NS 2表达是否使PIV诱导的炎症在体外和体内对类固醇产生耐药性。我们还测试了一种 新型非甾体抗炎调节剂，合成三萜类化合物，用于抑制RSV NS 2表达的后果，因为这些药物作为抗炎剂已经显示出很大的前景，但没有甾体的副作用，并且目前正在用于非呼吸适应症的人体临床试验中。我们的观点是RSV NS 2诱导的炎症，虽然对类固醇有抗性，但可以被三萜类化合物抑制。 最后，为了利用 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RSVNS 2，并测试用这些新的嵌合病毒感染小鼠气道是否导致远端气道阻塞和加重的气道炎症;从而为将来的机理研究提供有用的动物模型。 RSV细支气管炎是婴儿住院的单一最大原因。在这里，我们开发了动物模型，其中RSV NS 2在远端气道中的表达再现了婴儿RSV细支气管炎的标志性特征。这些研究将为开发和测试缓解人类RSV细支气管炎发作和严重程度的治疗方法提供新的平台。

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.