IMPROVE 2: Inhaled Mometasone to Promote Reduction in Vaso-occlusive Events

总体目标是了解吸入皮质类固醇导致系统性红斑狼疮的机制 对于没有哮喘的镰状细胞病(SCD)患者的临床益处，我们收集了一份 血液学、肺病学、免疫学和SCD患者专家团队与最先进的 对肺部和全身炎症、血管损伤、功能状态和患者进行表型鉴定的能力 报告结果。在SCD中，镰刀状是由血液脱氧引起的，在肺部则相反。肺 炎症干扰了再氧合，并增强了进一步的镰状、溶血、炎症和血管病变。 遮挡。在过去的十年里，我们的团队和其他人证明了肺部炎症存在于 在SCD小鼠中，不符合条件的SCD患者中有一半出现发作性咳嗽或喘息(ECW)的症状 他指出，这是诊断哮喘的标准之一，ECW是增加SCD相关疼痛和死亡的风险因素。在一个 试点试验，吸入类固醇可减少全身炎症、溶血和日常疼痛，并有以下趋势 大幅降低医疗保健利用率。我们的全球假设是吸入类固醇可以改善全身 非哮喘SCD合并ECW患者的炎症和血管损伤。为了检验这一假设，我们将 完成以下目标：目标1A：比较非哮喘SCD患者的肺部炎症特征 使用和不使用ECW和，AIM 1B：确定吸入类固醇对大鼠肺部炎症的影响 非哮喘性SCD患者合并ECW。目的2：测定吸入类固醇对外周血的影响 患有SCD和ECW的非哮喘患者的炎症和溶血征象。目标3：建立 在城市SCD临床试验环境中使用吸入性类固醇的安全规程，为期1年。我们将分析 使用飞行时间(CyTOF)质量细胞术(CyTOF)诱导痰和血 流式细胞术)和多重分析，以确定肺和全身炎症的模式 系统性红斑狼疮的临床表现及吸入激素对其的影响 炎症模式。一旦完成，我们将使用所获得的知识来设计吸入性药物的第三阶段试验 适用于患有SCD的非哮喘患者的类固醇。

With the overall goal of understanding the mechanisms by which inhaled corticosteroids lead to systemic clinical benefits in individuals with Sickle Cell Disease (SCD) who do not have asthma, we have assembled a team of experts in hematology, pulmonology, immunology and SCD patient engagement with state-of-the-art capabilities for phenotyping pulmonary and systemic inflammation, vascular injury, functional status and patient reported outcomes. In SCD, sickling is caused by de-oxygenation of blood and reversed in the lung. Pulmonary inflammation interferes with re-oxygenation and potentiates further sickling, hemolysis, inflammation and vaso- occlusion. Over the last decade, our group and others demonstrated that pulmonary inflammation is present in SCD mice, that symptoms of episodic cough or wheeze (ECW) occur in half of SCD patients who do not meet criteria for a diagnosis of asthma and that ECW is a risk factor for increased SCD-related pain and death. In a pilot trial, inhaled steroids reduced systemic inflammation, hemolysis and daily pain with trends towards substantial reductions in healthcare utilization. Our global hypothesis is that inhaled steroids improve systemic inflammation and vascular injury in non-asthmatic SCD patients with ECW. To test this hypothesis, we will complete the following aims: AIM 1A: Compare pulmonary inflammation profiles in non-asthmatic SCD patients with and without ECW and, AIM 1B: Determine the effect of inhaled steroids on pulmonary inflammation in non-asthmatic SCD patients with ECW. AIM 2: Determine the effect of inhaled steroids on peripheral blood inflammatory and hemolytic signatures in non-asthmatic individuals with SCD and ECW. AIM 3: Establish a safety protocol for using inhaled steroids in an urban SCD clinical trial setting for 1 year. We will analyze induced sputum and blood using mass cytometry by time of flight (CyTOF - which has several advantages over flow cytometry) and multiplex assays, to define patterns of pulmonary and systemic inflammation that underlie the clinical phenomenon of ECW in SCD and to determine the effects of inhaled steroids on those inflammatory patterns. Once complete, we will use the knowledge gained to design a phase III trial of inhaled steroids for non-asthmatic individuals with SCD.