Pediatric Severe Asthma: Role of Oxidant Stress and Alveolar Macrophage Function

描述（由申请人提供）：本提案的目的是培养Anne Fitzpatrick博士的科学发展和实验室技能，使她能够成为具有临床转化研究专业知识的独立研究者。菲茨帕特里克博士的长期目标是确定导致儿童严重哮喘的新的生物学机制。实现这一目标的必要步骤是：1)获得必要的实验室技能，使她能够进行独立的临床转化实验；2)参与哮喘儿童氧化应激和肺泡巨噬细胞（AM）功能的多学科机制研究。该研究职业奖将使Fitzpatrick博士不仅能够发展她的研究技能和专业知识，而且还可以追求教学阶段的研究，这对她发展成为一名独立研究者至关重要。埃默里大学的实验室、临床设施和学术环境将为Fitzpatrick博士提供理想的环境，以研究氧化应激和AM成熟及功能对严重哮喘儿童的生物学和临床影响。通过与实验室科学导师（Lou Ann Brown博士）、临床儿科哮喘专家（W. Gerald Teague博士）以及由经验丰富的科学和临床研究人员组成的广泛网络的合作，Fitzpatrick博士将为独立学术研究事业的发展奠定基础。严重哮喘是儿童发病的一个重要来源。虽然严重哮喘的发病机制尚不清楚，但症状被认为是由持续的气道炎症引起的，呼吸道感染是主要的触发因素。将严重哮喘与呼吸道感染风险联系起来的确切机制尚不明确。Fitzpatrick博士之前已经证明，患有严重哮喘的儿童AM功能受损，通过补充抗氧化剂（谷胱甘肽）可以恢复。这些数据表明，气道氧化应激可能直接抑制严重哮喘儿童的AM功能，这一发现可能解释了这一人群呼吸道感染风险增加的原因。该提案将验证严重哮喘诱导的炎症和氧化应激通过损伤AM巨噬细胞成熟导致AM功能受损的假设。研究将测试三个目标：1)严重哮喘患儿是否存在气道炎症和氧化应激，从而影响AM的成熟；2)抗炎药罗格列酮是否会恢复AM的成熟和功能；3) AM功能受损是否预示严重哮喘患儿呼吸道感染及症状控制不良。这一建议的结果可能会影响患者护理和临床评估，并将为儿童严重哮喘的病理生理学提供更深入的了解。这一建议将为进一步的研究奠定基础，确定的机制可能最终成为未来干预性试验的目标。

DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and bench laboratory skills of Dr. Anne Fitzpatrick so that she may become an independent investigator with expertise in clinical translational research. Dr. Fitzpatrick's long-term goal is to identify novel biological mechanisms responsible for severe asthma in children. Steps integral to the attainment of this goal are: 1) to acquire the necessary bench laboratory skills that will enable her to conduct independent clinical translational experiments; and 2) to engage in multidisciplinary mechanistic studies of oxidant stress and alveolar macrophage (AM) function in children with asthma. This Research Career Award will allow Dr. Fitzpatrick to not only develops her research skills and expertise, but also to pursue a didactic phase of study, which is essential for her development into an independent investigator. The laboratories, clinical facilities, and academic environment at Emory University will provide Dr. Fitzpatrick with the ideal setting to investigate the biological and clinical impact of oxidant stress and AM maturation and function in children with severe asthma. Through collaboration with a laboratory science mentor (Dr. Lou Ann Brown), a clinical pediatric asthma specialist (Dr. W. Gerald Teague), and an extensive network of experienced scientific and clinical researchers, Dr. Fitzpatrick will obtain the foundation for the development of an independent academic research career. Severe asthma is a significant source of morbidity in children. Although the pathogenesis of severe asthma is unclear, symptoms are thought to result from persistent airway inflammation, with respiratory infections as a major trigger. The exact mechanisms linking severe asthma and the risk of respiratory infection are not well defined. Dr. Fitzpatrick has previously demonstrated that children with severe asthma have impaired AM function, which is restored with antioxidant (glutathione) supplementation. These data suggest that airway oxidative stress may directly inhibit AM function in children with severe asthma, a finding which may account for the increased risk of respiratory infection in this population. This proposal will test the hypothesis that severe asthma-induced inflammation and oxidant stress result in compromised AM function via impairment of AM macrophage maturation. Three aims will be tested: 1) whether children with severe asthma have airway inflammation and oxidant stress, which impair AM maturation; 2) whether AM maturation and function will be restored with the anti-inflammatory agent rosiglitizone; and 3) whether impaired AM function predicts respiratory infection and poor symptom control in children with severe asthma. The outcome of this proposal may impact patient care and clinical assessment, and will offer greater insight into the pathophysiology of severe asthma in children. This proposal will lay the foundation for further studies, and the mechanisms identified may ultimately be targeted in future interventional trials.