Bacteria in Lower Airways and Airway Inflammation in Children with Asthma

描述（由申请人提供）：本提案的目的是培养Pia J. Hauk博士的科学发展和临床研究技能，使她成为一名独立的研究者。国家犹太健康中心及其研究实验室提供的临床服务将为Hauk博士提供理想的环境，在临床、分子和细胞水平上研究哮喘儿童下呼吸道细菌对气道炎症的影响。通过与主要导师梁耀明博士的合作，以及与经验丰富的临床和转化研究人员的广泛合作，以及完成临床科学教学培训计划，郝博士将为独立的学术生涯发展奠定基础。哮喘是美国主要的儿童慢性疾病。致病菌在健康、不吸烟的人的气道中定植是不寻常的，但在慢性肺病患者中已经证实。在哮喘母亲所生的高危出生队列中，新生儿细菌定植与5岁时哮喘患病率增加有关，提示细菌的致病作用。Hauk博士最近证明了幼儿哮喘患者的细菌内毒素和气道中性粒细胞之间的显著相关性。BAL中性粒细胞百分比与金属蛋白酶(MMP)-9、金属蛋白酶组织抑制剂(TIMP)-1和MMP-9/TIMP-1比值相关，表明通过革兰氏阴性菌存在的内毒素可能参与慢性气道炎症和早期气道重塑。该提案的具体目的是：(1)评估儿童下呼吸道致病菌对哮喘严重程度的影响；(2)对哮喘儿童气道炎症的特征与气道内细菌的存在或不存在进行表征；(3)研究哮喘患儿气道细菌存在与不存在的哮喘自然史。该建议的结果将提供更深入的病理生理学和影响患者护理建议抗生素治疗作为儿童哮喘的潜在治疗干预措施。

DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and clinical research skills of Dr. Pia J. Hauk so that she will become an independent investigator. Clinical services provided at National Jewish Health and its research laboratories will provide Dr. Hauk with the ideal setting in which to investigate the impact of bacteria in the lower airways of asthmatic children on airway inflammation at the clinical, molecular and cellular levels. Through collaboration with the primary mentor, Dr. Donald Y.M. Leung, an extensive network of experienced clinical and translational researchers and completion of a didactic training program in clinical science, Dr. Hauk will attain the foundation for the development of an independent academic career. Asthma is the leading chronic childhood illness in the US. Colonization of the airways with pathogenic bacteria is unusual in healthy, non-smoking individuals, but has been demonstrated in patients with chronic lung disease. Neonatal colonization with bacteria in a high-risk birth cohort born to mothers with asthma has been associated with increasing asthma prevalence at the age of 5 years suggesting a pathogenic role of bacteria. Dr. Hauk has recently demonstrated a significant correlation between bacterial endotoxin and airway neutrophils in young children with asthma. The percentages of BAL neutrophils correlated with metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1 and MMP-9/TIMP-1 ratio, indicating that presence of endotoxin through presence of Gram-negative bacteria may contribute to chronic airway inflammation and early airway remodeling. The specific aims of the proposal are: (1) to assess the effect of pathogenic bacteria in the lower airways of children on asthma severity; (2) to characterize airway inflammation in asthmatic children with presence versus absence of bacteria in the airways; (3) to study the natural history of asthma in asthmatic children with presence versus absence of bacteria in the airways. The outcome of this proposal will provide greater insight into the pathophysiology and impact patient care suggesting antibiotic therapy as a potential therapeutic intervention in childhood asthma. Asthma in children is a major public health problem. This study proposes to determine if children with asthma and bacteria in their lower airways have more airway inflammation and more severe disease when compared to asthmatic children without bacteria in the lower airways. If bacteria in the airways of children with asthma cause more severe disease, antibiotics may have to be considered more often as therapy.