Bacteria in Lower Airways and Airway Inflammation in Children with Asthma

描述(申请人提供)：这项建议的目的是培养皮娅·J·豪克博士的科学发展和临床研究技能，使她成为一名独立的调查员。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博士提供一个理想的环境，在其中从临床、分子和细胞水平研究哮喘儿童下呼吸道细菌对呼吸道炎症的影响。通过与主要导师梁永明博士、经验丰富的临床和翻译研究人员的广泛网络以及完成临床科学教学培训计划的合作，豪克博士将为独立学术生涯的发展奠定基础。哮喘是美国儿童时期的主要慢性疾病。在健康、不吸烟的人中，呼吸道被病原菌定植是不寻常的，但在慢性肺部疾病患者中已被证明。在患有哮喘的母亲所生的高危出生队列中，新生儿携带细菌与5岁时哮喘患病率的增加有关，这表明细菌起了致病作用。豪克博士最近证明，在哮喘儿童中，细菌内毒素与呼吸道中性粒细胞之间存在显著的相关性。BAL中性粒细胞百分比与基质金属蛋白酶-9(MMP9)、金属蛋白酶组织抑制因子(TIMP)-1及MMP9/TIMP-1比值呈正相关，提示内毒素可能通过革兰氏阴性菌的存在而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)表征呼吸道有细菌和无细菌的哮喘儿童的呼吸道炎症；(3)研究呼吸道有细菌和无细菌的哮喘儿童哮喘的自然病史。这项提案的结果将提供对病理生理学和影响患者护理的更多洞察力，建议将抗生素治疗作为儿童哮喘的潜在治疗干预措施。 儿童哮喘是一个主要的公共卫生问题。这项研究建议确定，与下呼吸道没有细菌的哮喘儿童相比，有哮喘和下呼吸道细菌的儿童是否有更多的呼吸道炎症和更严重的疾病。如果哮喘儿童呼吸道中的细菌导致更严重的疾病，可能不得不更多地考虑使用抗生素作为治疗方法。

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.