Bacteria in Lower Airways and Airway Inflammation in Children with Asthma

描述（由申请人提供）：本提案的目的是促进Pia J. Hauk博士的科学发展和临床研究技能，使其成为独立研究者。National Jewish Health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，以在临床，分子和细胞水平上研究哮喘儿童下气道中细菌对气道炎症的影响。通过与主要导师Donald Y.M.博士合作，梁博士拥有丰富的临床和翻译研究人员网络，并完成了临床科学的教学培训课程，Hauk博士将为独立学术生涯的发展奠定基础。哮喘是美国最主要的儿童慢性疾病。在健康的非吸烟人群中，致病菌在气道定植是不常见的，但在慢性肺病患者中已得到证实。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相关，表明细菌的致病作用。Hauk博士最近证明了在患有哮喘的幼儿中细菌内毒素和气道中性粒细胞之间的显著相关性。BALF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，提示通过革兰氏阴性菌的存在导致内毒素的存在可能有助于慢性气道炎症和早期气道重塑。该提案的具体目的是：（1）评估儿童下呼吸道中致病菌对哮喘严重程度的影响;（2）描述呼吸道中存在与不存在细菌的哮喘儿童的气道炎症特征;（3）研究呼吸道中存在与不存在细菌的哮喘儿童的哮喘自然史。该提案的结果将提供对病理生理学的更深入了解，并影响患者护理，表明抗生素治疗是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。这项研究旨在确定与下呼吸道没有细菌的哮喘儿童相比，下呼吸道有细菌的哮喘儿童是否有更多的气道炎症和更严重的疾病。如果哮喘儿童气道中的细菌导致更严重的疾病，可能必须更频繁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.