Th2 inflammation promotes airway surface liquid dehydration

Th2炎症促进气道表面液体脱水

• 批准号: 8826800
• 负责人: MICHAEL M MYERBURG
• 金额: $ 37.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826800
• 关键词: Address; Allergic Bronchopulmonary Aspergillosis; Allergic rhinitis; Anions; Asthma; Belief; Binding; Biological Assay; Biological Markers; Biopsy; Bronchoscopy; CD4 Positive T Lymphocytes; Cations; Cells; Chloride Ion; Chlorides; Clinical; Coughing; Coupled; Data; Dehydration; Development; Discipline of Nuclear Medicine; Disease; Distal; Environment; Epithelial Cells; Equilibrium; Exhalation; Exhibits; Functional disorder; Genes; Genetic Transcription; Helper-Inducer T-Lymphocyte; Human; Hydration status; Impairment; In Vitro; Inflammation; Inflammatory; Institutes; Interleukin-13; Intestines; Ion Exchange; Ions; Kidney; Lead; Life; Liquid substance; Lung; Measures; Mediating; Medical; Metabolic Clearance Rate; Methods; Monitor; Mucociliary Clearance; Mucous body substance; Nitric Oxide; Obstruction; Pathogenesis; Pathway interactions; Patients; Phenotype; Plug-in; Receptor Activation; Research; Respiratory Failure; STAT3 gene; Signal Pathway; Signal Transduction; Sodium; Sputum; Subgroup; Surface; Symptoms; System; T cell response; Techniques; Testing; Therapeutic; Thick; Tissue Sample; Tissues; Trachea; Universities; absorption; airway epithelium; airway obstruction; airway surface liquid; allergic airway disease; asthmatic; asthmatic airway; asthmatic patient; base; biophysical properties; bronchial epithelium; clinical phenotype; cystic fibrosis airway; cytokine; effective therapy; eosinophil; extracellular; in vivo; innovation; insight; interleukin-13 receptor; novel; patient population; prevent; pulmonary function; research study; response; restoration; therapeutic target

DESCRIPTION (provided by applicant): Mucus plugging is a common pathological feature of allergic airway diseases, such as asthma, and causes small airways obstruction, subsegmental lung collapse, and occasionally precipitates respiratory failure. Effective therapies for mucus plugging in Th2 type inflammatory airway diseases are lacking because of an inadequate understanding of the basic pathophysiology that drives the formation of thick dehydrated mucus. Contrary to the current paradigm that Th2 type cytokines promote airway liquid secretion, we have found that the Th2 type cytokine IL-13 promotes airway surface liquid (ASL) hyperabsorption leading to profound impairments in ciliary function and mucociliary transport in primary cultures of human bronchial epithelial cells. Interestingly, Th2 cytokine mediated ASL absorption occurs via non- electrogenic ion exchange, a mechanism of bulk fluid absorption never previously attributed to airway tissue. Thus, airway surface dehydration presents a novel mechanistic explanation for the development of mucus dysfunction in subgroups of asthma patients. More importantly, restoration of mucosal hydration in asthma patients with intense Th2 inflammation presents a compelling therapeutic target to mitigate mucus obstruction. To address the hypothesis that IL-13 causes ASL absorption though coupled Na/H and Cl/HCO exchange and thus promotes pathological mucus dysfunction during Th2 inflammation, two complementary aims are proposed. The first aim will determine the ion conductance and signaling pathways that mediate ASL volume absorption by Th2 cytokines. In primary cultures of human bronchial epithelium and relevant heterologous expression systems, the following hypotheses will be tested (i) NHE3 and pendrin activities increase following IL-13 exposure as assessed by monitoring the rate of intracellular and extracellular pH change, (ii) NHE3 or pendrin gene knockdown prevents IL-13 dependent ASL hyperabsorption, and (iii) NHE3 transcription increases following IL-13 binding to the IL-4R¿ / IL-13R¿1 heterodimeric receptor and activation of the STAT3 signaling pathway. Complementary to these in vitro experiments, the clinical 2nd aim will determine whether asthmatics with biological markers consistent with Th2 driven inflammation exhibit excessive ASL absorption, impaired mucociliary clearance, and increased NHE3/pendrin expression. Using a novel nuclear medicine technique that simultaneously measures in vivo airway fluid absorption and mucociliary clearance, airway clearance rates of patients with either Th2 low or high inflammatory profiles will be compared. Tissue samples will be collected by bronchoscopy and used to correlate NHE3 and pendrin expression with markers of Th2 inflammation and with rates of airway liquid absorption. Confirmation that Th2 inflammation promotes excessive ASL absorption and causes mucus obstruction, via NHE3 and pedrin, would establish a new conceptual framework and therapeutic avenue to manage mucus dysfunction in patients with asthma and other allergic airway diseases.

描述(申请人提供)：粘液堵塞是过敏性呼吸道疾病(如哮喘)的常见病理特征，可导致小气道阻塞、亚段肺萎陷，偶尔还会导致呼吸衰竭。对于Th2型炎症性呼吸道疾病的粘液堵塞缺乏有效的治疗方法，这是因为对驱动稠密脱水粘液形成的基本病理生理学了解不足。与目前Th2型细胞因子促进呼吸道液体分泌的范式相反，我们发现Th2型细胞因子IL-13促进了呼吸道表面液体(ASL)的高吸收，导致原代培养的人支气管上皮细胞的纤毛功能和粘液纤毛运输严重受损。有趣的是，Th2细胞因子介导的ASL吸收是通过非电生离子交换发生的，这是一种以前从未被认为是呼吸道组织的体液吸收机制。因此，呼吸道表面脱水为哮喘患者亚组中粘液功能障碍的发展提供了一种新的机制解释。更重要的是，在伴有强烈Th2炎症的哮喘患者中，恢复粘膜水化是缓解粘液阻塞的一个引人注目的治疗目标。为了阐明IL-13通过耦合的Na/H和Cl/HCO交换导致ASL吸收，从而促进Th2炎症过程中病理性粘液功能障碍的假设，提出了两个互补的目的。第一个目标将确定介导Th2细胞因子对ASL体积吸收的离子电导和信号通路。在原代培养的人支气管上皮和相关的异源表达系统中，将检验以下假设：(I)通过监测细胞内和细胞外pH的变化来评估IL-13暴露后NHE3和Pendrin的活性增加，(Ii)NHE3或Pendrin基因敲除可防止IL-13依赖的ASL高吸收，以及(Iii)当IL-13与IL-4R？/IL-13R？1异二聚体受体结合并激活STAT3信号通路后，NHE3的转录增加。作为这些体外实验的补充，临床第二个目标将确定具有与Th2驱动的炎症一致的生物标志物的哮喘患者是否表现出ASL过度吸收、粘液纤毛清除受损和NHE3/Pendrin表达增加。使用一种新的核医学技术，同时测量体内呼吸道液体吸收和粘液纤毛清除，将比较Th2低炎症和高炎症患者的气道清除率。组织样本将通过支气管镜检查收集，并用于将NHE3和Pendrin的表达与Th2炎症标志物和呼吸道液体吸收率相关联。证实Th2炎症通过NHE3和pedrin促进ASL的过度吸收并导致粘液阻塞，将建立一个新的概念框架和治疗途径，以管理哮喘和其他过敏性呼吸道疾病患者的粘液功能障碍。