Th2 inflammation promotes airway surface liquid dehydration

Th2炎症促进气道表面液体脱水

• 批准号: 8270112
• 负责人: MICHAEL M MYERBURG
• 金额: $ 37.88万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270112
• 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; Property; 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 airway; base; 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. PUBLIC HEALTH RELEVANCE: Mucus obstruction of the airway is a common but poorly understood feature of asthma and other allergic airway diseases. This project is based on the central hypothesis that mucus dysfunction occurs in these diseases because of airway surface dehydration, which impairs the primary innate mucociliary clearance mechanism from the lung. The information obtained from this research will provide insight into the pathogenesis of mucus plugging in allergic airway disease and may lead to innovative medical therapies.

描述（由申请人提供）：粘液堵塞是过敏性气道疾病（如哮喘）的常见病理特征，可导致小气道阻塞、亚段肺萎陷，偶尔会导致呼吸衰竭。Th 2型炎性气道疾病中粘液堵塞的有效疗法缺乏，因为对驱动稠脱水粘液形成的基本病理生理学的理解不足。与目前Th 2型细胞因子促进气道液体分泌的范例相反，我们发现Th 2型细胞因子IL-13促进气道表面液体（ASL）过度吸收，导致人支气管上皮细胞原代培养物中纤毛功能和粘液纤毛运输的严重损害。有趣的是，Th 2细胞因子介导的ASL吸收通过非产电离子交换发生，这是一种以前从未归因于气道组织的大量流体吸收机制。因此，气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，在具有强烈Th 2炎症的哮喘患者中恢复粘膜水合作用提出了一个令人信服的治疗目标，以减轻粘液阻塞。 为了解决IL-13通过偶联的Na/H和Cl/HCO交换引起ASL吸收并因此在Th 2炎症期间促进病理性粘液功能障碍的假设，提出了两个互补的目的。第一个目标将确定离子电导和信号传导途径，介导ASL容量吸收的Th 2细胞因子。在人支气管上皮和相关异源表达系统的原代培养物中，将测试以下假设：（i）如通过监测细胞内和细胞外pH变化速率所评估的，在IL-13暴露后NHE 3和pendrin活性增加，（ii）NHE 3或pendrin基因敲低防止IL-13依赖性ASL过度吸收，和（iii）在IL-13与IL-4 R <$/ IL-13 R <$1异二聚体受体结合并激活STAT 3信号传导途径后，NHE 3转录增加。作为这些体外实验的补充，临床第二个目的将确定具有与Th 2驱动的炎症一致的生物标志物的哮喘患者是否表现出过度ASL吸收、粘膜纤毛清除受损和NHE 3/pendrin表达增加。使用一种新的核医学技术，同时测量体内气道液体吸收和粘膜纤毛清除率，气道清除率的患者与Th 2低或高炎症谱将进行比较。将通过支气管镜检查收集组织样品，并用于将NHE 3和pendrin表达与Th 2炎症标志物和气道液体吸收速率相关联。证实Th 2炎症通过NHE 3和pedrin促进ASL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来管理哮喘和其他过敏性气道疾病患者的粘液功能障碍。 公共卫生相关性：气道粘液阻塞是哮喘和其他过敏性气道疾病的常见但知之甚少的特征。该项目基于中心假设，即由于气道表面脱水，导致这些疾病中发生粘液功能障碍，这损害了肺的主要先天性粘液纤毛清除机制。从这项研究中获得的信息将提供深入了解过敏性气道疾病中粘液堵塞的发病机制，并可能导致创新的医学治疗。