Th2 inflammation promotes airway surface liquid dehydration

Th2炎症促进气道表面液体脱水

• 批准号: 9042414
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042414
• 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; Electrophysiology (science); 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; knock-down; novel; patient population; prevent; pulmonary function; research study; response; restoration; therapeutic target; 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; Electrophysiology (science); 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; knock-down; 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（由适用提供）：粘液堵塞是过敏性气道疾病（例如哮喘）的常见病理特征，并导致小气道目标，亚段肺塌陷以及偶尔会导致宝贵的呼吸衰竭。由于对驱动浓厚的脱水粘液形成的基本病理生理学的了解不足，缺乏对Th2型炎症性气道疾病的有效疗法。与当前Th2型细胞因子促进气道液体分泌的范例相反，我们发现TH2型细胞因子IL-13促进了气道表面液体（ASL）高吸附，从而导致人核培养基中纤毛功能和粘膜纤维转运的人性纤维纤维传输严重损害。有趣的是，Th2细胞因子介导的ASL损耗是通过非电动离子交换发生的，这是一种以前从未归因于气道组织的大量流体损失机制。这是气道表面脱水为哮喘患者亚组中粘液功能障碍发展的新型机械解释。更重要的是，强烈TH2注射的哮喘患者中粘膜水合的恢复是减轻粘液异常的引人注目的治疗靶标。为了解决以下假设，即IL-13会导致ASL抽象，但通过Na/H和Cl/HCO交换耦合，从而促进了TH2注射期间的病理粘液功能障碍，提出了两个完整的目标。第一个目标将确定介导Th2细胞因子遭受ASL体积的离子电导和信号传导途径。在人支气管上皮和相关异源表达系统的一级培养中，将测试以下假设（i）NHE3和pendrin活性在IL-13暴露后通过监测细胞内和细胞外pH变化的速率（II）NHE3或pendrin Gene nhe3或pendrin Genection ii ii ii il-13 iil（II）ii il-13 ii il-13 iil（ii）ii il-13，以评估的IL-13暴露率增加。在IL-13与IL-4R¿ / IL-13R¿1杂二聚体受体和STAT3信号通路的激活后，转录增加了。与这些体外实验的补充，临床第二个目标将确定具有生物标记物的哮喘患者是否与Th2驱动注射暴露过多的ASL抽象，粘膜钙毛毛细管受损和NHE3/Pendrin表达增加。使用一种新型的核医学技术，该技术仅测量体内气道吸收和粘膜纤毛清除率，将比较具有Th2低炎症或高炎症谱的患者的气道清除率。组织样品将通过支气管镜检查收集，并用于将NHE3和Pendrin的表达与TH2注射标记以及气道液体吸收率相关联。确认TH2注射会通过NHE3和Pedrin促进过度的ASL抽象并引起粘液阻塞，这将建立一个新的概念框架和治疗途径，以控制哮喘和其他过敏性气道疾病患者的粘液功能障碍。