Rhinovirus, airway smooth muscle, and mechanisms of irreversible airflow obstruction

鼻病毒、气道平滑肌和不可逆气流阻塞机制

基本信息

批准号：
10735460
负责人：
Cynthia Koziol-White
金额：
$ 50.06万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-09 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735460
关键词：
ADRBK1 gene Actins Acute Adenosine Diphosphate Adult Affect Agonist Air Airway Disease Arrestin Beta 1 Asthma Attenuated Bronchoconstriction Bronchodilation Bronchodilator Agents CXCR4 Receptors CXCR4 gene Calcium Cell Line Cell physiology Cells Cessation of life Child Clinical Coculture Techniques Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Effector Cell Epithelial Cells Epithelium Exposure to G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Health Host Defense Human Immunity Impairment Infection Inflammation Inflammation Mediators Liquid substance Lung MMP9 gene Mediating Mediator Modeling Molecular Morbidity - disease rate Muscle Contraction Muscle relaxation phase Myosin Light Chains Natural regeneration PAR-2 Receptor Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Production Productivity Prostaglandins Proteinase-Activated Receptors Proteins Publishing Relaxation Research Rhinovirus Rhinovirus infection Rho-associated kinase Role Signal Induction Signal Pathway Signal Transduction Signaling Molecule Slice Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Symptoms System Therapeutic Therapeutic Uses Up-Regulation VEGF165 Viral Viral Respiratory Tract Infection Virus Work airway epithelium airway hyperresponsiveness airway inflammation airway obstruction asthma exacerbation attenuation beta-2 Adrenergic Receptors constriction exposed human population gastrointestinal epithelium inhibitor knock-down loss of function mortality new therapeutic target novel phosphoric diester hydrolase prevent receptor receptor coupling receptor function reduce symptoms release factor 3 repaired respiratory smooth muscle response therapeutic target trefoil factor

项目摘要

Project Abstract: Rhinoviruses (RV) have been impugned in the development of asthma and are the leading cause of acute asthma exacerbations. RV exposure evokes inflammation of the airways, but how RV modulates human airway smooth muscle cell (HASM) function to alter bronchomotor tone is unclear. HASM is the pivotal cell modulating airway tone, shortening in response to contractile agonist stimulation through increases in intracellular calcium, through activation of Rho kinase, and through modulation of actin dynamics. We previously showed that RV exposure evokes AHR in human precision cut lung slices (hPCLS), increases [Ca2+]i in HASM, and increases agonist-induced phosphorylation of myosin light chain in HASM from human airway epithelial cell (HAEC)/HASM co-cultures stimulated with RV-C15. We also demonstrate that RVC exposure attenuates β2 agonist-induced bronchodilation in hPCLS, cAMP production in HASM, and attenuates bronchodilator-induced reversal of HASM contraction. Our preliminary data shows that TFF3, and other inflammatory mediators, are released from HAEC and hPCLS following exposure to RVC, and that TFF3 attenuates bronchodilation of human small airways and production cAMP in HASM in response to bronchodilators. Furthermore, our data demonstrates that inhibition of TFF3 and putative TFF3 receptors can reverse RV-C15-induced attenuation of bronchodilation. Therefore, we posit RV-C15 modifies signaling mechanisms modulating bronchomotor tone in HASM through a TFF3- dependent mechanism, thereby altering responsiveness of the airways to bronchodilators. We also show that signaling downstream of Gαs-coupled receptors is attenuated in HASM following exposure to RV-C15- conditioned HAEC media. We propose a central hypothesis that RVC exposure of HAEC attenuates β2 agonist-induced bronchodilation via modulation of Gαs-coupled receptor function via TFF3-dependent mechanisms. We will utilize HASM cells, air-liquid interface-differentiated HAEC, and hPCLS to examine the aims of this proposal. In Aim 1, we will determine how RV exposure modulates Gαs-coupled receptor-induced signaling to attenuate bronchodilator-induced airway/HASM relaxation and how asthma alters these mechanisms. Aim 2 will examine how RV-C15-induced TFF3 release attenuates agonist-induced bronchodilation/relaxation of HASM and how asthma alters these mechanisms. Utilizing primary HAEC/HASM co-cultures and an ex vivo system of human small airways, we will delineate signaling pathway alterations regulating bronchomotor tone that can be targeted in the treatment of RV-induced exacerbations of asthma to restore bronchodilator responsiveness.

项目摘要：鼻病毒 (RV) 在哮喘的发生过程中受到质疑，并且是急性哮喘的主要原因 RV 暴露会引起气道炎症，但 RV 如何调节人体气道？平滑肌细胞 (HASM) 改变支气管运动张力的功能尚不清楚。HASM 是关键的调节细胞。气道张力，通过细胞内钙的增加响应收缩激动剂刺激而缩短，通过激活 Rho 激酶，并通过调节肌动蛋白动力学，我们之前证明了 RV。暴露会引起人体精密切割肺切片 (hPCLS) 中的 AHR，增加 HASM 中的 [Ca2+]i，并增加激动剂诱导人气道上皮细胞 (HAEC)/HASM 中 HASM 中肌球蛋白轻链的磷酸化我们还证明，RVC 暴露可减弱 β2 激动剂诱导的共培养物。 hPCLS 中的支气管扩张、HASM 中的 cAMP 产生，并减弱支气管扩张剂诱导的 HASM 逆转我们的初步数据显示 TFF3 和其他炎症介质是从 HAEC 中释放出来的。和 hPCLS 暴露于 RVC 后，TFF3 减弱人类小气道的支气管扩张， HASM 中对支气管扩张剂的反应产生 cAMP 此外，我们的数据表明，抑制 TFF3 和推定的 TFF3 受体可以逆转 RV-C15 诱导的支气管扩张减弱。认为 RV-C15 通过 TFF3- 修改 HASM 中调节支气管运动张力的信号机制依赖机制，从而改变气道对支气管扩张剂的反应性。暴露于 RV-C15-后，HASM 中 Gαs 偶联受体下游的信号传导减弱我们提出一个中心假设：HAEC 的 RVC 暴露会减弱 β2。通过 TFF3 依赖性调节 Gαs 偶联受体功能，激动剂诱导支气管扩张我们将利用 HASM 细胞、气液界面分化的 HAEC 和 hPCLS 来检查该机制。在该提案的目标 1 中，我们将确定 RV 暴露如何调节 Gαs 偶联受体诱导的。减弱支气管扩张剂引起的气道/HASM 松弛的信号传导以及哮喘如何改变这些目标 2 将研究 RV-C15 诱导的 TFF3 释放如何减弱激动剂诱导的。 HASM 的支气管扩张/松弛作用以及哮喘如何利用原发性 HAEC/HASM 来改变这些机制。共培养和人类小气道的离体系统，我们将描绘信号通路的改变调节支气管运动张力，可用于治疗 RV 引起的哮喘恶化恢复支气管扩张剂的反应性。