The Role of Hyaluronan And Inter-Alpha-Trypsin Inhibitor in Tissue Injury

透明质酸和间α-胰蛋白酶抑制剂在组​​织损伤中的作用

• 批准号: 10252589
• 负责人: Stavros Garantziotis
• 金额: $ 175.38万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252589
• 关键词: 2019-nCoV; Address; Affect; Area; Binding; CD44 gene; COVID-19; Cell Communication; Clinical Research; Complement; Environmental Exposure; Extracellular Matrix; Gases; Goals; Grant; Human; Hyaluronan; Immunologic Receptors; Inhalation; Injury; Legal patent; Lung; Lung Inflammation; Mediation; Modality; Molecular Weight; Participant; Patients; Production; Pulmonary Fibrosis; Receptor Cell; Research; Role; SARS coronavirus; Serum; Serum Proteins; Severe Acute Respiratory Syndrome; Stimulus; TLR4 gene; Tenascin; Therapeutic; Therapeutic Uses; Tissues; Touch sensation; Trypsin Inhibitors; Vision; Vitronectin; airway hyperresponsiveness; angiogenesis; asthma model; epithelial wound; healing; human coronavirus; inter-alpha-inhibitor; interstitial; lung injury; mouse model; neovascularization; novel; novel coronavirus; ozone exposure; receptor; response; tissue injury; wound healing

Environmental tissue injury affects extracellular matrix (ECM) both directly and indirectly: environmental stimuli may directly modify the composition of matrix, e.g. inhaled ozone exposure leads to breakdown of high molecular weight hyaluronan (an abundant ECM component) to low-molecular weight fragments; indirectly, environmental injury induces de-novo production of ECM components or translocation of ECM molecules into the interstitial space, e.g. the serum protein inter-alpha-trypsin inhibitor (IaI) extravasates to the interstitium in fibrotic lung injury. Our research focuses on these two abundant yet understudied molecules, and evaluates how they affect the response to tissue injury. Concretely, our research touches on 2 separate but inter-related subjects: 1) To investigate the role of IaI and hyaluronan in airway hyperreactivity after environmental exposures; 2) To investigate the role of IaI and hyaluronan in tissue healing after injury In the first Aim, we were able to show that low-molecular weight hyaluronan is released in the lung airways after ozone exposure in the murine model. Furthermore, we showed that hyaluronan binding through IaI and the cell receptor CD44 is necessary for the mediation of airway hyperreactivity. CD44 is acting in co-receptor fashion with the innate immune receptor TLR4. Finally, hyaluronan binding blockade, IaI blockade, or high molecular weight hyaluronan can be used therapeutically to ameliorate airway hyperreactivity in the mouse model. We have identified a number of agents that can effectively inhibit airway hyperresponsiveness in various mouse models of asthma. A patent application was granted recently. Expansion into clinical studies is actively pursued. In the second Aim, we investigate the role of IaI and hyaluronan in lung injury. We have showed that IaI and hyaluronan are necessary for angiogenesis after lung injury in the mouse model, and that IaI and hyaluronan colocalize in the fibrotic areas of human patients with pulmonary fibrosis, particularly around areas of neovascularization. Furthermore, we showed that IaI serum levels in pulmonary fibrosis patients are higher than in control subjects and correlate inversely with gas exchange capacity in these subjects. Furthermore we identified novel IaI interactions, namely with the ECM molecules complement C3, C4, vitronectin and tenascin C. These interactions appear to protect against lung inflammation as well as support epithelial wound healing. Other interacting agents have been also identified. IaI therefore emerges as a multipotent "tissue-healing" factor with potential therapeutic applications. In addition, recently we expanded our research to address the role of HA and IaI in COVID-19 lung injury This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.

环境组织损伤会直接和间接影响细胞外基质（ECM）：环境刺激可能直接修饰基质的组成，例如吸入的臭氧暴露会导致高分子量透明质酸（丰富的ECM成分）分解为低分子量片段； 间接地，环境损伤会导致ECM成分的De-Novo产生或ECM分子转移到间质空间中，例如血清蛋白间氨基胰蛋白酶抑制剂（IAI）在纤维化肺损伤中外出向间质外出。 我们的研究重点是这两个丰富而研究的分子，并评估它们如何影响对组织损伤的反应。 具体而言，我们的研究涉及2个单独但相互关联的受试者：1）研究IAI和透明质酸在环境暴露后在气道高反应性中的作用； 2）研究IAI和透明质酸在损伤后的组织愈合中的作用 在第一个目标中，我们能够证明鼠模型中的臭氧暴露后，在肺气道中释放了低分子量透明质酸。 此外，我们证明了通过IAI的透明质酸结合，并且细胞受体CD44对于介导气道高反应性是必需的。 CD44与先天免疫受体TLR4共同作用。最后，透明质酸结合阻滞，IAI阻滞或高分子量透明质酸可以治疗用来改善小鼠模型中的气道高反应性。 我们已经确定了许多可以有效抑制各种哮喘小鼠模型中气道高反应性的药物。 最近批准了专利申请。积极地扩展到临床研究。 在第二个目标中，我们研究了IAI和透明质酸在肺损伤中的作用。 我们已经表明，在小鼠模型中，IAI和透明质酸对于肺损伤后的血管生成是必需的，并且在人类肺纤维化的人类患者的纤维化区域中，IAI和透明质酸在纤维化区域中进行了共定位，尤其是在新生血管生成的地区。 此外，我们表明，肺纤维化患者的IAI血清水平高于对照组受试者，并且与这些受试者的气体交换能力成反比。 此外，我们确定了新型的IAI相互作用，即与ECM分子补体C3，C4，Vitronectin和TenascinC。这些相互作用似乎可以预防肺部炎症以及支持上皮伤口愈合。 也已经确定了其他相互作用的剂。 因此，IAI是具有潜在治疗应用的多能“组织 - 修复”因子。 此外，最近我们扩展了研究，以解决HA和IAI在Covid-19-19肺损伤中的作用。 该项目涉及研究人类冠状病毒，新型冠状病毒，Covid-19，严重急性呼吸综合症冠状病毒疾病，SARS冠状病毒，SARS-Coronavirus-2，SARS-COVIRUS-2，SARS-COV-2，SARS-COV-2，SARS-COV2，SARS-COV2，SARS-SARS-COVIRUS 2，与SARS COTIROTIAL CONAVIRUS 2，严重的急性呼吸道呼吸道综合征2与SARS相关的冠状病毒。