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

环境组织损伤直接或间接地影响细胞外基质(ECM)：环境刺激可直接改变基质的组成，如吸入臭氧可导致高相对分子质量的透明质酸(一种丰富的ECM成分)分解成小分子碎片；间接地，环境损伤可诱导ECM成分的从头产生或ECM分子向间质移位，如纤维化肺损伤时血清蛋白-α-胰蛋白酶抑制物(IAI)渗入间质。我们的研究集中在这两个丰富但未被研究的分子上，并评估它们如何影响对组织损伤的反应。 具体地说，我们的研究涉及两个独立但又相互关联的主题：1)探讨IAI和透明质酸在环境暴露后气道高反应性中的作用；2)探讨IAI和透明质酸在创伤后组织愈合中的作用。 在第一个目标中，我们能够在小鼠模型中显示臭氧暴露后低分子质量的透明质酸在肺内释放。此外，我们还发现透明质酸通过IAI和细胞受体CD44的结合是调节呼吸道高反应性所必需的。CD44与天然免疫受体TLR4以共同受体的方式发挥作用。最后，透明质酸结合阻滞剂、IAI阻滞剂或高分子量透明质酸可用于治疗改善小鼠模型的呼吸道高反应性。我们已经确定了一些可以有效抑制各种哮喘小鼠模型的气道高反应性的药物。最近批准了一项专利申请。正在积极寻求扩大到临床研究。 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。我们已经证明IAI和透明质酸对于小鼠肺损伤后的血管生成是必需的，并且IAI和透明质酸共存于人类肺纤维化患者的纤维化区域，特别是在新生血管周围。此外，我们还发现肺纤维化患者血清IAI水平高于对照组，且与这些患者的气体交换能力呈负相关。此外，我们还发现了新的IAI相互作用，即与ECM分子补体C3、C4、Vitronectin和Tenascin C的相互作用。这些相互作用似乎可以保护肺部炎症，并支持上皮伤口的愈合。还发现了其他相互作用剂。因此，IAI成为一种具有潜在治疗应用的多能“组织修复”因子。 此外，最近我们扩大了研究范围，以解决HA和IAI在新冠肺炎肺损伤中的作用 本项目涉及人类冠状病毒、新型冠状病毒、新冠肺炎、严重急性呼吸综合征冠状病毒病、SARS冠状病毒、SARS冠状病毒2、SARS冠状病毒2、SARS相关冠状病毒2、SARS冠状病毒2、SARS相关冠状病毒、SARS冠状病毒或SARS相关冠状病毒的研究。

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.