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: 8336649
• 负责人: Stavros Garantziotis
• 金额: $ 107.2万
• 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/8336649
• 关键词: Acute-Phase Proteins; Affect; Area; Asthma; Binding; Breathing; Bronchiolitis; CD44 gene; Cell Communication; Cells; Chronic Obstructive Airway Disease; Clinical Research; Complement; Endotoxins; Environment; Environmental Exposure; Epithelial; Extracellular Matrix; Fibrosis; Gases; Goals; Graft Rejection; Healed; Human; Hyaluronan; Hypoxia; Immune; Immunologic Receptors; Inflammation; Injury; Legal patent; Lung; Lung Inflammation; Malignant Neoplasms; Mediation; Modality; Modeling; Molecular Weight; Mus; Natural Immunity; Organ; Participant; Pathogenesis; Patients; Pollution; Production; Pulmonary Fibrosis; Receptor Cell; Reperfusion Injury; Research; Reticulum; Role; Serum; Serum Proteins; Solid; Sterility; Stimulus; Stress; TLR4 gene; Therapeutic; Tissues; Touch sensation; Transplantation; Vision; Vitronectin; Wound Healing; airway hyperresponsiveness; angiogenesis; cell motility; healing; injured airway; inter-alpha-inhibitor; interest; interstitial; lung injury; mouse model; neovascularization; novel; ozone exposure; receptor; response

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 3 separate but partially 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 angiogenesis and tissue healing after injury; and 3) To investigate the role of IaI and hyaluronan in lung transplant rejection. 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, 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 is pending and expansion into clinical studies is envisioned. In the second Aim, we investigate the role of IaI and hyaluronan in lung injury. We 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 were able to show that IaI serum levels in pulmonary fibrosis patients are higher than in control subjects and correlate inversely with gas exchange capacity in these subjects. Interestingly, hypoxia induces these IaI-hyaluronan interactions, a subject that we are investigating currently. Furthermore we identified novel IaI interactions, namely with the ECM molecules complement C3, C4 and vitronectin. 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. Finally, we investigated the effect of a inter-alpha heavy chain, called ITIH4, in inflammation. We have hitherto established that ITIH4 inhibits cell migration, but appears to promote cell activation after endtoxin lung injury. ITIH4 is an acute phase protein which is increased in cancer and COPD patients, so its effects are of particular interest. In the third Aim, we have investigated the pathogenesis of obliterating bronchiolitis, which is the main cause of reejction in lung transplant. Lung transplant rejection is much more common than any of the other solid organs, and we have pursued the hypothesis that this is due to the fact that the lung is in constant contact with the environment, therefore exposed to many immune activating stimuli. We showed that activation of innate immunity through inhaled endotoxin led to alloimmune lung injury in the murine model. Furthermore, we focused on sterile lung injury, which is very common in lung transplant (though pollution, aspiration, ischemia-reperfusion injury, etc.). We were able to show that sterile epithelial injury leads to alloimmune activation and bronchiolitis, specifically through the release of hyaluronan. Furthermore, we showed that endoplsmic reticulum stress is an important mechanism of hyaluronan production in transplant airways injury, and that it appears to promote fibrosis.

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，我们的研究涉及三个独立但部分相互关联的主题：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和透明质酸在损伤后血管生成和组织愈合中的作用；3)探讨IAI和透明质酸在肺移植排斥反应中的作用。 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，在小鼠模型中，透明质酸结合或高分子量透明质酸可用于治疗以改善呼吸道高反应性。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。一项专利申请正在申请中，并有望扩展到临床研究。 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。我们发现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，特别是新生血管周围。此外，我们能够证明肺纤维化患者的IAI血清水平高于对照组，并且与这些受试者的气体交换能力呈负相关。有趣的是，低氧诱导了这些IAI-透明质酸的相互作用，这是我们目前正在研究的一个主题。此外，我们还发现了新的IAI相互作用，即与ECM分子补体C3、C4和Vitronectin的相互作用。这些相互作用似乎可以预防肺部炎症，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。最后，我们研究了名为ITIH4的α间重链在炎症中的作用。到目前为止，我们已经证实ITIH4抑制细胞迁移，但在内毒素肺损伤后似乎促进细胞激活。ITIH4是一种急性期蛋白，在癌症和COPD患者中会增加，因此其作用特别令人感兴趣。 在第三个目的中，我们研究了闭合性毛细支气管炎的发病机制，这是肺移植排斥的主要原因。肺移植排斥反应比其他任何实体器官更常见，我们一直认为这是因为肺与环境不断接触，因此暴露在许多免疫激活刺激下。我们发现通过吸入内毒素激活先天免疫导致同种异体免疫性肺损伤。此外，我们还重点介绍了肺移植中常见的无菌肺损伤(污染、吸入、缺血再灌注损伤等)。我们能够证明无菌上皮损伤导致同种免疫激活和毛细支气管炎，特别是通过释放透明质酸。此外，我们发现内质网应激是移植气道损伤时透明质酸产生的一个重要机制，而且它似乎促进了纤维化。