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: 8553793
• 负责人: Stavros Garantziotis
• 金额: $ 89.96万
• 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/8553793
• 关键词: Affect; Area; Asthma; Binding; Breathing; CD44 gene; Cell Communication; Cells; Clinical Research; Complement; Environmental Exposure; Epithelial; Extracellular Matrix; Gases; Goals; Healed; Human; Hyaluronan; Immunologic Receptors; Inflammation; Injury; Legal patent; Lung; Lung Inflammation; Mediation; Modality; Modeling; Molecular Weight; Mus; Participant; Patients; Play; Production; Pulmonary Fibrosis; Receptor Cell; Research; Role; Serum; Serum Proteins; Stimulus; TLR4 gene; Tenascin; Therapeutic; Tissues; Touch sensation; Vision; Vitronectin; Wound Healing; airway hyperresponsiveness; angiogenesis; cell motility; healing; inter-alpha-inhibitor; 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 2 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 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. Two patent applications are pending and 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. 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. In a model of infectious lung injury, ITIH4 promotes bacterial clearance and thus inhibits lung injury. Thus, ITIH4 plays an important role in the lung response to environmental (infectious and non-infectious) injury.

环境组织损伤直接和间接影响细胞外基质（ECM）：环境刺激可能直接改变基质的组成，例如吸入臭氧暴露导致高分子量透明质酸分解（丰富的ECM组分）转化为低分子量片段;间接地，环境损伤诱导ECM组分的重新产生或ECM分子移位到间隙中，例如，血清蛋白间-α-胰蛋白酶抑制剂（Inter-alpha-Trypsin Inhibitor，IAPs）在纤维化肺损伤中外渗到肺组织中。 我们的研究集中在这两种丰富但研究不足的分子上，并评估它们如何影响对组织损伤的反应。 具体而言，我们的研究涉及两个独立但部分相关的主题：1）研究IRAs和透明质酸在环境暴露后气道高反应性中的作用; 2）研究IRAs和透明质酸在损伤后血管生成和组织愈合中的作用 在第一个目标中，我们能够证明在小鼠模型中臭氧暴露后肺气道中释放低分子量透明质酸。 此外，我们还发现透明质酸通过IL-6和细胞受体CD 44的结合是介导气道高反应性所必需的。 CD 44与先天免疫受体TLR 4以共受体方式起作用。最后，透明质酸结合阻断剂、抗透明质酸阻断剂或高分子量透明质酸可在治疗上用于改善小鼠模型中的气道高反应性。 我们已经确定了一些药物，可以有效地抑制气道高反应性在各种小鼠模型的哮喘。 目前正在申请两项专利，并积极扩大临床研究。 在第二个目标中，我们研究了IAE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，IreA和透明质酸对于肺损伤后的血管生成是必需的，并且IreA和透明质酸共定位于患有肺纤维化的人类患者的纤维化区域，特别是在新血管形成区域周围。 此外，我们还发现肺纤维化患者的血清中IX 4水平高于对照组，并与这些受试者的气体交换能力呈负相关。 此外，我们确定了新的Ifos相互作用，即与ECM分子补体C3，C4，玻连蛋白和腱生蛋白C。 这些相互作用似乎可以防止肺部炎症并支持上皮伤口愈合。 其他相互作用的代理商也已确定。 因此，伊曲康作为具有潜在治疗应用的多能“组织愈合”因子而出现。 最后，我们研究了称为ITIH 4的α间重链在炎症中的作用。 迄今为止，我们已经确定，ITIH 4抑制细胞迁移，但似乎促进细胞激活后，内毒素肺损伤。 在感染性肺损伤模型中，ITIH 4促进细菌清除，从而抑制肺损伤。因此，ITIH 4在肺对环境（感染性和非感染性）损伤的反应中起重要作用。