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: 9550141
• 负责人: Stavros Garantziotis
• 金额: $ 99.65万
• 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/9550141
• 关键词: Affect; Area; Asthma; Binding; Breathing; CD44 gene; Cell Communication; Clinical Research; Complement; Environmental Exposure; Epithelial; Extracellular Matrix; Gases; Goals; Human; Hyaluronan; Immunologic Receptors; Injury; Legal patent; Lung; Lung Inflammation; Mediation; Modality; Molecular Weight; Participant; Patients; Production; Pulmonary Fibrosis; Receptor Cell; Research; Role; Serum; Serum Proteins; Stimulus; TLR4 gene; Tenascin; Therapeutic; Therapeutic Uses; Tissues; Touch sensation; Trypsin Inhibitors; Vision; Vitronectin; Wound Healing; airway hyperresponsiveness; angiogenesis; 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 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. 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.

环境组织损伤可直接或间接影响细胞外基质（ECM）：环境刺激可直接改变基质的组成，如吸入臭氧暴露可导致高分子量透明质酸（ECM的丰富成分）分解为低分子量碎片；间接地，环境损伤诱导ECM成分的重新生成或ECM分子转移到间质空间，例如，血清蛋白α -胰蛋白酶间质抑制剂（IaI）在纤维化肺损伤中向间质外渗。我们的研究重点是这两种丰富但尚未被充分研究的分子，并评估它们如何影响组织损伤的反应。