Extracellular Matrix Synthesis and Turnover in Asthma

哮喘中的细胞外基质合成和周转

• 批准号: 7900078
• 负责人: MARK A ARONICA
• 金额: $ 36.42万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900078
• 关键词: Adherence; Adhesions; Adult; Affect; Allergens; Allergic inflammation; Antigens; Architecture; Area; Asthma; Binding; Biological Assay; Bone Marrow; Bronchoalveolar Lavage Fluid; Cells; Chronic; Confocal Microscopy; Data; Deposition; Development; Extracellular Matrix; Extracellular Matrix Proteins; Genes; Growth Factor; Human; Hyaluronan; Immunohistochemistry; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Lead; Leukocytes; Lung; Lymphocyte; Mechanics; Modeling; Mus; Organ; Play; Positioning Attribute; Process; Production; Recovery; Research Personnel; Role; Severity of illness; Structure; Testing; Tissues; Withdrawal; Wound Healing; airway epithelium; asthmatic airway; base; cell motility; chemokine; human subject; inter-alpha-inhibitor; programs; scaffold

DESCRIPTION (provided by applicant): The cellular architecture of tissues is organized by the extracellular matrix (ECM) and this organization is required for proper organ function. Alterations in the extracellular matrix (ECM) play an important role in the airways of asthmatics. However, the role of specific matrix components, mechanisms by which they function and how these changes relate to asthma are still poorly understood. The ECM was once thought to be inert scaffolding, having only a mechanical role in supporting and maintaining tissue structure. However, ECM has been shown to influence the distribution, activation status and survival, as well as adhesion of inflammatory cells and can act as a reservoir for inflammatory mediators and growth factors. The organization of the ECM induced by chronic inflammation may lead to alterations in airway structure and function, a process that has been referred to as remodeling in humans. This is of particular relevance in the asthmatic airways, in which the profile of ECM proteins is altered. Hyaluronan (HA) is an important component of the ECM normally found in adult tissues in small amounts but is present in higher amounts during wound healing. HA levels are increased in the bronchoalveolar lavage fluid (BALF) from asthmatics, and their level is associated with the severity of disease. Based on our preliminary data, we hypothesize that synthesis of hyaluronan and its interaction with l-alpha-l and TSG-6 are necessary for the matrix organization that directs the retention and positioning of leukocytes in the inflamed lung, with chronic inflammation leading to excess matrix deposition and subsequent altered airway structure and function. To test this hypothesis we will perform the following specific aims. Specific Aim 1: Define the role of TSG-6 and l-alpha-l in a murine allergen challenge model. Specific Aim 2: Determine the role of the HA matrix in inflammatory cell recruitment to the lung. Specific Aim 3: Determine the role of chronic-intermittent antigen exposure on matrix synthesis and turnover, determine if these changes are reversible or fixed after antigen withdrawal and determine the effects on airway structure and function.

描述（由申请人提供）：组织的细胞结构由细胞外基质（ECM）组织，并且该组织是正常器官功能所必需的。细胞外基质（ECM）的改变在哮喘患者的气道中发挥着重要作用。然而，人们对特定基质成分的作用、其发挥作用的机制以及这些变化与哮喘的关系仍知之甚少。 ECM曾经被认为是惰性支架，仅在支撑和维持组织结构方面发挥机械作用。然而，ECM 已被证明会影响炎症细胞的分布、激活状态和存活以及粘附，并且可以充当炎症介质和生长因子的储存库。慢性炎症引起的 ECM 组织可能会导致气道结构和功能的改变，这一过程被称为人类重塑。这与哮喘气道尤其相关，其中 ECM 蛋白的分布发生了改变。透明质酸 (HA) 是 ECM 的重要成分，通常少量存在于成人组织中，但在伤口愈合过程中含量较高。哮喘患者的支气管肺泡灌洗液 (BALF) 中的 HA 水平升高，其水平与疾病的严重程度相关。根据我们的初步数据，我们假设透明质酸的合成及其与 l-alpha-1 和 TSG-6 的相互作用对于指导白细胞在发炎肺部的保留和定位的基质组织是必需的，慢性炎症会导致过量的基质沉积并随后改变气道结构和功能。为了检验这一假设，我们将实现以下具体目标。具体目标 1：定义 TSG-6 和 l-alpha-1 在小鼠过敏原激发模型中的作用。具体目标 2：确定 HA 基质在炎症细胞募集到肺部中的作用。具体目标 3：确定慢性间歇性抗原暴露对基质合成和更新的作用，确定这些变化在抗原撤除后是否可逆或固定，并确定对气道结构和功能的影响。

项目成果

TSG-6 protein is crucial for the development of pulmonary hyaluronan deposition, eosinophilia, and airway hyperresponsiveness in a murine model of asthma.

TSG-6 蛋白对于哮喘小鼠模型中肺部透明质酸沉积、嗜酸性粒细胞增多和气道高反应性的发展至关重要。

• DOI: 10.1074/jbc.m112.389874
• 发表时间: 2013
• 期刊: The Journal of biological chemistry
• 作者: Swaidani,Shadi;Cheng,Georgiana;Lauer,MarkE;Sharma,Manisha;Mikecz,Katalin;Hascall,VincentC;Aronica,MarkA
• 通讯作者: Aronica,MarkA

The Rise and Fall of Hyaluronan in Respiratory Diseases.

• DOI: 10.1155/2015/712507
• 发表时间: 2015
• 期刊: International journal of cell biology
• 作者: Lauer ME;Dweik RA;Garantziotis S;Aronica MA
• 通讯作者: Aronica MA

Deficiency in the serum-derived hyaluronan-associated protein-hyaluronan complex enhances airway hyperresponsiveness in a murine model of asthma.

血清来源的乙酰透明质酸相关蛋白-乙酰透明质酸复合物的缺乏会增强小鼠哮喘模型中的气道高反应性。

• DOI: 10.1159/000314362
• 发表时间: 2010
• 期刊: International archives of allergy and immunology
• 影响因子: 2.8
• 作者: Zhu,Long;Zhuo,Lisheng;Kimata,Koji;Yamaguchi,Etsuro;Watanabe,Hideto;Aronica,MarkA;Hascall,VincentC;Baba,Kenji
• 通讯作者: Baba,Kenji