Distinct regulation of pulmonary inflammation by isoforms of Interleukin-33

Interleukin-33 异构体对肺部炎症的独特调节

• 批准号: 8811331
• 负责人: Irina G. Luzina
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811331
• 关键词: Address; Aging; Animal Model; Asthma; Attenuated; Autoimmune Diseases; Binding; Biology; CCL2 gene; Cause of Death; Cell Culture Techniques; Cells; Collagen; DNA; Data; Deposition; Development; Disease; Environmental Exposure; Fibroblasts; Fibrosis; Future; Gene Delivery; Gene Expression; General Population; Genes; Hamman-Rich syndrome; Health; Healthcare; Heterogeneity; High Endothelial Venule; Human; Hypersensitivity; Immune system; Inflammation; Inflammatory; Interleukin-6; Interleukins; Interstitial Lung Diseases; Investigation; Lead; Left; Lung; Lung diseases; MMP3 gene; Mediating; Medicine; Military Personnel; Mission; Modeling; Mus; Names; Nuclear; Pathogenesis; Pathway interactions; Patient Care; Patients; Play; Process; Production; Protein Isoforms; Proteins; Pulmonary Fibrosis; Pulmonary Inflammation; Quality of life; Regulation; Regulator Genes; Research; Role; Scleroderma; Severities; Social Welfare; Systemic disease; Veterans; Work; base; cell type; cytokine; extracellular; improved; indium-bleomycin; knockout gene; response; targeted treatment; venule

DESCRIPTION (provided by applicant): Combined pulmonary inflammation and fibrosis, often referred to as "interstitial lung disease" (ILD), is debilitat- ing and even deadly. ILD may develop for a variety of reasons, and with no confirmed therapies, ILD is the main cause of death in patients with scleroderma, whereas median survival is only 2 to 3 years in patients with another ILD, idiopathic pulmonary fibrosis (IPF). Military exposures, aging, and autoimmune diseases make ILD prevalent in Veterans. Although much progress has been made in uncovering the mechanisms of ILD, the disease still remains poorly understood. Recent findings implicate nuclear factor from high endothelial venules (NFHEV), also known as interleukin (IL)-33, in the pathogenesis of scleroderma and IPF. NFHEV/IL-33 is des- ignated by these two different names because of its dual biology. As a nuclear factor, it is expressed in a varie- ty of cell types and binds directly to DNA. As a cytokine, proteolytically activated extracellular IL-33 is a power- ful inducer of Th2 responses, such as those in allergies and asthma. The latter activities of the IL-33 cytokine are under active investigation, whereas the former activities of NFHEV as a nuclear factor have been underap- preciated and not studied in sufficient detail or in association with a disease process. Our data suggest that, as a nuclear factor, NFHEV drives ILD. NFHEV is elevated in the lungs of patients with ILD and predominant over the IL-33 form. In these patients, NFHEV is expressed in inflammatory cells and, notably, fibroblasts, which are central to the pathogenesis of ILD. Consistent with this, the expression of NFHEV is elevated in the lungs of mice in the bleomycin model of ILD. Gene delivery of NFHEV in cell culture and in the animal model leads to increased production of MCP-1, IL-6, MMP3, MMP10, and MMP13, all of which are known to contribute to ILD. Gene delivery of NFHEV also induces inflammation and local collagen deposition. Although extracellular IL-33 in patients may also be somewhat elevated, there is an accompanying elevation in soluble T1/ST2, which neu- tralizes IL-33 cytokine activity but has no effect on the function of NFHEV. Gene deficiency of T1/ST2 has min- imal if any attenuating effect on the severity of ILD in the bleomycin model. Based on these data, the Hypothe- sis of this proposal is that NFHEV is a central T1/ST2-independent regulator of ILD, acting through stimulation of proinflammatory and profibrotic gene expression. If successful in validating this role of NFHEV, this study will lay the groundwork for future development of NFHEV-targeting strategies and thus lead to better therapies for ILD. To assess the validity of this Hypothesis, three Specific Aims will be addressed. Aim 1 is to prove, in the bleomycin model of interstitial lung disease, that NFHEV worsens pulmonary inflammation and fibrosis through T1/ST2-independent regulation of proinflammatory and profibrotic gene expression. Aim 2 is to define pathophysiologically important NFHEV-expressing cell types by determining whether ubiquitous and/or cell type-specific deficiency of NFHEV protects against pulmonary inflammation and fibrosis in the bleomycin mod- el of interstitial lung disease. This Aim will utilize mice with inducible cell type-specific NFHEV gene knockout. Aim 3 will take advantage of the spatial heterogeneity of inflammation and fibrosis in the lungs of human pa- tients with IPF to determine whether increased expression of NFHEV is associated with active fibrotic foci, cel- lular inflammation, and expression of candidate NFHEV-driven proinflammatory and profibrotic factors. This work investigates unknown aspects of NFHEV biology in association with a deadly lung disease prevalent in Veterans. The results will lay the groundwork for future development of NFHEV-targeting therapies in Veterans and in the general population. Thus, this proposal directly addresses the needs of Veterans and contributes to the VA Healthcare Mission.

描述（由申请人提供）： 肺部炎症和纤维化的结合，通常被称为“间质性肺病”（ILD），会使人衰弱甚至致命。 ILD 的发生可能有多种原因，由于尚无确定的治疗方法，ILD 是硬皮病患者的主要原因，而另一种 ILD 特发性肺纤维化 (IPF) 患者的中位生存期仅为 2 至 3 年。军事暴露、衰老和自身免疫性疾病使得间质性肺病在退伍军人中普遍存在。尽管在揭示 ILD 机制方面已经取得了很大进展，但对该疾病仍然知之甚少。最近的研究结果表明，高内皮微静脉 (NFHEV) 的核因子（也称为白细胞介素 (IL)-33）参与了硬皮病和 IPF 的发病机制。 NFHEV/IL-33 由于其双重生物学而被指定为这两个不同的名称。作为一种核因子，它在多种细胞类型中表达并直接与 DNA 结合。作为一种细胞因子，蛋白水解激活的细胞外 IL-33 是 Th2 反应的强大诱导剂，例如过敏和哮喘中的反应。 IL-33细胞因子的后者活性处于活跃状态 调查，而 NFHEV 作为核因子的先前活性一直被低估，并且没有进行足够详细的研究或与疾病过程的关联。我们的数据表明，作为一个核心因素，NFHEV 会导致 ILD。 NFHEV 在 ILD 患者的肺部升高，并且比 IL-33 形式更显着。在这些患者中，NFHEV 在炎症细胞中表达，尤其是在成纤维细胞中表达，而成纤维细胞是 ILD 发病机制的核心。与此相一致的是，在 ILD 博来霉素模型中，NFHEV 的表达在小鼠肺部有所升高。在细胞培养物和动物模型中，NFHEV 的基因传递会导致 MCP-1、IL-6、MMP3、MMP10 和 MMP13 的产生增加，所有这些都已知会导致 ILD。 NFHEV 的基因传递还会诱导炎症和局部胶原蛋白沉积。尽管患者细胞外IL-33也可能有所升高，但可溶性T1/ST2也随之升高，它中和IL-33细胞因子活性，但对NFHEV的功能没有影响。在博莱霉素模型中，T1/ST2 基因缺陷对 ILD 严重程度的影响即使有减弱作用，也是最小的。基于这些数据，本提案的假设是 NFHEV 是 ILD 的一个独立于 T1/ST2 的中央调节因子，通过刺激促炎和促纤维化基因表达发挥作用。如果成功验证 NFHEV 的这一作用，这项研究将为未来开发 NFHEV 靶向策略奠定基础，从而带来更好的 ILD 治疗方法。为了评估该假设的有效性，将解决三个具体目标。目标 1 是证明，在间质性肺疾病的博莱霉素模型中，NFHEV 通过 T1/ST2 独立的促炎和促纤维化基因表达调节来恶化肺部炎症和纤维化。目标 2 是通过确定普遍存在的和/或细胞类型特异性的 NFHEV 缺陷是否可以在间质性肺疾病的博莱霉素模型中预防肺部炎症和纤维化，从而定义病理生理学上重要的 NFHEV 表达细胞类型。该目标将利用具有可诱导细胞类型特异性 NFHEV 基因敲除的小鼠。目标 3 将利用人类 IPF 患者肺部炎症和纤维化的空间异质性来确定 NFHEV 表达增加是否与活动性纤维化病灶、细胞炎症和候选 NFHEV 驱动的促炎症因子的表达相关和促纤维化因子。这项工作调查了 NFHEV 生物学的未知方面与退伍军人中流行的致命肺部疾病的关系。研究结果将为未来在退伍军人和普通人群中开发 NFHEV 靶向疗法奠定基础。因此，该提案直接满足了退伍军人的需求，并为退伍军人管理局的医疗保健使命做出了贡献。