Curcumin Treatment of Lung Fibrosis: Improved Delivery and Target Cells

姜黄素治疗肺纤维化：改善递送和靶细胞

• 批准号: 7789215
• 负责人: STANLEY R HOFFMAN
• 金额: $ 22.13万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789215
• 关键词: Address; Affect; Alternative Medicine; Alveolar; Animals; Apoptosis; Area; Behavior; Biological Availability; Bleomycin; Cells; Chinese People; Clinical Trials; Collagen; Curcumin; Disease; Enzymes; Epithelial Cells; Fibrosis; Future; Gel; Goals; Herbal Medicine; Human; Injection of therapeutic agent; Lead; Legal patent; Link; Lung; Lung diseases; Mainstreaming; Medicine; Metabolism; Methods; Molecular; Mus; Myofibroblast; Oral Administration; Patients; Peptides; Phospholipids; Protective Agents; Recording of previous events; Rodent; Rodent Model; Role; Route; Signaling Molecule; Spices; Structure of parenchyma of lung; Subcutaneous Injections; Testing; Tissues; Tumeric; Work; absorption; cancer therapy; cell behavior; cell motility; cell type; effective therapy; human disease; improved; in vivo; injured; interest; lung injury; monocyte; neutrophil; novel; overexpression; public health relevance; research study; targeted delivery; therapeutic target

DESCRIPTION (provided by applicant): Curcumin is a major component of the spice turmeric which has been used in traditional Chinese and Indian herbal medicine to treat a wide range of conditions. This history demonstrates that curcumin is not toxic and may indeed have value in the treatment of human diseases. Our long-term goal is to use curcumin to treat lung injury/fibrosis in human patients. The value of work in this area is strongly supported by observations that curcumin protects rodents against lung injury/fibrosis induced by a variety of agents. A major drawback to the use of curcumin as a treatment for human diseases is its poor absorption and rapid metabolism following oral administration. Experiments on novel routes of administration of curcumin to mice will address this problem. While curcumin affects the activity of a wide variety of enzymes and signaling molecules, the cellular mechanism through which it provides protection against lung injury/fibrosis has not been determined. Our studies on the mechanism of curcumin will take advantage of our recent work on another protective agent, CSD peptide, which has beneficial effects on at least five cell types. In mice in which lung injury/fibrosis is induced using bleomycin, the CSD peptide inhibits the apoptosis of alveolar epithelial cells, the migration of neutrophils, monocytes, and fibrocytes into damaged lung tissue, and the overexpression of collagen by lung myofibroblasts. Therefore, we will determine which of these target cell types is also affected by curcumin treatment. In summary, this application will test the linked hypotheses that alternate approaches to delivering curcumin in vivo will lead to enhanced levels of circulating curcumin resulting in more robust protection against lung injury/fibrosis and that the beneficial effects of curcumin will result in changes in the behavior of one or more of several cell types already shown to be targets for therapeutic treatments that inhibit lung injury/fibrosis. Specifically, we will: 1) Determine whether alternative methods of delivering curcumin result in higher levels of circulating curcumin and in greater beneficial effects in inhibiting the progression of lung injury/fibrosis than are provided by the traditional oral administration in curcumin chow. 2) Determine whether the beneficial effects of curcumin on the progression of bleomycin-induced lung injury/fibrosis involve changes in the behavior of alveolar epithelial cells, neutrophils, monocytes, fibrocytes, and/or myofibroblasts. The successful completion of these studies will bring us much closer to performing clinical trials using curcumin as a treatment for lung injury/fibrosis in human patients. PUBLIC HEALTH RELEVANCE: Mainstream medicine currently provides no effective treatments for lung diseases in which the injured tissue becomes stiff or fibrotic. Curcumin, derived from the spice turmeric, is a treatment from alternative medicine that blocks these diseases in rodent models. The proposed experiments will reveal more efficient ways to increase the level of curcumin in the bodies of treated animals and will indicate which of the several cell types in the lung are beneficially affected by curcumin, thereby bringing us a step closer to testing curcumin as a treatment for lung injury/fibrosis in human patients.

描述（由申请人提供）：姜黄素是香料姜黄的主要成分，已用于传统的中国和印度草药治疗各种疾病。这一历史表明，姜黄素是无毒的，可能确实具有治疗人类疾病的价值。我们的长期目标是使用姜黄素治疗人类患者的肺损伤/纤维化。姜黄素保护啮齿类动物免受各种药物诱导的肺损伤/纤维化的观察结果强烈支持了这一领域工作的价值。使用姜黄素作为人类疾病治疗的主要缺点是其口服给药后吸收差和代谢快。对小鼠施用姜黄素的新途径的实验将解决这个问题。虽然姜黄素影响多种酶和信号分子的活性，但其提供肺损伤/纤维化保护的细胞机制尚未确定。我们对姜黄素机制的研究将利用我们最近对另一种保护剂CSD肽的研究，CSD肽对至少五种细胞类型具有有益作用。在使用博来霉素诱导肺损伤/纤维化的小鼠中，CSD肽抑制肺泡上皮细胞的凋亡，中性粒细胞、单核细胞和纤维细胞向受损肺组织中的迁移，以及肺肌成纤维细胞的胶原蛋白过表达。因此，我们将确定哪些靶细胞类型也受到姜黄素治疗的影响。总之，本申请将测试相关的假设，即体内递送姜黄素的替代方法将导致循环姜黄素的水平提高，从而导致对肺损伤/纤维化的更稳健的保护，并且姜黄素的有益作用将导致已经显示为抑制肺损伤/纤维化的治疗性治疗的靶标的几种细胞类型中的一种或多种的行为的变化。具体而言，我们将：1）确定递送姜黄素的替代方法是否导致更高水平的循环姜黄素以及在抑制肺损伤/纤维化的进展方面比在姜黄素食物中的传统口服给药提供的更大的有益效果。2)确定姜黄素对博来霉素诱导的肺损伤/纤维化进展的有益作用是否涉及肺泡上皮细胞、中性粒细胞、单核细胞、纤维细胞和/或肌成纤维细胞的行为变化。这些研究的成功完成将使我们更接近于使用姜黄素作为人类患者肺损伤/纤维化治疗的临床试验。 公共卫生相关性：主流医学目前没有提供有效的治疗肺部疾病，其中受伤的组织变得僵硬或纤维化。姜黄素，来自香料姜黄，是一种替代医学的治疗方法，可以在啮齿动物模型中阻断这些疾病。拟议的实验将揭示更有效的方法来增加治疗动物体内的姜黄素水平，并将表明肺部的几种细胞类型中的哪一种受到姜黄素的有益影响，从而使我们更接近于测试姜黄素作为人类患者肺损伤/纤维化的治疗方法。