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: 8062291
• 负责人: STANLEY R HOFFMAN
• 金额: $ 18.25万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8062291
• 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; migration; 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，姜黄已在传统中国和印度草药中用于治疗多种病症。这段历史表明姜黄素无毒，确实可能在治疗人类疾病方面具有价值。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。姜黄素可以保护啮齿类动物免受多种药物引起的肺损伤/纤维化，这一观察结果有力地支持了该领域工作的价值。使用姜黄素治疗人类疾病的一个主要缺点是其吸收差且口服后代谢快速。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，但其提供针对肺损伤/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，它对至少五种细胞类型具有有益的作用。在使用博莱霉素诱导肺损伤/纤维化的小鼠中，CSD 肽抑制肺泡上皮细胞的凋亡，抑制中性粒细胞、单核细胞和纤维细胞迁移到受损肺组织中，以及肺肌成纤维细胞过度表达胶原蛋白。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，本申请将测试相关假设，即体内递送姜黄素的替代方法将导致循环姜黄素水平提高，从而对肺损伤/纤维化提供更强有力的保护，并且姜黄素的有益作用将导致行为的变化已经证明几种细胞类型中的一种或多种是抑制肺损伤/纤维化的治疗靶标。具体来说，我们将： 1) 确定与传统口服姜黄素饲料相比，提供姜黄素的替代方法是否会导致循环姜黄素水平更高，并在抑制肺损伤/纤维化进展方面产生更大的有益效果。 2) 确定姜黄素对博莱霉素诱导的肺损伤/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/或肌成纤维细胞行为的变化。这些研究的成功完成将使我们更接近于使用姜黄素治疗人类患者的肺损伤/纤维化进行临床试验。 公共健康相关性：主流医学目前没有针对受损组织变硬或纤维化的肺部疾病提供有效的治疗方法。姜黄素源自香料姜黄，是一种替代医学疗法，可在啮齿动物模型中阻止这些疾病。拟议的实验将揭示更有效的方法来增加治疗动物体内姜黄素的水平，并将表明姜黄素对肺部的几种细胞类型有有益的影响，从而使我们更接近测试姜黄素作为一种治疗方法用于人类患者的肺损伤/纤维化。