Curcumin Treatment of Lung Fibrosis: Improved Delivery and Target Cells

描述(申请人提供)：姜黄素是香料姜黄的主要成分，在传统的中国和印度草药中已被用于治疗各种疾病。这一历史表明，姜黄素是无毒的，确实可能在治疗人类疾病方面有价值。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。姜黄素保护啮齿动物免受多种药物引起的肺损伤/纤维化的观察有力地支持了这一领域的工作价值。使用姜黄素治疗人类疾病的一个主要缺点是口服后吸收差，代谢迅速。对小鼠进行姜黄素给药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，但其保护肺损伤/纤维化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有有益的作用。在博莱霉素诱导的小鼠肺损伤/纤维化模型中，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向受损肺组织的迁移，并抑制肺成纤维细胞胶原的过度表达。因此，我们将确定这些靶细胞类型中的哪些也受到姜黄素处理的影响。总之，这项应用将检验相关的假设，即体内替代输送姜黄素的方法将导致循环中姜黄素水平的提高，从而对肺损伤/纤维化产生更有力的保护，以及姜黄素的有益作用将导致几种细胞类型中的一种或多种的行为发生变化，这些细胞类型已被证明是抑制肺损伤/纤维化治疗的靶点。具体地说，我们将：1)确定替代给药方法是否会导致循环中的姜黄素水平更高，并在抑制肺损伤/纤维化的进展方面产生比传统口服姜黄素更好的效果。2)确定姜黄素对博莱霉素性肺损伤/纤维化的有利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改变。这些研究的成功完成将使我们更接近于使用姜黄素作为治疗人类患者肺损伤/纤维化的临床试验。 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的方法，在这些疾病中，受损组织变得僵硬或纤维化。姜黄素是从香料姜黄中提取的，是一种替代医学的治疗方法，可以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提高被治疗动物体内的姜黄素水平，并将表明肺部几种细胞类型中的哪一种对姜黄素有益，从而使我们更接近于测试姜黄素作为治疗人类患者肺损伤/纤维化的方法。

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.