Pulmonary administration of a water-soluble curcumin complex reduces severity of acute lung injury.
Pulmonary administration of a water-soluble curcumin complex reduces severity of acute lung injury.
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DOI：
10.1165/rcmb.2011-0175oc
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发表时间：
2012-12
影响因子：
6.4
通讯作者：
M. V. Suresh;M. Wagner;G. Rosania;K. Stringer;K. Min;L. Risler;D. Shen;G. E. Georges;Aravind Reddy Tarugu;J. Parkkinen;Raju C Reddy
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文献类型：
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作者：
M. V. Suresh;M. Wagner;G. Rosania;K. Stringer;K. Min;L. Risler;D. Shen;G. E. Georges;Aravind Reddy Tarugu;J. Parkkinen;Raju C Reddy
局部或全身炎症可导致急性肺损伤（ALI），并与毛细血管渗漏、肺顺应性降低和低氧血症相关。姜黄素是一种植物衍生的多酚类化合物，具有有效的抗炎特性，但其溶解度差和口服生物利用度有限，降低了其治疗潜力。通过与羟基丙基-γ-环糊精（CD）络合，制备了姜黄素新配方。这大大提高了水溶性和稳定性，有利于直接肺输送。体外研究表明，与使用DMSO或乙醇溶解的未络合姜黄素相比，CDC增加了姜黄素与Calu-3人气道上皮细胞单层的关联和运输。重要的是，在CDC暴露后，Calu-3细胞单层的完整性得以保留，而等量的未络合姜黄素溶液会破坏它。然后，我们在小鼠模型中测试了直接向肺输送CDC是否会降低ALI的严重程度。荧光显微镜检查显示姜黄素与整个肺细胞的关联。LPS后给予CDC可减轻多种炎症和损伤标志物，包括支气管肺泡灌洗液和肺组织中的肺水肿和中性粒细胞。CDC还降低了肺部的氧化应激和促炎转录因子NF-κB的激活。这些结果证明了CDC在小鼠肺部炎症和损伤模型中的有效性，并支持开发以肺为靶点的姜黄素为基础的治疗ALI患者的可行性。
Local or systemic inflammation can result in acute lung injury (ALI), and is associated with capillary leakage, reduced lung compliance, and hypoxemia. Curcumin, a plant-derived polyphenolic compound, exhibits potent anti-inflammatory properties, but its poor solubility and limited oral bioavailability reduce its therapeutic potential. A novel curcumin formulation (CDC) was developed by complexing the compound with hydroxypropyl-γ-cyclodextrin (CD). This results in greatly enhanced water solubility and stability that facilitate direct pulmonary delivery. In vitro studies demonstrated that CDC increased curcumin's association with and transport across Calu-3 human airway epithelial cell monolayers, compared with uncomplexed curcumin solubilized using DMSO or ethanol. Importantly, Calu-3 cell monolayer integrity was preserved after CDC exposure, whereas it was disrupted by equivalent uncomplexed curcumin solutions. We then tested whether direct delivery of CDC to the lung would reduce severity of ALI in a murine model. Fluorescence microscopic examination revealed an association of curcumin with cells throughout the lung. The administration of CDC after LPS attenuated multiple markers of inflammation and injury, including pulmonary edema and neutrophils in bronchoalveolar lavage fluid and lung tissue. CDC also reduced oxidant stress in the lungs and activation of the proinflammatory transcription factor NF-κB. These results demonstrate the efficacy of CDC in a murine model of lung inflammation and injury, and support the feasibility of developing a lung-targeted, curcumin-based therapy for the treatment of patients with ALI.