开鬼门-洁净府协同调控水通道蛋白-平衡防治重症急性胰腺炎ALI-AKI的机理

Acute lung injury (ALI) and acute kidney injury (AKI), the main complications of severe acute pancreatitis (SAP), are the determinants of the disease severity and prognosis, which leads to the early high mortality. It is a worldwide challenge of controling ALI-AKI to lower the mortality of SAP. Aquaporin (AQP) was involved in the pathogenesis of ALI and AKI in the course of SAP, and the herbal prescription of Qingyitang could ameliorate the severity of ALI in the experimental SAP through up-regulating the expression of AQP in lung, together with the preliminary study of herbal formula Yue-Bi-Tang （YBT）and Wu-Ling-San with protection of ALI and AKI and the hypothesis of formula tissue pharmacology, we hypothesized: YBT Kai-Gui-Men and WLS Jie-Jing-Fu could protect the ALI-AKI of SAP through regulating the expression of AQP in pancreas-lung-kidney. Focus on the dosage-concentration-effect relationship of herbal formulas in pancreas-lung-kidney of SAP with the co-expressed AQP1、3、4 as the therapeutic targets in the three organs, We planed to:Fisrt, study and compare the pharmacokinetics of YBT, YLS and YBT+WLS in normal rats and rats of SAP with ALI and AKI. Second, compare and screen the distribution and concentrations of the targeted components in pancreas-lung-kidney of SAP. Third,explore the pharmacodynamics of YBT, WLS, YBT+WLS in SAP with ALI_+AKI based on the expression of AQP and the inflammatory injury of lung and kidney. Finally, to elucidate the mechnism and targets of YBT Kai-Gui-Men and WLS Jie-Jing-Fu in cooperative treatment ALI+AKI in SAP, reduce the morbidity of organ injury or failure of lung and kidney and lower the early mortality, which help uncover the formula tissue pharmacology of YBT and WLS in the equal protection of ALI and AKI. All these studies would help to optimize and compose new herbal formula.

重症急性胰腺炎（SAP)并发急性肺损伤（ALI)-急性肾损伤（AKI）决定疾病严重程度和预后，是早期病死率高的主要原因和难以解决的世界性难题。水通道蛋白（AQP)参与SAP并发的ALI-AKI；清胰汤能上调肺AQP-1而减轻AP大鼠ALI；结合预实验越婢汤、五苓散保护ALI-AKI的基础和方剂组织药理学，假设：越婢汤-五苓散通过开鬼门-洁净腑以调控SAP胰-肺-肾AQP表达而保护ALI-AKI。拟选择胰、肺、肾共同表达的AQP1、3、4作为治疗靶点，关注方剂成分胰/肺/肾靶组织内浓度-效应关系；比较胰-肺-肾方剂成分谱及其浓度；基于AQP-炎性损伤研究越婢汤、五苓散、越婢汤+五苓散在SAP并ALI-AKI的药效学，最终阐明开鬼门、洁净腑协同减少多器官损伤、防治SAP并发肺-肾损伤的机理和靶点；阐释越婢汤-五苓散平衡保护SAP肺-肾损伤的方剂组织药理学;优化组合新方。

重症急性胰腺炎（SAP)并发急性肺损伤（ALI)-急性肾损伤（AKI）决定疾病严重程度和预后，是早期病死率高的主要原因和难以解决的世界性难题。水通道蛋白（AQP)参与SAP并发的ALI-AKI；清胰汤能上调肺AQP-1而减轻AP大鼠ALI；结合预实验越婢汤、五苓散保护ALI-AKI的基础和方剂组织药理学，我们假设：越婢汤-五苓散通过开鬼门-洁净腑以调控SAP胰-肺-肾AQP表达而保护ALI-AKI。我们通过摸索建立了SAP合并ALI-AKI的大鼠模型，选择胰、肺、肾共同表达的AQP1、3、4为靶点，基于AQPs-炎性损伤研究越婢汤、五苓散、越婢汤+五苓散在SAP并ALI-AKI的药效学和药动学，我们发现：（1）3.5%牛黄胆酸钠逆行胰胆管注射法可成功建立 SAP 并 ALI-AKI 大鼠模型，具有相应的组织病理学、分子病理学改变；（2）越婢汤可能通过降低血清 TNF-α水平减轻大鼠全身及组织炎症反应；同时通过降低肺 AQP4 水平减轻大鼠肺水肿和病理损伤，肺 AQP4 可能是其调节水液代谢的作用靶点；越婢汤更可能通过 AQPs 防治 ALI的优势效应；越婢汤能改善大鼠肾脏病理损伤，可能与炎症反应的减轻及 ALI 与 AKI 的相互影响有关；（3）五苓散能调控模型大鼠肺和肾 AQP4 表达而改善组织水肿及病理损伤，且下调肾组织中 AQP4 m RNA 作用优于越婢汤及合方，说明五苓散具有保护肾脏损伤的优势；组织中 AQP4 可能是五苓散调节肺肾水液代谢的作用靶点；（4）越婢汤、五苓散单用比合用能更好的改善胰腺组织病理损伤。尽管两方合用保护ALI-AKI的效果并不一定优于单方使用，但合方仍具有单用时的抗炎、减轻组织病理损伤及下调模型大鼠肺 AQP4 蛋白表达的作用，并最终减轻炎症反应的策源地：胰腺的炎症损伤。由于 ALI 和 AKI的交互关系，两方均能达到肺肾同治的效果。这一结论可为以后临床治疗提供一种新的思路，是否合用两方可视具体情况而定。（5）就目前探索条件而言，越婢汤有效成分在大鼠体内分布具有一定剂量-浓度和时间-浓度效应关系；来源于麻黄的盐酸麻黄碱在越婢汤中含量最高；空肠给药方式可能较灌胃给药更有助于药物吸收；五苓散所测成分含量低。