二肠同治调控Nrf2-HO-1-HMGB1通路-平衡Ghrelin-PS表达以协同减轻重症急性胰腺炎心脑损伤的PK-PD机理

Acute heart injury (AHI) and acute brain injury (ABI) induced by acute gastrointestinal injury(AGI) together with intestinal microecological disorder, determinating the severity and prognosis of severe acute pancreatitis, were the main cause of high mortality at the early stage and the clinical challenge to be settled urgently. Progress on Nrf2-HO-1-HMGB1 (NHH) with downstream proinflammatory brain-gut peptides of P substance and anti-inflammatory ghrelin,the basis of protective effect on heart injury of Da-Cheng-Qi decoction focusing on large intestine and Dao-Chi powder focusing on small intestine, combined with the theory of brain-gut axis and simultanous treatment on two intestines (STTI) from the Science of epidemic febrile disease of traditional Chinese medicine, we hypothized that STTI could improve AGI and intestinal microecological disorder to synergistic relieve the heart-brain injury in rats with severe acute pancreatitis through balancing the expression of Ghrelin-P substance and Ghrelin via regulating the signal channel of Nrf2-HO-1-Hmgb1. The project tried to study the mechnism of STTI on the gastrointestinal microecological disorder and AGI to protect AHI-ABI through balancing the proinflammatory and anti-inflammatory response. First, to compare the pharmacokinetics of Dao-Chi powder, Da-Cheng-Qi decoction, Dao-Chi powder and Da-Cheng-Qi decoction in severe acute pancreatitis including heart and brain. Second, to explore the pharmcodynamincs and synergistic superiority of STTI with relieving the heart-brain injury in rats with severe acute pancreatitis through balancing the expression of Ghrelin-P substance and ghrelin via the signal channel of Nrf2-HO-1-Hmgb1. Finally, to certify the synergistic effect of STTI for AHI and ABI in severe acute pancreatitis, which help identify the Zangxiang theory of heart-lung of traditional Chinese medicine, promote the inheritane and innovation with its clinical application of Seasonal febrile disease theory in critical illness.

急性胃肠道损伤（AGI)-肠道微生态紊乱诱发的急性心脑损伤（AHI/ABI），决定重症急性胰腺炎（SAP)的严重程度和预后，是早期病死率高的主要原因和亟待解决的临床难题。Nrf2-HO-1-HMGB1（NHH）与脑肠肽Ghrelin-P物质（GPS)促炎-抗炎的进展、大承气汤从大肠出发和导赤散从小肠出发保护SAP心脏损伤的基础，结合脑肠轴和导赤承气汤二肠同治理论，假设：二肠同治调控SAP肠心脑NHH-GPS表达以协同防治AHI/ABI。拟研究二肠同治调控肠道微生态-改善AGI以平衡促炎/抗炎-保护SAP心脑损伤的协同机制：比较导赤散、大承气汤、导赤散+大承气汤在SAP大鼠的药动学；结合NHH-GPS研究二肠同治改善肠道微生态以保护AHI/ABI的药效优势；最终证实通泻大肠+清利小肠的二肠同治AGI能防治SAP急性心脑损伤的协同效应，验证心肺脏腑理论，促进温病理论的传承创新及在危重症的应用。

重症急性胰腺炎（SAP）持续性的全身炎症反应综合征易诱发胰外器官功能障碍甚至衰竭，是第一个死亡高峰的主要原因，在很大程度上决定着SAP患者的结局和预后。其中急性胃肠道损伤（AGI）-肠道微生态紊乱诱发的急性心脑损伤（AHI/ABI）可能是早期病死率高的主要原因和亟待解决的世界性难题。SAP合并AGI，表现为典型阳明腑实证的痞满燥实坚，中医常常以大承气汤（DCQD）通泻阳明；SAP合并心脏损伤和胰性脑病等心脑损伤，基于中医学“心与小肠相表里”从小肠出发清利太阳小肠以治心脑损伤。结合脑肠轴及相关脑肠肽参与心脑炎性损伤的研究进展和《温病学》二肠同治理论，提出DCQD通泻阳明大肠联合导赤散（DCS）清利太阳小肠以二肠同治保护SAP合并AHI-ABI的假说。Nrf2/HO-1/HMGB1信号通路与脑肠肽SP/Ghrelin促/抗炎平衡参与组织损伤，可能是二肠同治防治AHI-ABI的中医药治疗靶点与作用环节。因此，本研究的目的：（1）基于Nrf2/HO-1/HMGB1信号通路与脑肠肽SP/Ghrelin，研究DCQD、DCS、合方（HF）防治SAP合并AGI-AHI-ABI的药效、靶器官和机理，以期证实二肠同治的协同效应；（2）分别比较DCS、HF在假手术大鼠和SAP大鼠的药动学及组织成分谱，以筛选中药复方药效成分；并分别比较在SAP大鼠体内DCQD和HF、DCS和HF的药动学差异，以明确两方合用对单方来源成分在SAP大鼠体内药动学的影响；（3）对来源于DCS的有效成分齐墩果酸作用于AP的有效性进行验证并作机制探索。本研究发现：DCQD与导赤散作用于SAP的优势靶器官不同：前者为胰腺和结肠，后者为小肠和心；HF的保护效应并不优于单方。上述保护作用的机制部分通过激活Nrf2/HO-1抗氧化应激轴，抑制损伤组织HMGB1表达，平衡Ghrelin/SP表达实现。首次阐明DCS及HF在体药动学及组织成分谱；小肠是DCS作用于SAP大鼠的优势靶器官，有效成分可能为益母草苷和齐墩果酸；但两方合用抑制了单体成分的组织分布。两方合用对不同方剂成分的体内药动学过程影响不同，其中对大部分单体成分在SAP大鼠体内的药动学过程起抑制作用，但也促进了DCS部分单体成分的药动学过程，这为运用DCS防治心脏损伤提供了药动学基础。DCS来源单体齐墩果酸可预防AP，其机制可能与缓解腺泡细胞自噬通量受损相关。