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摘要:
疼痛是胰腺癌患者最常见的症状之一。胰腺癌相关疼痛来源多样、机制复杂，严重影响患者生活质量，并对预后造成不良影响，有效的疼痛管理可延长胰腺癌患者的生存期。由于胰腺癌相关疼痛的发病机制尚未阐明，仅部分疼痛管理可基于机制，而大部分疼痛的管理则需凭借医师经验。本文从胰腺癌相关疼痛的病理生理机制及治疗策略两方面进行论述，以期为胰腺癌临床镇痛实践提供参考。
Abstract:Pain is one of the most common symptoms in pancreatic cancer patients. Pancreatic cancer-related pain has various sources and complex mechanisms, which seriously affects patients' quality of life and adversely affects their prognosis. Effective pain management may prolong the survival of pancreatic cancer patients. Since the pathogenesis of pancreatic cancer-related pain has not been elucidated, part of the pain management may be based on the mechanism, and part of the pain management may be based on physician's experience only. This article discusses both the pathophysiological classification and treatment strategies of pancreatic cancer-related pain, with the aim of providing reference for clinical analgesic practice in pancreatic cancer.
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Keywords:
- pancreatic cancer /
- pain /
- analgesia
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阻塞性睡眠呼吸暂停(obstructive sleep apnea，OSA)和缺血性脑卒中均为常见疾病，且二者常为共患病，对患者的生活质量有很大影响。OSA是指睡眠过程中由于反复上呼吸道完全或部分梗阻引起的睡眠呼吸紊乱，主要特征为慢性间歇性缺氧和睡眠片段化[1]。研究表明，30~70岁人群中，至少34%的男性和17%的女性患有轻度OSA，13%的男性和6%的女性患有中重度OSA，而中重度OSA患者缺血性脑卒中的发生率是正常人的4倍，说明OSA是缺血性脑卒中的独立危险因素[2-3]。自“人类微生物组计划”和“人类肠道宏基因组计划”推进后，有研究发现，OSA动物模型的肠道中均存在不同程度的菌群失调[4]。但对于肠道菌群在OSA患者发生缺血性脑卒中的作用机制目前尚不清晰。因此，本文就OSA诱导肠道菌群失调与缺血性脑卒中的机制与研究进展进行综述，以期为阐明OSA引起缺血性脑卒中的潜在病理机制提供依据。
1. 肠道菌群概述
肠道菌群是寄生在肠道内的微生物总称，包括细菌、病毒、真菌、古细菌等，总数可达人体自身细胞数量的10倍。健康人肠道中以细菌为主，且70%~90%为拟杆菌门和厚壁菌门，拟杆菌门主要由拟杆菌属和普雷沃氏菌属组成，而厚壁菌门包括梭状芽胞杆菌属、乳酸杆菌属、芽孢杆菌属、肠球菌属和瘤胃球菌属[5]。拟杆菌门与厚壁菌门的丰度和比值可作为衡量肠道菌群失调的标准，当肠道菌群失调时厚壁菌门/拟杆菌门的比值升高[6]。正常情况下，肠道菌群处于动态平衡，当机体的环境、饮食、睡眠等发生变化时，该平衡可被打破，进而导致结直肠肿瘤、炎症性肠病、肥胖、心脑血管疾病，以及焦虑、抑郁的发生[7]。
2. OSA、肠道菌群与缺血性脑卒中
2.1 OSA与肠道菌群
睡眠片段化作为OSA的特点之一，指上呼吸道反复塌陷、呼吸阻力增加、频繁微觉醒导致的睡眠连续性破坏。研究表明，睡眠片段化与肠道菌群失调有关，主要表现为厚壁菌门丰度增加及拟杆菌门丰度减少，这可能进一步导致肠道屏障破坏和炎症细胞因子升高[8]。Poroyko等[9]对小鼠进行了睡眠片段化暴露，并将其粪菌移植至睡眠正常的无菌小鼠体内，发现后者血液中白细胞数量增加，肠道菌群产生的内毒素水平升高、结肠上皮屏障被破坏、肠道通透性增加使血液循环中细胞因子激增，这表明睡眠片段化可诱导肠道功能紊乱和肠道生态改变。此外，OSA患者间歇性缺氧导致肠黏膜反复缺氧，肠道形成缺氧环境，使肠道细菌结构和丰度改变，表现为厚壁菌门/拟杆菌门的比值升高，产生短链脂肪酸(short-chain fatty acids，SCFAs)细菌和抗炎相关细菌减少，导致肠道屏障功能被破坏、肠黏膜营养状态紊乱、肠道上皮组织损伤、肠道生态环境被破坏，最终导致三甲胺-N-氧化物(trimethylamine-N-oxide，TMAO)增多、SCFAs减少[10]。
2.2 OSA诱导的肠道菌群失调与缺血性脑卒中
研究表明，肠道菌群相关代谢产物的改变可通过“微生物-肠-脑轴”参与缺血性脑卒中的发生[11]，下文就TMAO及SCFAs与缺血性脑卒中的相关性进行阐述。
2.2.1 TMAO与缺血性脑卒中
TMAO是由肠道菌群分解代谢膳食中的胆碱、磷脂酰胆碱形成的三甲胺并经肝脏中的黄素单氧酶氧化产生[12]，已被证实具有促动脉粥样硬化、促血小板活化及促炎作用[13-14]。Zhu等[15]通过Kaplan-Meier生存分析和Cox比例风险回归分析发现，接受了冠状动脉造影的受试者血浆TMAO水平升高与血栓事件发生有较强的相关性，并从TMAO水平较低的健康志愿者中分离出富血小板血浆, 发现TMAO可能以二磷酸腺苷(adenosine diphosphate, ADP)等方式促进胞内Ca2+的释放，增加血小板反应性，进而增加血栓形成及缺血性脑卒中的发生风险。另有研究发现，TMAO能促进巨噬细胞转化为泡沫细胞并黏附在血管壁上，从而形成动脉粥样硬化[11]；还能通过抑制胆固醇的逆向转运影响肠道和肝脏的脂质代谢增加动脉粥样硬化形成风险, 进而增加缺血性脑卒中的发生风险[16]。Zhang等[17]在一项前瞻性队列研究中发现，肠道菌群失调后肠道屏障被破坏，TMAO能够穿过肠道屏障及血脑屏障，加重炎症反应，因此TMAO水平可作为急性缺血性脑卒中患者预后和死亡率的独立预测因子。
2.2.2 SCFAs与缺血性脑卒中
SCFAs是由拟杆菌门发酵食物中的膳食纤维产生，主要包括乙酸盐、丁酸盐和丙酸盐，其作为肠道菌群和大脑之间的介质，在一定程度上具有预防缺血性脑卒中发生的作用。研究表明，急性缺血性脑卒中患者通常存在神经炎症，而SCFAs通过激活G蛋白偶联受体(G protein-coupled receptor，GPR)41、GPR 43和抑制组蛋白去乙酰化酶(histone deacetylase，HDAC)，促进Th1和Th17效应细胞及Treg细胞分化从而调节炎症反应；可直接或间接影响沿“微生物-肠-脑轴”的神经功能，如神经递质产生、免疫激活、受体信号传导和小胶质细胞的变化[18]。另一项研究通过Logistic回归模型证实了SCFAs水平与缺血性脑卒中患者预后相关[19]。当缺血性脑卒中发生后，通过粪菌移植增加SCFAs含量、重建肠道微生态及恢复肠道菌群正常组成，可发挥神经保护作用，显著减少缺血性脑卒中引起的大脑损伤[20]。
综上，OSA引起的睡眠片段化和间歇缺氧能够改变肠道菌群的丰度和多样性，使TMAO产生增多，SCFAs产生减少，进而增加缺血性脑卒中的发生风险。
3. OSA、肠道菌群与缺血性脑卒中相关危险因素
目前，OSA直接引起缺血性脑卒中发生的研究证据不足，有研究表明，其可能通过诱导缺血性脑卒中相关危险因素(如高血压、糖尿病、动脉粥样硬化)的发生，间接导致缺血性脑卒中[21]。而OSA诱导的肠道菌群失调与上述危险因素密切相关。现就OSA和肠道菌群及其代谢产物对动脉粥样硬化、高血压、糖尿病的影响进行详细阐述。
3.1 OSA、肠道菌群与动脉粥样硬化
临床研究发现，动脉粥样硬化是缺血性脑卒中的独立危险因素，且卒中血栓形成的根本原因是动脉粥样硬化斑块形成[22]。OSA可通过氧化应激、炎症、血脂异常诱导动脉粥样硬化的发生，然而Xue等[23]采用盐酸去亚甲基小檗碱(demethyleneberberine，DMB)处理间歇性缺氧和高碳酸血症联合高脂饮食诱导的动脉粥样硬化APOE-/-小鼠，发现OSA还可通过改变肠道微生物群促进动脉粥样硬化形成，并通过诱导肠道菌群失调影响胆固醇及脂质代谢，加速动脉粥样硬化斑块形成或进一步恶化，其中TMAO发挥主要作用。这与Wang等[24]的研究结果一致，其将APOE-/-小鼠分为3组，分别给予富含胆碱的食物、富含TMAO食物及正常饮食，并在腹膜巨噬细胞中测定与动脉粥样硬化有关的巨噬细胞受体(CD36)和A1类清道夫受体(SR-A1)，结果表明TMAO可提高二者在巨噬细胞表面的表达程度，进而抑制胆固醇逆向转运，加速血管壁内斑块形成并经过丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)加速血管炎性反应的出现。也有研究表明，TMAO通过激活Src同源磷酸酪氨酸磷酸酶(Src homology phospho-tyrosyl phosphatase，SHP)和法尼醇X受体(farnesoid X receptor, FXR) 下调胆固醇7α羟化酶(cholesteral 7α-hydroxylase, CYP7A1)及胆固醇27α羟化酶(cholesteral 27α-hydroxylase, CYP27A1)，从而抑制胆固醇的逆向转运，加速血管壁内斑块形成[25]。
3.2 OSA、肠道菌群与高血压
OSA是一种常见的慢性呼吸系统疾病，也是高血压、冠心病、脑卒中等心脑血管疾病的危险因素。研究表明，30%~70%的成年OSA患者表现为全身性高血压，并且随着OSA的加重，全身性高血压的发生风险增加[26]。既往研究表明，OSA诱导高血压的机制包括交感神经过度激活、氧化应激、炎症和代谢失调等[27]，但具体机制尚不明确。Durgan等[28]研究发现，单纯OSA可能不会引起血压升高，仅与高脂饮食共同存在时才导致血压升高，其机制可能为高脂饮食导致参与丁酸盐产生的细菌显著减少，参与乳酸产生的细菌显著增加[29]，具体机制如下：丁酸盐产生减少导致肠道上皮屏障功能破坏，从而使肠道菌群相关代谢物穿过血脑屏障，刺激交感神经系统，参与神经炎症的过程促进血压升高；亦或通过增强血管张力，尤其是肾脏血管张力，导致大鼠发生OSA时出现高血压。另有研究发现，肠道菌群失调可通过免疫过程参与高血压的发生。Liu等[30]研究证明，OSA与高脂饮食同时存在时可通过增加血液中TMAO水平、释放血清干扰素-γ(interferon-γ，IFN-γ)及转化生长因子-β1(transforming growth factor-β1，TGF-β1)、消耗乳杆菌影响大鼠的肠道微生物群等途径增加高血压的严重程度。利用鼠李糖乳杆菌降低血液中TMAO水平、调节CD4+ T淋巴细胞诱导的I型炎性反应可预防高血压的发生。这些研究结果证实了肠道菌群与OSA相关高血压的因果关系，提示调控肠道菌群可预防OSA相关高血压，或可作为该病的治疗靶点。
3.3 OSA、肠道菌群与糖尿病
糖尿病是OSA患者常见的并发症，也是OSA引起器官损害的重要机制，其可导致缺血性脑卒中的发生风险增加、病变加重、溶栓后出血风险升高、预后更差。因此，对于肥胖、吸烟、男性等OSA高危人群应尽早筛查，早期干预、预防相关并发症的出现至关重要。伍娟等[31]研究发现，OSA患者间歇性缺氧使机体产生大量活性氧并发生氧化应激，导致血管内皮紊乱及胰岛素抵抗，并导致肝脏糖异生作用增强；此外，OSA患者间歇性缺氧使机体发生炎症反应导致炎症介质增加，进一步抑制脂肪和肌肉组织对糖的摄取，并提高抗胰岛素激素水平，促进胰岛素抵抗，引发糖代谢紊乱。OSA诱导的肠道菌群失调与糖尿病的发生密切相关。Khalyfa等[32]通过模拟OSA常见的低氧/复氧病理生理过程，运用16s RNA测序技术证明OSA患者的肠道菌群可能发生改变，使肠道通透性增加，并改变血浆外泌体，诱导脂肪细胞功能障碍，致使胰岛素抵抗增加。研究显示，将OSA小鼠粪菌移植至受体小鼠后，受体小鼠也出现了胰岛素抵抗，这进一步证实了OSA诱导的肠道菌群失调可增加糖尿病的发生风险[33]。此外，OSA诱导的肠道菌群失调可使脂多糖增加，其通过Toll样受体依赖途径或非依赖途径激活炎症反应，引起肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)、白细胞介素(interleukin, IL)-6、NO合酶、核因子κB(nuclear factor-κB，NF-κB)等炎症因子的抑制因子表达增加，进而导致胰岛素抵抗[33]。
4. 小结
综上，本文通过总结国内外相关文献阐述了OSA诱导肠道菌群失调引起缺血性脑卒中的相关机制，及肠道菌群失调与动脉粥样硬化、高血压、糖尿病等缺血性脑卒中相关危险因素的相关性，揭示缺血性脑卒中和OSA常为共患病的原因。且考虑到房颤等心源性疾病本身与缺血性脑卒中有关，本文重点探讨了肠道菌群失调和OSA与非心源性缺血性脑卒中及其相关危险因素的关系，提示对OSA患者进行肠道菌群的调节可能成为预防缺血性脑卒中发生的一种新策略。
作者贡献：陈思负责资料收集和论文撰写；申乐负责论文修订并审阅定稿。利益冲突：所有作者均声明不存在利益冲突 -
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