重症急性胰腺炎肠道屏障功能损伤机制研究进展

重症急性胰腺炎患者因肠道粘膜屏障功能受损,细菌与内毒素移位,导致严重感染发生和多器官功能损害,对疾病恶化起重要作用。肠道缺血缺氧、菌群失调、炎症因子等多种因素共同作用可能是肠道粘膜屏障破坏的机制。     

Dexamethasone attenuates methacholine‐mediated aquaporin 5 downregulation in human nasal epithelial cells via suppression of NF‐κB activation

Background

Cholinergic stimulation plays a major role in inflammatory airway diseases. However, its role in airway surface liquid homeostasis and aquaporin 5 (AQP5) regulation remains unclear. In this study we sought to determine the effects of methacholine and dexamethasone on AQP5 expression in human nasal epithelial cells (HNEpC).

Methods

HNEpC were cultured with methacholine or dexamethasone at 4 concentrations in vitro. The subcellular distribution of AQP5 was explored using immunocytochemistry. The pharmacologic effects of methacholine and dexamethasone on the expression of the phosphorylation of cyclic adenosine monophosphate–responsive element binding protein (p‐CREB), AQP5, and nuclear factor‐kappaB (NF‐κB) were examined using Western blotting.

Results

AQP5 was found to be located in cell membrane and cytoplasm and present in every group without a statistically significant difference. Methacholine inhibited expression of AQP5 and p‐CREB in HNEpC, whereas dexamethasone increased these protein levels dose‐dependently in a statistically significant manner. In turn, HNEpC treated with methacholine and dexamethasone showed the same trends as those intervened separately with these 2 drugs. Moreover, dexamethasone had the ability to reverse the inhibitory effect of methacholine. Western blotting revealed that, after incubation with 10^?4 mol/L methacholine, NF‐κB increased significantly, by 186.67%, compared with the untreated control group. Again, such an increase could be significantly reversed after dexamethasone treatment.

Conclusion

NF‐κB activation is important for inhibition of p‐CREB/AQP5 expression after methacholine intervention, and dexamethasone adjusts it to the opposite side. This observation could provide additional insight into the anti‐inflammatory effects of glucocorticoids that contribute to maintaining airway surface liquid and mucosal defense.

     

重症急性胰腺炎肠屏障功能障碍研究

重症急性胰腺炎患者常伴有肠屏障功能障碍,正常肠道屏障由机械屏障、化学屏障、免疫屏障与微生物屏障4部分构成.肠屏障功能障碍通常指上述4种屏障功能出现不同程度的破坏,本文就重症急性胰腺炎肠道屏障功能障碍时上述4种屏障的病理生理改变作一概述.     

Melatonin ameliorates vascular endothelial dysfunction,inflammation, and atherosclerosis by suppressing the TLR4/NF‐κB system in high‐fat‐fed rabbits

Vascular endothelial dysfunction (VED) and inflammation contribute to the initiation and progression of atherosclerosis. Melatonin (MLT) normalizes lipid profile, improves endothelial function, and possesses anti‐inflammatory properties. However, the precise mechanisms are still unclear. This study investigated whether MLT could ameliorate VED, inflammation, and atherosclerosis by suppressing the Toll‐like receptor 4 (TLR4)/nuclear factor kappa B (NF‐κB) system in high‐fat‐fed rabbits. Rabbits were randomly divided into three groups that received a standard diet (control group), high‐cholesterol diet (atherosclerosis group), or high‐cholesterol diet plus 10 mg/kg/day MLT (MLT group) for 12 wk. After treatment, high‐fat diet significantly increased serum lipid and inflammatory markers in rabbits in atherosclerosis group compared with that in control group. In addition, high‐fat diet also induced VED and typical atherosclerotic plaque formation and increased intima/media thickness ratio, which were significantly improved by MLT therapy as demonstrated in MLT group. Histological and immunoblot analysis further showed that high‐fat diet enhanced the expressions of TLR4, myeloid differentiation primary response protein (MyD88), and NF‐κB p65, but decreased inhibitor of NF‐κB (IκB) expression. By contrast, MLT therapy decreased the expressions of TLR4, MyD88, and NF‐κB p65 and increased IκB expression. This study has demonstrated that MLT ameliorates lipid metabolism, VED, and inflammation and inhibits the progression of atherosclerosis in high‐fat‐fed rabbits. Moreover, our study indicates for the first time that suppression of the TLR4/NF‐κB system in local vasculature with atherosclerotic damage is important for the protective effects of MLT.     

持续低效血液透析滤过对重症急性胰腺炎患者肠黏膜屏障功能及免疫功能的影响

目的 评价持续低效血液透析滤过（SLEDF）对重症急性胰腺炎（SAP）患者肠黏膜屏障功能及免疫功能的影响。方法 将51例SAP患者随机分为持续静脉静脉血液滤过（CVVH）组25例和SLEDF组26例,在常规治疗基础上分别接受CVVH和SLEDF治疗。比较两组患者预后、血、尿淀粉酶恢复正常时间、治疗前和治疗第2、4、8、14d血D-乳酸、内毒素（ET）、二胺氧化酶(DAO)、CD3⁺、CD4⁺、CD8⁺T淋巴细胞水平、CD4⁺/CD8⁺T淋巴细胞比值及血液净化相关并发症发生情况。结果 两组患者死亡率、血、尿淀粉酶恢复正常时间比较差异均无统计学意义,血D-乳酸、ET、DAO、CD3⁺、CD4⁺、CD8⁺T淋巴细胞水平和CD4⁺/CD8⁺T淋巴细胞比值在治疗前和治疗第2、4、8、14d比较差异均无统计学意义（P>0.05）。两组患者治疗第4、8、14d D 乳酸、ET和DAO水平均较同组治疗前降低,第8、14d均较同组治疗第4d降低（P＜0.05）。两组患者治疗第4、8、14d的CD3⁺、CD4⁺、CD8⁺T淋巴细胞水平和CD4⁺/CD8⁺T淋巴细胞比值均较同组治疗前升高,第8、14d均较同组治疗第4d升高（P＜0.05）;两组患者治疗第4、8d的CD8⁺T淋巴细胞水平较同组治疗前降低,第8、14d较第4d降低（P＜0.05）。结论 SLEDF和CVVH改善SAP患者肠道屏障功能障碍和免疫功能异常的作用相似,其中SLEDF操作方便,医疗费用低,值得临床推广。     

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

Melatonin is involved in the physiological regulation of the β‐amyloid precursor protein (βAPP)‐cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ₄₂‐induced downregulation of a disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) as well as upregulation of β‐site APP‐cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH‐SY5Y cell cultures. We also demonstrate that the intrinsic mechanisms of the observed effects occurred via regulation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and glycogen synthase kinase (GSK)‐3β as melatonin reversed Aβ₄₂‐induced upregulation and nuclear translocation of NF‐κBp65 as well as activation of GSK3β via its receptor activation. Furthermore, specific blocking of the NF‐κB and GSK3β pathways partially abrogated the Aβ₄₂‐induced reduction in the BACE1 and PS1 levels. In addition, GSK3β blockage affected α‐secretase cleavage and modulated nuclear translocation of NF‐κB. Importantly, our study for the first time shows that peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1 (Pin1) is a crucial target of melatonin. The compromised levels and/or genetic variation of Pin1 are associated with age‐dependent tau and Aβ pathologies and neuronal degeneration. Interestingly, melatonin alleviated the Aβ₄₂‐induced reduction of nuclear Pin1 levels and preserved the functional integrity of this isomerase. Our findings illustrate that melatonin attenuates Aβ₄₂‐induced alterations of βAPP‐cleaving secretases possibly via the Pin1/GSK3β/NF‐κB pathway.     

Immunohistochemical study of nuclear factor‐κB expression in esophageal squamous cell carcinoma: prognostic significance and sensitivity to treatment with 5‐FU

Nuclear factor‐κB (NF‐κB) is expressed in many types of cancers. It has been suggested that the expression of NF‐κB is associated with poor prognosis and resistance to chemoradiation therapies. This study evaluated the relationship between the expression of NF‐κB and the prognosis and sensitivity of esophageal squamous cell carcinoma (ESCC) to chemotherapy. One hundred and nine ESCC specimens, from patients who had undergone radical esophagectomy, were divided into two groups depending on the expression of NF‐κB. Surgical data and prognosis were compared between the two groups. NF‐κB‐positive tumors were detected in 61.5% of the cases. In 69 patients with stage II and III disease, 41 patients who were NF‐κB‐positive showed poor survival. The sensitivity of esophageal squamous cell carcinoma cell lines to 5‐fluorouracil (5‐FU) was analyzed by their NF‐κB expression, and the effect of 5‐FU was evaluated on the proliferation and activity of two cell lines of cultured ESCCs expressing NF‐κB. ESCCs with activated NF‐κB had poor sensitivity to 5‐FU. These results suggest that the increased expression of NF‐κB is associated with poor prognosis in patients with ESCC. NF‐κB may be a target for ESCC therapy because of its selective expression in this type of cancer.