Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice.
Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice.
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DOI：
10.1053/j.gastro.2018.06.036
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发表时间：
2018-10
期刊：
影响因子：
29.4
通讯作者：
Husain SZ
中科院分区：
文献类型：
--
作者：
Wen L;Javed TA;Yimlamai D;Mukherjee A;Xiao X;Husain SZ
内镜逆行胰胆管造影（PEP）后胰腺炎被认为是由胰管高压引起的，其机制尚不清楚。我们研究了静水压力对小鼠胰腺炎发展的影响。我们对瑞士韦伯斯特小鼠、B6129小鼠（对照）和B6129蛋白磷酸酶3、催化亚基、β亚型基因被破坏的小鼠（Cnab - / -小鼠）进行了研究。在夹紧近端胆总管的同时，逆行胆管或管内注入生理盐水恒静水压力诱导小鼠急性胰腺炎，并将这些小鼠作为PEP模型。部分小鼠胰腺输注aav6 - nfat -荧光素酶，监测钙调磷酸酶活性或钙调磷酸酶抑制剂FK506。在6和24小时采集血液和胰腺样本，通过ELISA、组织学、免疫组织化学或荧光显微镜分析。在PEP诱导后15 min分离的胰腺腺泡细胞中测量Ca2+信号和线粒体通透性。在体内24小时内跟踪胰腺内Ca2+活化磷酸酶钙调磷酸酶。在先前报道的PEP模型中，观察到导管内压力高达130 mmHg；我们发现施加100和150 mmHg静水压力10分钟均可诱发胰腺炎。胰腺组织有炎症标志物（白细胞介素6 [IL6]、il - 1b和肿瘤坏死因子[TNF]水平升高）、STAT3激活、血清淀粉酶和il - 6升高、紧密连接完整性丧失。短暂的高压使Ca2+加工失调（Ca2+振荡减少，高原Ca2+信号峰值增加）并降低线粒体膜电位。我们观察到小鼠胰腺中钙调磷酸酶的激活。缺乏钙调磷酸酶催化亚基的Cnab - / -小鼠和给予FK506的小鼠没有发生压力诱导的胰腺炎症、水肿或紧密连接完整性丧失。在PEP小鼠模型中，短暂的高导管压力导致胰腺炎症和紧密连接完整性的丧失。这些过程需要钙调磷酸酶信号传导。钙调磷酸酶抑制剂可用于预防由梗阻引起的急性胰腺炎。
Pancreatitis following endoscopic retrograde cholangiopancreatography (PEP) is thought to be provoked by pancreatic ductal hypertension, via unknown mechanisms. We investigated the effects of hydrostatic pressures on the development of pancreatitis in mice. We performed studies with Swiss Webster mice, B6129 mice (controls), and B6129 mice with disruption of the protein phosphatase 3, catalytic subunit, beta isoform gene (Cnab−/− mice). Acute pancreatitis was induced in mice by retrograde biliopancreatic ductal or intraductal infusion of saline with a constant hydrostatic pressure while the proximal common bile duct was clamped —these mice were used as a model of PEP. Some mice were given pancreatic infusions of AAV6-NFAT-luciferase, to monitor calcineurin activity or the calcineurin inhibitor FK506. Blood samples and pancreas were collected at 6 and 24 hrs and analyzed by ELISA, histology, immunohistochemistry, or fluorescence microscopy. Ca2+ signaling and mitochondrial permeability were measured in pancreatic acinar cells isolated 15 min after PEP induction. Ca2+-activated phosphatase calcineurin within the pancreas was tracked in vivo over 24 hrs. Intraductal pressures of up to 130 mmHg were observed in the previously reported model of PEP; we found application of hydrostatic pressures of 100 and 150 mmHg for 10 min consistently induced pancreatitis. Pancreatic tissues had markers of inflammation (increased levels of interleukin 6 [IL6], IL1B, and tumor necrosis factor [TNF]), activation of STAT3, increased serum amylase and IL6, and loss of tight junction integrity. Transiently high pressures dysregulated Ca2+ processing (reduced Ca2+ oscillations and an increased peak plateau Ca2+ signal) and reduced the mitochondrial membrane potential. We observed activation of pancreatic calcineurin in the pancreas in mice. Cnab−/− mice, which lack the catalytic subunit of calcineurin, and mice given FK506 did not develop pressure-induced pancreatic inflammation, edema, or loss of tight junction integrity. Transient high ductal pressure produces pancreatic inflammation and loss of tight junction integrity in a mouse model of PEP. These processes require calcineurin signaling. Calcineurin inhibitors might be used to prevent acute pancreatitis that results from obstruction.
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DOI：
10.1152/ajpgi.00500.2006
发表时间：
2007-06-01
影响因子：
4.5
作者：
Husain, Sohail Z.;Grant, Wayne M.;Shah, Ahsan U.
通讯作者：
Shah, Ahsan U.
影响因子：
29.4
作者：
Jin S;Orabi AI;Le T;Javed TA;Sah S;Eisses JF;Bottino R;Molkentin JD;Husain SZ
通讯作者：
Husain SZ
影响因子：
4.8
作者：
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通讯作者：
Lerch, MM
DOI：
10.1016/j.giec.2014.09.002
发表时间：
2015-01-01
影响因子：
--
作者：
Chavalitdhamrong, Disaya;Adler, Douglas G;Draganov, Peter V
通讯作者：
Draganov, Peter V
影响因子：
9.6
作者：
HARVEY, MH;WEDGWOOD, KR;REBER, HA
通讯作者：
REBER, HA