Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene
Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene
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DOI：
10.1053/gast.2003.50052
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发表时间：
2003-02-01
期刊：
影响因子：
29.4
通讯作者：
Chanson, M
中科院分区：
文献类型：
--
作者：
Frossard, JL;Rubbia-Brandt, L;Chanson, M
背景与目的：急性胰腺炎早期导致腺泡细胞损伤的机制尚不明确。通过间隙连接通道的信号传导通过协调腺泡内的腺泡细胞活动而有助于外分泌胰腺的稳态。为了探讨间隙连接通讯在腺泡细胞损伤反应中的作用，我们分析了Cx 32（胰腺外分泌中表达的主要间隙连接蛋白）缺陷小鼠注射雨蛙肽诱导急性胰腺炎的过程。研究方法：通过测量血清淀粉酶活性、胰腺水肿、腺泡细胞坏死、胰腺肿瘤坏死因子α浓度和髓过氧化物酶活性来证明胰腺炎的严重程度。用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法（TUNEL）、caspase-3活性和Bax/Bcl-2表达检测腺泡细胞凋亡。免疫荧光和染料偶联法检测连接蛋白的表达和功能。结果如下：Cx 32缺陷小鼠表现出急性胰腺炎的有害过程，胰腺外分泌坏死、水肿和炎症增加。此外，Cx 32缺陷小鼠胰腺外分泌部TUNEL阳性腺泡细胞数量减少，caspase-3活性降低，但Bax或Bcl-2胰腺表达无变化。有趣的是，已知在体内诱导细胞凋亡的化学物质对Cx 32缺陷的胰腺腺泡细胞没有影响。结论.胰腺连接蛋白缺乏可将轻度可逆性急性胰腺炎转变为严重疾病，并降低腺泡细胞对凋亡刺激的敏感性。结果表明，腺泡细胞间通讯在急性胰腺炎严重程度的调节中起着关键作用。
Background & Aims: The early events leading to acinar cell injury during acute pancreatitis are poorly characterized. Signaling through gap junction channels contributes to the homeostasis of the exocrine pancreas by coordinating acinar cell activity within an acinus. To explore the role of gap junctional communication in acinar cell response to injury, we analyzed the course of acute pancreatitis induced by injection of cerulein in mice deficient for Cx32, the major gap junction protein expressed in the exocrine pancreas. Methods: The severity of pancreatitis was evidenced by measuring serum amylase activity, pancreatic edema, acinar cell necrosis, pancreatic tumor necrosis factor alpha concentration, and myeloperoxidase activity. Acinar cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), caspase-3 activity, and Bax/Bcl-2 expression. Expression and function of connexin were evaluated by immunofluorescence and dye coupling. Results: Cx32-deficient mice exhibited a deleterious course of acute pancreatitis with increased necrosis, edema, and inflammation of the exocrine pancreas. In addition, the exocrine pancreas of Cx32-deficient mice showed a decreased number of TUNEL-positive acinar cells and decreased caspase-3 activity but no change in Bax or Bcl-2 pancreatic expression. Interestingly, chemicals known to induce apoptosis in vivo had no effect on Cx32-deficient pancreatic acinar cells. Conclusions. Deficiency of a pancreatic connexin converts a mild reversible form of acute pancreatitis into a severe disease and decreases the sensitivity of acinar cells to apoptotic stimuli. The results show that acinar cell-to-cell communication plays a key role in the modulation of severity of acute pancreatitis.